Metal Compounds against Neglected Tropical Diseases

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Metal Compounds against Neglected Tropical Diseases Yih Ching Ong,†,∥ Saonli Roy,‡,∥ Philip C. Andrews,*,§ and Gilles Gasser*,† †

Laboratory for Inorganic Chemical Biology, Chimie ParisTech, PSL University, 11 rue Pierre et Marie Curie, F-75005 Paris, France Department of Chemistry, University of Zurich, Wintherthurerstrasse 190, CH-8057 Zurich, Switzerland § School of Chemistry, Monash University, Wellington Road, Clayton, Victoria 3800, Australia

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ABSTRACT: Many first-line treatments for neglected tropical diseases identified by the World Health Organization (WHO) are limited by one or more of the following: the development of drug resistance, toxicity, and side effects, lack of selectivity, narrow therapeutic indices, route of administration, and bioavailability. As such, there is an urgent need to develop viable alternatives to overcome these limitations. The following review provides an overview of all existing metal complexes studied and evaluates the status of these complexes on the respective disease of choice.

CONTENTS 1. Introduction and the Main Challenges for Developing Metal-Based Drugs for Neglected Tropical Diseases 2. Chagas Disease 2.1. Background 2.2. Main Challenges in the Current Treatments for Chagas Disease 2.3. Current Literature 2.3.1. Metal Complexes Containing Bioactive Ligands 2.3.2. Metal Complexes of Nonbioactive Ligands 3. Dengue 3.1. Introduction to Dengue 3.2. Mechanism of Infection 3.3. Symptoms 3.4. Main Challenges for Treatment of Dengue 3.5. Current Literature 3.5.1. Use of Metal Complexes as Antiviral Treatment Candidates 4. Echinococcosis 4.1. Symptoms 4.2. Main Challenges for the Current Treatment of Echinococcosis 4.3. Current Studies 5. Leishmaniasis 5.1. Leishmania and Leishmaniasis 5.1.1. Life Cycle of the Leishmania Parasite 5.1.2. Leishmaniasis and Its Epidemiology 5.2. Main Challenges for the Current Treatments of Leishmaniasis © XXXX American Chemical Society

5.2.1. Challenges in Using First-Line Pentavalent Antimonials 5.2.2. Challenges in Using Alternative Drugs 5.3. Reviewing Metal-Based Antileishmanial Compounds in the Literature 5.4. Molecular Targets and Mechanisms 5.4.1. Trypanothione and Trypanothione Reductase 5.4.2. Generation of ROS Species 5.4.3. Inhibition of Iron Superoxide Dismutase (Fe−SOD) 5.4.4. Synergistic Metal−Ligand Interactions 5.4.5. DNA Intercalation as a Mode of Action 5.4.6. Cathepsin B as the Target of Interest 5.4.7. Interleukin-1β 5.5. Bismuth in Medicine 5.6. Encapsulation as a Mode of Delivery 5.6.1. Background on Types of Encapsulation 5.6.2. Studies Involving Encapsulation 6. Lymphatic Filariasis 6.1. Introduction and Main Challenges for Treatment of Lymphatic Filariasis 6.2. Current Literature 7. Onchocerciasis (River Blindness) 7.1. Introduction and Main Challenges for Treatment of Onochocerciasis 7.2. Current Literature 8. Schisotosomiasis

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Special Issue: Metals in Medicine

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Received: July 5, 2018

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DOI: 10.1021/acs.chemrev.8b00338 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 8.1. Life Cycle of Schistosoma 8.2. Pathology 8.3. Main Challenges in the Current Treatment for Schistosomiasis 8.4. Current Literature 8.4.1. Gold Compounds 8.4.2. Compounds Derived from Praziquantel 8.4.3. Compounds Derived from Oxamniquine 8.4.4. Compounds Derived from Chloroquine 8.4.5. Compounds Derived from Epiisopiloturine 9. Human African Trypanosomiasis (Sleeping Sickness) 9.1. Symptoms of T. brucei gambiense 9.2. Symptoms of T. brucei rhodesiense 9.3. Life Cycle of T. brucei 9.4. Main Challenges and Current Treatments for Human African Trypanosomiasis 9.5. Current Literature 10. Conclusion Author Information Corresponding Authors ORCID Author Contributions Notes Biographies Acknowledgments References

Review

economic status and hence is unable to afford expensive medicines. For this reason, the majority of research undertaken for NTDs comes from/through academia/open sources/ nonprofit organizations such as the WHO, Drugs for Neglected Diseases Initiative (DNDi), Gates Foundation, Nuffield Foundation, and Wellcome Trust. As well-explained in all papers in this special issue on Metals in Medicine and as emphasized below, the main challenge for developing metal compounds targeted toward NTDs is that metal complexes offer fantastic opportunities in pharmaceutical research because of their specific, unique physicochemical properties. One has to remember that complexes of arsenic, mercury, bismuth, platinum, antimony, gold, iron, gadolinium, samarium, technetium, or palladium, to cite a few, are or have been used in medicine and that other metal-based compounds e.g. ruthenium are currently in clinical trials.3−10 There is a need to develop new drugs which are easy to synthesize, are scalable for large-scale synthesis, are cheap and affordable for the patients, and are able to bypass resistance mechanisms. The last point in particular is a reason why we believe that metal complexes are the drug of the future, as they are capable of acting via more than one mode of action and/or inhibiting more than one target enzyme. A prominent example is auranofin, one of the oldest drugs which are currently being repurposed for more than one disease, including rheumatoid arthritis, leishmaniasis, and schistosomiasis. In this review, we aim to systematically report all metal complexes that have been tested against at least one of the NTDs listed above, emphasizing the role of the metal in any observed activity. We have sectioned this review by NTD (in alphabetical order), describing first the disease, then current medications used to treat it, and lastly any limitations. Very importantly, only metal complexes that have been completely characterized are discussed herein. Furthermore, we will not describe any works related to the use of nanoparticles. We will only focus our attention on well-defined metal complexes. We acknowledge that different perspectives, highlights, and reviews have been published over the years on this subject; however, these have been sporadic and often narrow in scope, so we intend that this forms the first comprehensive overview of this topic.5,7,11−18 Of note, to the best of our knowledge, no metal complexes have been tested against chikungunya, dracuncuculiasis (guinea-worm disease), foodborne trematodiases, leprosy (Hansen’s disease), mycetoma, chromoblastomycosis, other deep mycoses, rabies, scabies, and other ectoparasites, soil-transmitted helminthases, taeniasis/cystericerosis, trachoma, and yaws (endemic treponematoses). As a final remark, we understand that malaria is not considered as an NTD by the WHO and is therefore not discussed in this review.

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1. INTRODUCTION AND THE MAIN CHALLENGES FOR DEVELOPING METAL-BASED DRUGS FOR NEGLECTED TROPICAL DISEASES According to the World Health Organization (WHO),1,2 neglected tropical diseases (NTDs) are medical conditions which affect the poorest populations who live in isolated rural zones, urban slums, or conflict areas, who are without adequate sanitation, water, and housing, and who are in close contact with infectious vectors and domestic animals and livestock. The WHO has recently added several newly categorized NTDs to its portfolio, bringing the list to 20, namely, Buruli ulcer, Chagas disease, dengue and chikungunya, dracunculiasis (guinea-worm disease), echinococcosis, foodborne trematodiases, human African trypanosomiasis (sleeping sickness), leishmaniasis, leprosy (Hansen’s disease), lymphatic filariasis, mycetoma, chromoblastomycosis and other deep mycoses, onchocerciasis (river blindness), rabies, scabies, and other ectoparasites, schistosomiasis, soil-transmitted helminthiases, snakebite envenoming, taeniasis/cysticercosis, trachoma, and yaws (endemic treponematoses). These NTDs, which affect more than 1 billion people, especially children, prevail in 149 countries. It is interesting to highlight that many of these diseases can be prevented, eliminated, and even eradicated without “complex” medical interventions by simply improving access to existing safe and cost-effective tools such as the use of mosquito nets.2 This said, “drug” intervention is very often inevitable and is the reason why an adequate medication arsenal is required. As explained in this review, the majority of the drugs used against NTDs are “old” and often have undesired side effects. Unfortunately, the main pharmaceutical companies have a low interest in the development of novel drug candidates or vaccines for NTDs since the target population, despite being extremely large, is almost exclusively in developing countries with low socio-

2. CHAGAS DISEASE 2.1. Background

One of the most important NTDs is Chagas disease, which was named after Carlos Justiniano Chagas, a Brazilian physician who discovered the disease in 1909.19 Chagas disease, also known as American trypanosomiasis, is a parasitic disease caused by the protozoan Trypanosoma cruzi. These parasites are typically transmitted through the feces of a bug called triatomine, also known as the “kissing bug”. They are able to enter the body by penetrating through broken skin, mucous membranes, or the soft skin of the eye.20 Triatomine is a blood-sucking bug, which becomes infected by the parasite from feeding on the blood of an B


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Figure 1. Structures of organic drugs and drug candidates effective against Chagas disease.

peripheral polyneuropathy considerably limit the use of these drugs.25 Other naturally occurring or chemically synthesized compounds with potential trypanocidal activity include ketoconazole, itrakonazole, allopurinol, and diverse nitroheterocyclic derivatives (Figure 1). Despite excellent activity, these compounds suffer from problems related to aqueous solubility, toxicity, low clinical efficacy, and resistance.24

infected human or animal. The infected bug then transfers the parasite to other noninfected victims by depositing feces on the skin while sucking blood from them. An alternative way of transmitting Chagas disease to humans or animals is through the consumption of food or drink which is contaminated with the feces of a triatomine carrying the parasite. Patients infected with T. cruzi have mild symptoms such as fever, swelling of lymph nodes and tissues, conjunctivitis, and skin lesions. A lack of treatment over several years can result in critical complications, such as a dilated esophagus or colon, leading to difficulties with eating or passing stools, heart arrhythmia, and sudden heart failure. Chagas disease is mainly endemic to poor and rural villages of Latin America, but it has spread worldwide due to the globalization and migration of unknowingly chronic-phase infected populations to and from Latin America.21 As shown by a recent estimation by WHO, Chagas disease still remains one of the largest public health problems affecting approximately 8 million people worldwide, with over 10000 people dying every year and more than 25 million people at risk of acquiring this disease.

2.3. Current Literature

The development of new antiparasitic drugs with fewer side effects and enhanced trypanocidal activity is undoubtedly highly required. In the search for a novel class of therapeutics to control Chagas disease, the use of metal complexes appears to be a promising approach. Indeed, over the past two decades, transition-metal complexes have been used as potential chemotherapeutic agent alternatives to the existing wholly organic drugs.26 It has been previously shown that several important biochemical pathways and enzymes (e.g., cysteine protease cruzain, trypanothione reductase, trans-sialidase) of T. cruzi can be targeted with new metal-based anti-Chagas drug candidates.27 Two main strategies, namely, (i) metal complexes containing bioactive molecules (trypanocidal ligands) and (ii) metal complexes containing nonbioactive ligands,26−30 have been employed for designing metal−organic and organometallic complexes with antitrypanosomal activity. These are described below. 2.3.1. Metal Complexes Containing Bioactive Ligands. 2.3.1.1. Metal Azole Complexes as Sterol Biosynthesis Inhibitors via Inhibition of Various Targets. A main target for the development of new drugs is the sterol biosynthesis pathway. The sterol biosynthesis pathway in Trypanosomatidae has been well-established as an important metabolic pathway.31 This pathway produces a special class of sterols, such as ergosterol, which are absent in mammalian host cells and are required for their growth and viability. Highly potent sterol biosynthesis inhibitors (SBIs) are azole derivatives such as clotrimazole (CTZ), ketoconazole (KTZ), and itraconazole (Figure 1).32 They are known to have excellent activity as chemotherapeutic agents against fungal parasites. CTZ, KTZ, and other azole derivatives inhibit parasitic cytochrome P45014DM (CYP450), which is an enzyme responsible for catalyzing lanosterol 14α-demethylation. The

2.2. Main Challenges in the Current Treatments for Chagas Disease

Over recent decades, noticeable progress has been made in the prevention and control of Chagas disease. However, to date, no vaccine is available, so primary prevention is fully based on largescale vector-control programs. Chemotherapy and specific treatment of the disease are a controversial matter, and Chagas disease has suffered from an inadequate research and development pipeline. Pharmaceutical companies are reluctant to invest in research projects dedicated to the discovery of new drug candidates for Chagas disease due to a potentially low return on investment.22 At present, the only treatment options are a nitroimidazole-based drug, benznidazole (Bz), which has been in use now for over 40 years, and a nitrofuran-based drug, nifurtimox (Nfx), which only works in the acute phase of the disease (Figure 1).23,24 Recent studies have shown that the high activities of Bz and Nfx are due to the release of nitro anion radicals that react with nucleic acids and damage the parasite’s DNA. However, low efficacy and associated severe toxic side effects such as hypersensitivity, rash, fever, generalized edema, lymphadenopathy, joint and muscle pain, bone marrow suppression (neutropenia, thrombocytopenic purpura), and C


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was nontoxic to Vero cells at 10−7 M, the compound was found to be more sensitive compared to CTZ in annihilating the intracellular amastigote form of the T. cruzi within Vero cells. In a separate study, a number of new M−CTZ complexes (M = Ru, Rh, Cu, Pt, and Au), namely, [Ru(bipy)(CTZ)2](PF6)2, [RhCl(COD)(CTZ)], [AuCl3(CTZ)], K2[PtCl4(CTZ)2], and [Cu(CTZ)2]PF6 [bipy = 2,2′-bipyridine; COD = 1,5-cyclooctadiene], demonstrated a metal−drug synergy.36 Corresponding Rh and Au complexes showed higher activity compared to Pt and Cu complexes and free CTZ (58% inhibition on T. cruzi epimastigotes). [RuCl2(CTZ)2] was found to be the most active of the series and showed a 10-fold increase in antiproliferative activity compared to free CTZ against T. cruzi. However, the compounds showed poor in vivo activity, most likely due to their low solubility in aqueous media. To improve the activity and solubility of [RuCl2(CTZ)2], the chlorido ligands were replaced with a bipy ligand. However, a lower activity was observed for this bipy complex. The authors suggested that hydrolysis of the weaker Ru−Cl bond could be an important step towards the formation of active species, while the strongly chelating ligand bipy might not be participating in a similar hydrolysis process. For [RuCl2(CTZ)2], the N3 atom (Figure 2) of CTZ is coordinated to ruthenium, therefore blocking the binding site of CTZ. However, [RuCl2(CTZ)2] possesses CYP450 inhibition properties comparable to those of CTZ in vitro.36 This result suggests that [RuCl2(CTZ)2] is most likely hydrolyzed inside cells, releasing free CTZ and causing the inhibition of the CYP450 enzyme. The resulting [RuCl2] fragment could undergo a series of chloride ligand exchange reactions with water and could interact with the parasite DNA. Therefore, the high activity observed for [RuCl2(CTZ)2] compared to free CTZ is most likely originating from the multitargeting properties of the metal complex. In a follow-up study to both improve the activity of CTZ and KTZ and broaden the search for new drug candidates with higher activity, Navarro et al. introduced a set of new M−CTZ and M−KTZ complexes (M = Ru, Rh, Cu, and Au), namely,

inhibition is mediated through binding of the unsubstituted N3 atom of the imidazole group with the heme center of the enzyme (Figure 2).33

Figure 2. Schematic representation of the possible interaction mode of an azole agent with N3 and the heme center of P45014DM. Adapted with permission from ref 33. Copyright 1987 Elsevier.

In addition to anti-T. cruzi properties, this azole class of SBIs has imidazole moieties which may offer the possibility for coordination with transition-metal ions of medicinal importance or with potential medicinal properties (i.e., DNA binding). The resulting metal complexes may then act as dual-targeting agents.33,34 A pioneering work by Sanchez-Delgado et al. led to the development of a new set of drug candidates with transition metals, including ruthenium, copper, gold, platinum, and rhodium. These candidates aim to combine the sterol biosynthesis inhibition of CTZ and KTZ with the DNA binding properties of the central metal atom. The first reported CTZ− metal complex was a ruthenium complex, [RuCl2(CTZ)2].35 In vitro studies on this compound showed high anti-T. cruzi activity (ca. 90% inhibition at 10−5 M) on the proliferation of the epimastigote form of T. cruzi compared with free CTZ and KTZ. The EC50 values were calculated to be 10−7 and 3 × 10−6 M for [RuCl2(CTZ)2] and CTZ, respectively. While [RuCl2(CTZ)2]

Figure 3. Structures of Ru−CTZ and Ru−KTZ complexes. D


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of CTZ. The authors also mention that 10a has approximately 30 times higher activity than the reference drug nifurtimox (IC50 = 8.0 μM). 10a (IC50 = 1.9 μM) was found to be more cytotoxic than CTZ (IC50 = 55.1 μM) on murine macrophages (J774 strain), with a selectivity index (SI) value of 8 for T. cruzi epimastigotes (cf. CTZ SI = 31). However, mode of action studies showed that 10a did not affect the parasite DNA, although it inhibited the T. cruzi biosynthetic pathway of conversion of squalene to squalene oxide. The authors suggest 10a deserves further evaluation as a prospective antiparasitic agent. 2.3.1.2. Selenium Thiocyanates as Inhibitors of Squalene Synthase. During ergosterol biosynthesis, a key enzyme is squalene synthase, which directly catalyzes the first step for the formation of squalene, an obligated metabolite in the biosynthesis pathway. Compounds that inhibit the activity of the squalene synthase, such as WC-9, a (4-phenoxyphenoxy)ethyl thiocyanate42 (Figure 4), are effective inhibitors of T. cruzi

[RuCl 2 (KTZ) 2 ], [RuCl 3 (KTZ) 2 (H 2 O)]·2H 2 O, [RuCl 3 (CTZ)3]·2CH3OH, [CuCl2(CTZ)4]·2H2O, [CuCl2(CTZ)]2, [CuCl2(KTZ)3], [CuCl2(KTZ)]2·2H2O, [Au(CTZ)(PPh3)]PF6, and [Au(KTZ)(PPh3)]PF6·H2O.37,38 All complexes showed higher activity than the parent organic drugs against the epimastigote form of the parasite. Ru(II) complexes were found to be more active than Ru(III) complexes. An activity enhancement of the ligand attached to a metal ion compared to the ligand itself was observed. However, the degree of activity enhancement could not be correlated either to the number of ligands attached to the metal center or to the nature of the metal ions. Following the same approach to develop new CTZ−metal hybrid compounds with improved anti-T. cruzi activity and higher water solubility, eight new Ru(II) and Ru(III) complexes containing p-cymene and CTZ as ligands were reported by Martinez et al.39 They include four coordination complexes (Figure 3; 1a, 2a, 3a, 4a), cis,fac-[RuIICl2(DMSO)3(CTZ)], cis,cis,trans-[RuIICl2(DMSO)2(CTZ)2], Na[RuIIICl4(DMSO)(CTZ)], and Na[trans-RuIIICl4(CTZ)2], and four organometallic complexes (6a, 7a, 8a, 9a), [RuII(η6-p-cymene)Cl2(CTZ)], [RuII(η6-p-cymene)(bipy)(CTZ)][BF4]2, [RuII(η6-pcymene)(en)(CTZ)][BF4]2, and [RuII(η6-p-cymene)(acac)(CTZ)][BF4] (bipy = 2,2′-bipyridine; en = ethylenediamine; acac = acetylacetonate).36 All compounds were tested against the proliferation of the epimastigote form of T. cruzi in vitro, and 6a was found to be more active (LD50 = 0.1 μM) than the other complexes (LD50 range 1.1−7.7 μM). 6a has a 58-fold higher activity than free CTZ. The authors also mention that the activity of 6a was increased by almost 6-fold compared with that of the ruthenium complex [RuCl2(CTZ)2] discussed earlier. The mammalian cell toxicity of these complexes was evaluated against human osteoblasts, and 6a did not display any toxicity up to 7.5 μM. An identical concept was employed with KTZ, with the view of improving its properties by metal complexation. Iniguez et al. synthesized a set of new Ru−KTZ complexes (Figure 3; 1b, 5b, 6b−9b), including coordination complexes (1b, 5b) as well as organometallic compounds (6b−9b).40 When the compounds were tested against the proliferation of T. cruzi epimastigotes in vitro, some of the organometallic complexes, 6b−8b, exhibited activities and selectivities comparable to those of KTZ. Complex [RuII(η6-p-cymene)Cl2(KTZ)] (6b), a compound structurally analogous to the CTZ complex [RuII(η6-p-cymene)Cl2(CTZ)] (6a), was found to be the most active complex of this series. The organometallic compounds 6b−8b also showed lower toxicity toward human fibroblasts and osteoblasts. Of note, the water solubility of complex [RuII(η6-p-cymene)Cl2(KTZ)] was higher compared to that of [RuCl2(CTZ)2]. A dual-targeting anti-T. cruzi mechanism of action was proposed by the authors through analogy with the proposed mechanism of action for [RuCl2(CTZ)2]. In analogy with cisplatin, after entering the cell, the Cl ligands of complex [RuII(η6-p-cymene)Cl2(KTZ)] are replaced by water, leading to the formation of a cationic Ru−KTZ complex, which could release the KTZ ligand by slow dissociation. The final cationic Ru species might interact with parasitic DNA and lead to nuclear damage, and the liberated KTZ inhibits sterol biosynthesis.40 An organometallic Ru(II)−cyclopentadienyl−CTZ complex, [RuCp(PPh3)2(CTZ)](CF3SO3)] (10a) (Figure 3), was recently reported by Gambino and co-workers.41 10a was found to be highly cytotoxic on T. cruzi epimastigotes (IC50 = 0.25 μM), and the activity was 6-fold higher compared with that

Figure 4. Selenium-containing derivatives of WC-9.

proliferation in vitro. Chao et al.43 prepared eight seleniumcontaining derivatives of WC-9, 11−18 (Figure 4), in 2017, which displayed potent inhibition against the proliferation of T. cruzi amastigotes in vitro, with selectivity indices ranging from 307 to 1796. These inhibitory effects of the selenium compounds are more effective than those of their group 6 analogues: OCN < SCN < SeCN. 2.3.1.3. Metal Hydrazone Complexes as Inhibitors of the Cysteine Protease Cruzain. The T. cruzi cysteine protease cruzain (TCC) enzyme was found to be a valid chemotherapeutic target. Bioactive aryl(4-oxothiazolyl)hydrazone derivatives (Figure 5) are potent inhibitors of TCC.44 Leite and co-workers reported a series of aryl(4-oxothiazolyl)hydrazone (ATZ) derivatives and screened their activity against the epimastigote form of T. cruzi.45 Although the compounds were effective against the epimastigote form of T. cruzi at noncytotoxic levels, the ATZs displayed only limited activity against the trypomastigote form of T. cruzi.45 To enhance the biological efficacy and the pharmacological properties of ATZs as well as to develop a new set of anti-T. cruzi agents, Leite and co-workers reported several Ru−ATZ complexes, 13a−13h, of general formula [RuCl2(ATZ)(COD)] (COD = 1,5-cyclooctadiene) (Figure 5).46 All complexes were screened in vitro against the epimastigote and trypomastigote forms of T. cruzi (Y strain). Complexes 13a−13h had an IC50 range of 3.3−27.2 μM against trypomastigotes at 24 h (cf. benznidazole IC50 = 5.0 μM) and E


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Figure 5. Structures of Ru-ATZ complexes [RuCl2(ATZ)(COD)]. ATZ = aryl(4-oxothiazolyl)hydrazone.

Figure 6. Structures of Ru−NO donor compounds.

an IC50 range of 1.8−87.4 μM for epimastigotes at 11 days (cf. benznidazole IC50 = 1.9 μM). The cytotoxicity of the complexes was determined using BALB/c mice splenocytes. All complexes except 13h were found to be more cytotoxic to the splenocytes (1−5 μg/mL) than the drug benznidazole (25 μg/mL on splenocytes). Complexes 13f−13h were able to inhibit the growth of the parasite at a concentration below 10 μM, and their activities were found to be similar to those of the commercial drugs benznidazole and nifurtimox. These biological data suggest that the Ru complexes are probably trypanocidal agents. 2.3.1.4. Ru−NO Donor Complexes as Generators of Reactive Oxygen Species (ROS). During the past two decades, it has been demonstrated that nitric oxide plays an important role in the pharmacological modulation of the immune system.47,48 While controlling normal cellular metabolism in host cells, it inhibits growth of the parasites. It is welldocumented that classical NO donors such as SNAP (Snitroso-N-acetylpenicillamine) and SNP (sodium nitroprusside) inhibit the life cycle of the parasites by inactivating parasite cysteine proteases.49 Several strains of T. cruzi are resistant to existing antitrypanosomal drugs, and nitric oxide-based therapies are interesting alternatives to unveil new drugs active against resistant T. cruzi strains.50−52 Concurrently with organic NO donors, metal-based NO donors have recently been investigated for their potential to combat T. cruzi infection and summarized in reviews.53

Franco and co-workers reported several ruthenium(II) nitrosyl tetraammine complexes coordinated to N-heterocyclic ligands (L) to give trans- and cis-ruthenium complexes 14−16 (Figure 6) which can work as nitric oxide (NO) donors in biological media.54−57 14a−14k have the formula trans[RuII(NO)(NH3)4(L)]X3 {L = imidazole coordinated through a nitrogen (imN) or an imidazole coordinated through a carbon (imC)), pyridine (py), L-histidine (L-hist), sulphite (SO32−), pyrazine (pz), nicotinamide (nic), 4-picoline (4-pic), triethylphosphite ([P(OEt)3]), isonicotinamide (isn), isonicotinic acid (ina), X = BF4−, Cl− or PF6−; 15a−15c are cis-[RuII(NO)(bipy)2(L)]X3 {L = imidazole, imN = 1-methylimidazole or sulphite ion (SO322−)} (Figure 6). These types of complexes are an interesting class of compound in terms of their d5 and d6 low spin electronic configurations, being resistant to oxidation and highly soluble in water. Capitalizing on the excellent properties of these complexes, Silva et al. reported in vitro and in vivo antiproliferative and trypanocidal activities of 14a−14k and 15a−15c.51 All trans-[RuII(NO)(NH3)4(L)]X3 compounds, 14a−14k (Figure 6), were tested against the epimastigote form of T. cruzi. The compounds where L = imN, py, L-hist, pz, nic, and isn exhibited greater antiproliferative activity against T. cruzi (IC50 range of 56−136 μM) compared with the standard NO donor sodium nitroprusside (SNP) (IC50 value of 244 μM).51 Although the compound trans-[Ru(NO)(NH3)4pz](BF4)3 (14f) was found to be the most active of the series, the authors F


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Figure 7. Structures of Bz and Ru−Bz complexes.

did not use this complex for in vivo experiments due its cytotoxicity results on Vero cells (IC50 = 120 μM). All the transRu−NO donor compounds were selected for assessment of activity against the bloodstream trypomastigote form of T. cruzi. When incubated under similar conditions, trans-[Ru(NO)(NH3)4imN](BF4)3, trans-[Ru(NO)(NH3)4-L-hist](BF4)3, trans-[Ru(NO)(NH3)4SO3]Cl, trans-[Ru(NO)(NH3)4pz](BF4)3, trans-[Ru(NO)(NH3)4P(OEt)3](PF6)3, and trans-[Ru(NO)(NH3)4ina](BF4)3 (IC50 range of 51−63 μM) were found to be as effective as SNP (IC50 value of 52 μM) on T. cruzi trypomastigotes. Trans-[Ru(NO)(NH3)4imN](BF4)3 (14a) and trans-[Ru(NO)(NH3)4isn](BF4)3 (14j) were selected for in vivo experiments in T. cruzi-infected mice due to their higher in vitro activity and lower cytotoxicity compared with trans[Ru(NO)(NH3)4pz](BF4)3 (14f) and SNP. A total of 60% of the mice treated with [Ru(NO)isn] and 40% of the mice treated with [Ru(NO)imN] survived for more than 120 days, making these compounds very promising for the treatment of T. cruzi infection. The authors suggested trypanocidal activities originate from the release of NO molecules. In an extended study, trans[Ru(NO)(NH3)4imN](BF4)3 (14a), trans-[Ru(NO)(NH3)4py](BF4)3 (14c), and trans-[Ru(NO)(NH3)4isn](BF4)3 (14j) complexes were shown to lyse the bloodstream form of the parasite in mice at a nanomolar concentration.58 Souza and Verlinede et al. reported that the bloodstream form of trypanosomatid protozoa had no functional tricarboxylic acid cycle and was highly dependent on the glycolysis pathway for ATP production. One of the key enzymes of this metabolic pathway for the T. cruzi parasite is glyceraldehyde-3-phosphate dehydrogenase (GAPDH).59,60 This great dependency on glycolysis makes the GAPDH enzyme a potential target for the design of new anti-T. cruzi drugs.59,60 Toward this goal, Silva et al. synthesized a second generation of ruthenium NO donor compounds of the type cis-[RuII(NO)(bipy)2(L)]X3, where L = imidazole (imN), 1-methylimidazole (1-miN), or sulfite ion (SO32−), 15a−15c (Figure 6), and investigated their activity against the GAPDH enzyme of T. cruzi,52 in vitro proliferation of T. cruzi epimastigotes, and bloodstream trypomastigote forms. The three complexes cis-[Ru(NO)(bpy)2imN](PF6)3, cis-[Ru(NO)(bpy)2-1-miN](PF6)3, and cis-[Ru(NO)(bpy)2SO3]PF6 showed higher antiproliferative activity against T. cruzi on the epimastigote form compared to the metal-free ligands Bz and SNP, while cis-[Ru(NO)(bpy)2imN](PF6)3 (15a) showed higher activity on the bloodstream trypomastigote form compared to the two other compounds. All three complexes showed a promising inhibitory effect against the GAPDH of T. cruzi at a concentration of 200 μM (IC50 values of 89, 97, and 153 μM, respectively), while the trans-[Ru(NO)(bpy)2SO3]PF6

complex did not inhibit the GAPDH enzyme. The authors suggest that the presence of bpy and NO ligands at the cis position facilitates intermolecular interactions with the target enzyme.52 Toward the goal of developing more potent ruthenium NO donor molecules, Silva and co-workers reported a new Ru−NO donor complex, namely, trans-[RuCl([15]aneN4)NO]2+ 16, {[15]aneN4 = 1,4,8,12-tetraazacyclopentadecane} (Figure 6).61 The activity of 16 assessed in vitro against epimastigotes revealed that the complexes alone were only 10−20% effective, while in combination with reducing agents such as ascorbic acid the compound became 100% effective at 1.0 mM concentration, suggesting the NO-releasing efficiency of the complexes is highly dependent on the presence of reducing agents. The standard drug Bz inhibited 53% of the trypomastogote form at a concentration of 1.0 mM after 24 h of incubation, while complex 16 mixed with ascorbic acid inhibited 100% of the trypomastigote form after 8 h of incubation at concentrations of 0.1, 0.5, and 1.0 mM. Furthermore, Vero cells infected with the intracellular amastigote form of T. cruzi were also treated with 1.0 mM 16 in the presence of the reducing agent ascorbic acid. A higher activity than for Bz was observed at the same concentration in the presence of the reducing agent. Bastos et al. reported a comparison study of four nitro/ nitrosylruthenium complexes, 17a−17d, as anti-T. cruzi agents.62 They synthesized and characterized four complexes, namely, cis-[RuCl(NO2)(dppb)(5,5′-mebipy)] (17a), cis-[Ru(NO2)2(dppb)(5,5′-mebipy)] (17b), ct-[RuCl(NO)(dppb)(5,5′-mebipy)](PF6)2 (17c), and cc-[RuCl(NO)(dppb)(5,5′mebipy)](PF6)2 (17d), where 5,5′-mebipy is 5,5′-dimethyl2,2′-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane (Figure 6). The anti-T. cruzi activity of all complexes was determined against the proliferation of the epimastigote and trypomastigote forms of the T. cruzi Y strain in vitro. Complex 17c was more effective than the other complexes and Bz at a concentration of 10 μM. In vivo results also showed that complex 17c was more potent in reducing the percentage of T. cruzi-infected macrophages compared to the other complexes and Bz. This study revealed that Ru−NO complexes are indeed potential drug candidates against T. cruzi infections and the amount of NO released by 17c in infected macrophages is higher than in the other complexes. As mentioned above, Bz is one of the widely used organic drugs for the treatment of Chagas disease. Despite clinical success, it suffers from several issues such as poor aqueous solubility and undesired toxic side effects.63−65 With the view of overcoming the limitation and improving the properties of Bz, Silva et al. envisioned the delivery of Bz as its G


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Figure 8. Structures of quinoxaline 1,4-di-N-oxide (QDO) derivatives and the oxovanadium(IV) complexes with 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives as ligands.

Figure 9. Structures of ruthenium(II) and rhenium(V) complexes with 5-nitrofuryl semicarbazones.

the N-oxide moiety of the quinoxaline is through the production of radical species that cause parasitic damage by affecting its redox metabolism. This radical mechanism is very similar to the nitro pharmacophore of known antitrypanosomal drugs (i.e., nifurtimox and benznidazole). Several derivatives of QDO have been identified as new anti-T. cruzi agents.68 To improve the bioactivity of QDO, the Cerecetto group reported vanadyl complexes of the type [VIVO(L)2], where L = 6 (or 7)-substituted 3-aminoquinoxaline-2-carbonitrile 1,4-di-Noxide derivatives 20a−20g (Figure 8).69 It was also hypothesized that the same modification may help to optimize the solubility of quinoxalines and thereby enhance their bioavailability. Compared to the reference drugs Bz (IC50 = 8.5 μM) and Nfx (IC50 = 7.7 μM), vanadyl complexes 20a−20g were moderately less active in vitro against the epimastigote form of T. cruzi (IC50 range of 8.5−35 μM). Complexation of the quinoxaline scaffold with vanadium improved the solubility of the complexes in hydrophilic media, leading to a higher activity of the vanadyl complexes compared to their parent compounds. 2.3.1.6. Metal Semicarbazones and Metal Thiosemicarbazones as Generators of ROS. 5-Nitrofuran derivatives possess potent antibacterial and antiparasitic activities and have been used for many years in the treatment of a wide variety of infectious diseases.70 Nfx is a 5-nitrofuran derivative and is considered the most effective drug in the treatment of Chagas disease. Nfx exerts its activity through the bioreduction of its nitro group, followed by the release of reactive oxygen species (ROS), leading to parasitic damage.63,70 Cerecetto et al. showed in several studies that 5-nitrofuryl-containing semicarbazone (SC) and thiosemicarbazone (TSC) molecules have antiChagas activity.71,72 Following the approach of metal coordination with bioactive ligands such as CTZ and KTZ, Gambino and co-workers reported several Ru, Pt, and Pd complexes of 5-nitrofurylcontaining SCs and TSCs. Of note, in a recent review, Gambino et al. summarized all ruthenium complexes with 5-nitrofuryl-SC and -TSC ligands having potential anti-T. cruzi activity.73 Otero et al. reported a series of four new Ru(II) complexes with the formula [RuIICl2(dmso)2L] (21a−21d) and two Re(V) complexes of the type [ReVOCl2(PPh3)L] (22a, 22b), where dmso = dimethyl sulfoxide, PPh3 = triphenylphosphine, and L =

metal complexes. The ruthenium complex trans-[Ru(Bz)(NH3)4SO2](CF3SO3)2 (18) (Figure 7) is readily soluble in water (3.7 mg/mL) compared to the free Bz ligand (0.4 mg/ mL).66 The in vitro antiproliferative activity of this compound was assayed against the epimastigote form of T. cruzi. The complex exhibited a higher activity (IC50 = 127 ± 8 μM) than the reference drug Bz (IC50 > 1 mM). The in vitro trypanocidal activity was tested on the epimastigote form of the T. cruzi Y strain (partially Bz-resistant strain), and the activity of 18 was found to be higher (IC50 = 79 ± 3 μM) than that for Bz (IC50 < 1 mM). Unfortunately, no in vivo activity was observed for this compound with doses up to 350 μmol/kg given for 15 consecutive days in T. cruzi-infected Swiss mice. At the same time, no acute toxic effect was also observed at doses up to 400 μmol/kg. The same group reported a structurally distinct ruthenium complex, namely, cis-[Ru(NO2)(bpy)2(Bz)](PF6) (19) (Figure 7), which showed high in vitro efficacy against the trypomastigote form of the T. cruzi Y strain at a very low concentration (IC50 value of 7.28 μM) compared to Bz (IC50 value of 110.48 μM).67 19 was selective to T. cruzi, and no toxicity was observed against mammalian cells at low concentration. To investigate the trypanocidal activity in the amastigote form of T. cruzi, infected Vero cells were treated with 19. The compound was found to be more efficient to inhibit the amastigotes compared to Bz. Cellular entry followed by NO release in the intracellular compartments of 19 was confirmed using the fluorescent dye 4,5-diaminofluorescein diacetate (DAF-2 DA). Encouragingly, by contrast to 18, 19 is active in vivo and was able to cure mice infected with T. cruzi Y strain trypomastigotes. Additionally, the effective dose of 19 was 100− 1000 times (4−0.4 μmol/kg) lower than the optimal dose of Bz (385 μmol/kg). The higher activity of this compound most likely originates from the simultaneous delivery of the Bz drug and metal-coordinated NO2, which increases the production of intracellular NO. 2.3.1.5. Metal Quinoxaline Scaffolds as Generators of ROS. Several compounds having a quinoxaline scaffold are known to have interesting biological properties.68 The oxidized form of this scaffold, quinoxaline 1,4-di-N-oxide (QDO; Figure 8), is known to have antitrypanosomal activity. The mode of action of H


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Figure 10. Structures of Ru(II), Ru(III), Pd(II), and Pt(II) complexes with bioactive 5-nitrofuryl-containing TSCs.

5-nitrofuryl SC derivatives (Figure 9).74,75 All rhenium complexes were found to be unstable in aqueous media and could not be used as potential drug candidates. Although the Ru complexes all showed excellent DNA binding properties and were able to produce intraparasite free radicals, complexes 21a− 21c showed poor in vitro anti-T. cruzi activity at 5 μM when compared with the metal-free ligands and Nfx. This lack of activity was proposed to be due to a high hydrophilicity and high protein binding capacity that could prevent the compounds from reaching their parasitic targets.75,76 A series of rationally designed Ru(II) and Ru(III) complexes of the formulas [RuIICl2(HL)2] (23a−23d), [RuIIICl3(HL)(DMSO)] (24a−24d), [RuIIICl(PPh3)(L)2] (25a−25d), and [RuIICl2(HL)(HPTA)2]Cl2 (26a−26d), where L = 5-nitrofuryl-TSC derivatives (HL neutral, L monoanionic), HPTA = protonated form of 1,3,5-triaza-7-phosphaadamantane, and PPh3 = triphenylphosphine (Figure 10), were synthesized and

biologically evaluated.73,77 All complexes showed poor activity against T. cruzi epimastigotes (0.01−0.8% inhibition at 5 μM), slightly lower than that of the parent TSC (0.3−1.5% inhibition at 5 μM) . The reason for this low activity was proposed to be the poor water solubility of the complexes. The authors also mention that the addition of the hydrophilic phosphine PTA ligand in complexes 26a−26d improves the solubility of the complexes (1−5 mM at physiological pH) compared to other ruthenium complexes. Despite this, the biological activity of the complexes did not improve to any significant degree. Pd(II) and Pt(II) complexes derived from 5-nitrofuryl-TSC ligands 27a−27h, 28a−28h, 29a−29h, and 30a−30h (Figure 10) of the general formulas [MCl2(HL)] and [M(L)2], where M = Pd and Pt, HL = neutral thiosemicarbazones, and L = monodeprotonated forms, were reported by Gambino and coworkers.78−81 Pd and Pt metals were chosen for their known DNA binding abilities. All complexes were tested against the I


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proliferation of T. cruzi epimastigotes and the activities compared with those of the metal-free ligands and Nfx. For Pd−TSC complexes at 5 μM concentration, most of the complexes exerted 1.7-fold higher activity than Nfx. Complexes 27a, 27d, and 27f showed higher antiepimastigote activity (IC50 range of 2.4−2.7 μM) than other Pd complexes (IC50 range of 4.5−100 μM). Although the IC50 values are similar for each ligand and its complexes, Pd complexes containing one 5nitrofuryl-TSC ligand were generally more potent as trypanocidal agents than Pd complexes with two TSC ligands (i.e., the activity follows this trend: complex [PdCl2(HL)] > free ligand > complex [Pd(L)2]). It is proposed that the poor activity of the [Pd(L)2] complexes is due to their poor solubility in the biological media. Interestingly, [PdCl2(HL)] complexes proved to be efficient inhibitors of trypanothione reductase, an enzyme which has been identified as being unique to the parasite and is considered as a potential target against trypanosomiasis. Additionally, DNA binding levels of [PdCl2(HL)] complexes were also higher than those of [Pd(L)2] complexes. All Pt−TSC complexes exhibited similar activity compared to the metal-free ligands and Nfx. Among the Pt−TSC complexes, complexes [Pt(L2)2] (30c) and [Pt(L3)2] (30e) showed higher activity than the metal-free ligands against T. cruzi Tulahuen 2 strain epimastigotes. Compound 30e was determined to be the most active compound of the series, with an activity 5-fold higher than that of the metal-free ligand (HL3) and Nfx. Unlike Pd−TSC complexes, Pt complexes containing two 5-nitrofuryl-TSCs showed higher activity than the Pt complexes containing one 5nitrofuryl-TSC ligand. The activity follows the order [Pt(L)2] > free ligand > complex [PtCl2(HL)]. Recently, Demoro et al. prepared four organoruthenium compounds of the form [Ru2(p-cymene)2(L)2]X2 (31a−31d), where X = Cl or PF6 and L = 5-nitrofuryl-TSCs (Figure 10). The compounds were screened against the inhibition of T. cruzi in epimastigote form as well as in trypomastigote form.73,82 In vitro results from the epimastigote form showed that the IC50 values of all the compounds 31a−31c were >100 μM. Only complex [Ru2(p-cymene)2(L4)2]Cl2 (31d) showed moderate activity with an IC50 value of 86.10 ± 14.11 μM. However, this potency was approximately nine-fold lower than that of the free TSC ligand L4 (IC50 = 9.52 ± 1.59 μM). The most significant observation was that all four complexes showed higher activity on the trypomastigote form, which is the infective form in the mammalian host compared to the epimastigote form (present in the gut of the insect vector). Complex 31d, [Ru2(p-cymene)2(L4)2]Cl2, was the most active compound against trypomastigotes, and its activity is higher than that of the corresponding Nfx and thiosemicarbazone ligand. A comparison of [Ru2(pcymene)2(L2)2]Cl2 (IC50 value of 75.96 μM for the T. cruzi Y strain and 14.30 μM for the Dc28c strain) and [Ru2(pcymene)2(L2)2](PF6)2 (IC50 value of 193.4 μM for the T. cruzi Y strain and 231.3 μM for the Dc28c strain) showed that the less soluble hexaphosphate analogue was 2.54−16.17 times less active against T. cruzi epimastigotes than the more soluble chloride analogue. It has been previously proposed that the toxic effect of Nfx on mammalian cells as well as in T. cruzi involves the intracellular bioreduction of the nitro group to the nitro radical anion (NO2•−), which increases the production of ROS, such as O2•−, H2O2, and the superoxide anion.63,64,70,83 It has already been confirmed that ROS production increases in different growth phases of T. cruzi and that such ROS have an important role in programmed cell death.84,85 The promising results obtained

from the organometallic compounds designed by Demoro et al. encouraged them to assume a hypothesis of a “multitarget mechanism of action”. The compounds could generate intraparasite ROS from the 5-nitrofuryl moiety and/or inhibit cruzipain (a cysteine protease) through the thiosemicarbazone pharmacophore.82 On the other hand, the compounds could also interact with DNA mainly through the Ru−arene moiety. The proposed mechanism of action was supported by measuring the free radical production capacity of the metal complexes, DNA binding study, and cruzipain inhibitory activity measurements. To generate free radicals, all the Ru−p-cymene compounds were incubated with epimastigote T. cruzi (Dm28c strain). A spin trapping agent, namely, DMPO (5,5dimethyl-1-pyrroline N-oxide), was added to detect free radical species. The generation of DMPO−nitroheterocyclic radical species generated by all the Ru−Cp−TSC complexes was assessed by electron spin resonance (ESR) spectroscopy. The DNA interaction mechanism of these compounds was also studied using atomic force microscopy (AFM) and DNA viscosity measurements. All ruthenium compounds were found to have low to moderate cruzipain inhibition potency at 10 and 50 μM concentrations. The authors conclude that although the main target(s) of the compounds is (are) not yet fully identified, the biological results on these metal compounds suggest a combined “multitarget mechanism”.82 To improve the aqueous solubility and pharmacological profile of this class of metal complexes, Otero and co-workers employed hydrophilic phosphine pta = 1,3,5-triaza-7-phosphaadamantane as a coligand. The structures of the novel metal complexes (32a−33d and 33a−33d) are presented in Figure 11.86 The potencies of all the complexes were tested against

Figure 11. Structures of [PdCl(L)(pta], [PtCl(L)(pta)], and [Ru(η5C5H5)(PPh3)L] complexes bearing bioactive 5-nitrofuryl-containing thiosemicarbazones (TSCs).

Vero cells infected with the trypomastigote form of T. cruzi. The complexes were found to have similar or lower activity than the corresponding free ligands. However, the Pt and Pd complexes of ligand L4 (32d and 33d) were the most active (IC50 = 9.8 ± 0.3 and 4.9 ± 0.2 μM). Importantly, these Pd and Pt complexes showed no cytotoxicity on mammalian cells. The selectivity indices for the Pd (32a−32d) and Pt (33a−33d) complexes were determined to be 10 and 20, respectively.87 No significant difference in activity between platinum and palladium complexes was observed. The Gambino group has also reported the synthesis and biological activity of structurally related Ru(II)−cyclopentadienyl compounds (34a−34c) of the form [Ru(η5-C5H5)(PPh3)L] [HL = 5-nitrofuryl-TSC] (Figure 11).88 The compounds were evaluated in vitro on the blood circulating J


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Figure 12. Structures of ferrocenyl (Fc) and cyrhetrenyl (Cy) imines derived from 5-nitrofuran and 5-nitrothiophene.

Figure 13. Structures of 2-mercaptopyridine N-oxide (MPO) and its Pt(II), Pd(II), Au(I), and VO(IV) complexes.

trypomastigote form of T. cruzi (Dm28c strain). All compounds were found to be active against T. cruzi in the micromolar range. Interestingly, compound [RuCp(PPh3)L3] (34b) was found to be 49 times more active than the reference trypanocidal drug Nfx (IC50 = 20.1 ± 0.8 μM).87 In vitro tests showed that these RuII− Cp complexes were much more effective on T. cruzi compared to the previously developed Ru(II) classical and organometallic compounds [RuCl2(HL)(HPTA)2]Cl2, [Ru2(p-cymene)2(L)2]Cl2, and [Ru2(p-cymene)2(L)2](PF6)2 with the same bioactive 5-nitrofuryl-TSC ligands. Importantly, the Ru−Cp compounds showed moderate to very good selectivity toward the parasites with respect to mammalian cells.73,77 [RuCp(PPh3)L3] (34b) was found to be the most promising drug candidate for further development compared to all previously reported compounds having a 5-nitrofuryl pharmacophore with an excellent selectivity toward T. cruzi (SI > 49). Similarly to the previously studied metal complexes of this bioactive ligand, the mode of action of these compounds was studied in detail.82,88 To understand the mechanism, free radical species generated by the Ru−Cp−TSC complexes were monitored by ESR spectroscopy. All compounds were found to have free radical production capacity.68 DNA binding studies using an ethidium bromide (EB) fluorescent DNA probe showed similar affinities toward DNA for all complexes. 2.3.1.7. Metal Imines Generating ROS Species. Nitrofuran and nitrothiophene derivatives analogous to Nfx are known to generate free radical species during the bioreduction of their nitro group to the nitro anion radical (NO2•−).89,90 On the basis of the similar idea of introducing a metal-specific mode of action into known antitrypanosomal drugs, Arancibia et al. reported a series of new cyrhetrenyl (Cy) imines (35b, 35d, 35f, and 35h; Figure 12) and ferrocenyl (Fc) imines (35a, 35c, 35e, and 35g; Figure 12) of 5-nitrofuran and 5-nitrothiophene derivatives. The rationale behind this design was to achieve reactive oxygen species (ROS) production by the 5-nitrofuran and 5-nitrothiophene moieties and at the same time to have organometallic moieties, which may show some metal-specific mode of action, therefore enhancing the activity of the parent organic drug in either an additive or a synergistic manner.91,92 All compounds were assayed in vitro on the epimastogote and trypomastigote forms of T. cruzi (Dm28c strain), and the results

were compared with the activity of Nfx. IC50 values obtained on the epimastigotes indicated that the complexes containing the electron-withdrawing Cy group (35b and 35f) were more active than those containing the electron-donating Fc group (35a and 35e). The activities of complexes 35b and 35f were almost comparable with the activity of Nfx. More interesting results were obtained on the trypomastigotes. While the activities of the ferrocenyl imines (35a, IC50 = 12.3 ± 1.7 μM; 35e, IC50 = 18.3 ± 0.7 μM) were comparable with that of Nfx (IC50 = 19.8 μM), those of cyrhetrenyl imines (35b, IC50 = 3.7 ± 0.1 μM; 35f, IC50 = 3.7 ± 0.7 μM) were much higher. The cyrhetrenyl imine containing the 5-nitrofuran group (35b) was the most active complex of the series. All the cyrhetrenyl and ferrocenyl imines attached to the 5-nitrofuran and 5-nitrothiophene groups through the conjugated bridge (35a, 35b, 35e, and 35f) were found to be more active than the nonconjugated ones (35c, 35d, 35g, and 35h). Although the authors could not provide any particular plausible mechanism for this observation, they suggested that the reason behind the high activity of 35b could be associated with the high electron-withdrawing nature of the Cy group. They assumed that a resonance stabilization occurs due to conjugation between the Cy and furan groups in complex 35b, leading to an easier reduction of the NO2 group to the NO2•− radical. At the same time, the authors also considered that the presence of the organometallic moiety enhanced the lipophilic character of the compound and induced a synergic effect between the Cy and 5-nitrofuran groups. Therefore, they concluded that the consideration of electronic effects could be an interesting factor in designing new anti-T. cruzi drug candidates. 2.3.1.8. Metal−2-Mercaptopyridine N-Oxide (MPO) Complexes as Inhibitors of NADH-Fumarate Reductase (NADH = Nicotinamide Adenine Dinucleotide Hydride). The enzyme NADH-fumarate reductase is present in several parasitic protozoa, including T. cruzi. This enzyme plays an important role in the metabolism of the parasite by catalytically converting fumarate to succinate using NADH as a cofactor. Since NADHfumarate reductase is a parasite-specific enzyme and is not present in mammalian cells, it was considered as a potential target for antitrypanosomal drug design. MPO (Figure 13) is a potent inhibitor of this enzyme and shows excellent activity K


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Figure 14. Basic structures of purine and 1,2,4-triazolo[1,5-α]pyrimidines and their derivatives: metal complexes with tp, dmtp, and HmtpO ligands.

against the epimastigote form of T. cruzi with an IC50 of 0.08 μM. Moreover, it is also active against T. cruzi trypomastigotes (IC50 = 20 μM). Turrens et al. also observed that MPO inhibits the growth of the intracellular amastigote form of T. cruzi in cultured mammalian myoblasts at a concentration of 2.4 μM.93 Of interest, several transition-metal (Mn2+, Ni2+, Fe3+, Co3+, VO2+, VO4+, Cr3+, Cu2+, Zn2+, Bi3+, and Ga3+) complexes coordinated to MPO were found to be active as antifungal and antibacterial agents.94−97 Vieites et al. prepared complexes [Pt(mpo)2], [Pd(mpo) 2], and [Au2(mpo)2(PPh3)2] and analyzed their mode of action in detail (Figure 13).98−100 All complexes were assayed in vitro against the proliferation of T. cruzi epimastigotes in two different strains (Tulahuen 2 strain for the Pd and Pt complexes and Dm28c strain for the Au complex). Higher activity of the complexes against T. cruzi (IC50 range of 0.067−1.27 μM) compared to those of the metal-free MPO ligand and the reference drug Nfx (7.7 μM on epimastigotes) was observed. The Pt(II), Pd(II), and Au(I) complexes were 39-, 115-, and 67-fold more active than Nfx. Cytotoxicity data on mammalian cells revealed that the Pt complex [Pt(mpo)2] showed very low cytotoxicity toward these cells compared to [Pd(mpo)2] and [Au2(mpo)2(PPh3)2] (Figure 13). Although two different strains of T. cruzi were used, a preliminary comparison of the biological results among these three complexes showed that the Pt and Au complexes exhibited higher selectivity toward T. cruzi than the Pd complex. To gain insight into the “mode of action” and potential target of these complexes, the authors performed several experiments such as DNA binding study with metal ions, determination of the capacity of the derivatives to produce intraparasite free radicals, and T. cruzi trypanothione reductase and NADHfumarate reductase inhibition assays. The results strongly suggest that the complexes are involved in the inhibition of the enzyme NADH-fumarate reductase. Recently, the Gambino group reported an oxidovanadium(IV) complex of 2-mercaptopyridine N-oxide, [VO(mpo)2] (Figure 13), and its in vitro activity against T. cruzi epimastigotes.101,102 It was noted that the high activity of the [VO(mpo)2] complex on T. cruzi and low toxicity on mammalian cells lead to a higher selectivity index (SI = 61.14) when compared with that of the reference drug Bz (SI = 12.44). 2.3.1.9. Metal Complexes of 1,2,4-Triazolo[1,5-a]pyrimidine and Its Derivatives. 1,2,4-Triazolo[1,5-a]pyrimidine and its derivatives (Figure 14) are another attractive class of building blocks to develop drugs against tropical parasitic disease.103 Therefore, not surprisingly, metal com-

plexes based on 1,2,4-triazolo[1,5-α]pyrimidine and its derivatives were also synthesized and evaluated for anti-T. cruzi properties.103,104 A series of transition-metal as well as lanthanoid complexes of 1,2,4-triazolo[1,5-α]pyrimidine (tp), 5-methyl-1,2,4-triazolo[1,5-α]pyrimidine-7(4H)-one (HmtpO), and 5,7-dimethyl-1,2,4-triazolo[1,5-α]pyrimidine (dmtp) are presented in Figure 14. Among all transition-metal complexes of tp ligands, the Cu(II) complex [Cu(NO3)(H2O)(phen)(tp)](NO3) was found to be the most active against T. cruzi epimastigotes (IC50 value of 70f > 70d > 70g > 70h > 70e. Complexes 70a, 70b, 70c, and 70f displayed a >1000-fold difference between the toxicity of the compound toward the macrophages and the activity of the compound against L. tropica, indicating the high selectivity of tris-p-tolylantimony(V) dicarboxylate complexes. As they are pentavalent antimony compounds, it is expected that they would have a mechanism of action similar to that of the pentavalent antimonials currently used. Antimony and bismuth porphyrin complexes were also studied. Gomes and Demicheli et al. tested the N-binding porphyrin tetrakis[(4-carbomethoxyphenyl)porphyrin], [H2T4CMPP] (71), its Sb(V) derivative [SbV(T4CMPP)Br2]Br (71a), and its Bi(III) derivative [Bi(T4CMPP)]NO3 (71b) (Figure 40) against antimony-sensitive/wildtype (WT) and antimony-resistant (Sb-R) L. amazonensis promastigotes.200 The porphyrin 71 showed antileishmanial activity with IC50 values of approximately 93.8 ± 1.2 and 52.4 ± 1.2 μM against the WT and Sb-R strains, respectively, 1.78 times more active toward the resistant strain.

Figure 40. Porphyrin structure with Sb(V) and Bi(III) derivatives.

The Sb(V) complex 71a (Figure 40) displayed high activity with an IC50 values of 4.4 ± 1.2 μM against WT and 1.2 ± 0.2 μM against Sb-R, 3.67 times more active toward the resistant strain and 21.3−43.6 times more active than the parent porphyrin 71. These are very low concentrations, indicating the high activity of Sb(V) compounds toward Leishmania. The antimony(V) complex 71a was also tested on the intracellular amastigotes in the macrophage-infected model and showed IC50 values of 53.0 ± 1.2 and 72.8 ± 1.3 μM for the WT and Sb-R strains, respectively.200 The reference drug potassium antimony tartrate had an IC50 of 110 μM against the WT promastigotes and was almost inactive against the Sb-R strain.200 This suggests that Sb(V) complex 71a works by a different mode of action, as it is able to bypass the mechanisms responsible for antimony resistance, as shown by its high activity toward both WT and SbR strains at low micromolar concentrations. Conversely, the Bi(III) complex 71b was not a suitable antileishmanial candidate as it has a lower activity (IC50 of >100 μM) compared to the parent porphyrin 71 (IC50 = 52.4 ± 1.2 μM) and has no detectable antileishmanial activity, even at the maximum concentration of 100 μM. 5.4.1.1.6. Selenium. Baquedano et al.201 designed a series of 23 selenocynates and diselenides containing bioactive scaffolds and conducted in vitro testing on L. infantum amastigotes and human THP-1 cells. From this series, compounds 72−74 (Figure 41) showed a range of selectivity indices, 25.8−55.5, which are higher than that of the reference drug miltefosine (SI = 7.0). Further investigations showed that compounds 72 (3,5dimethyl-4-isoxazolyl selenocyanate) and 73 [3,3′Z


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nitroprusside is a drug commonly used to lower blood pressure and to relieve heart failure. Sodium nitroprusside was shown to act as an exogenous source of NO, independent of the iNOS. The expression of iNOS is a macrophage mechanism to combat parasites such as Leishmania. Pereira et al.204 showed that antileishmanial activity of the ruthenium(II) tetraamine nitrosyl complex trans-[Ru(NO)(NH3)4imN](BF4)3 (imN = imidazole coordinated by nitrogen) (Figure 42) depends on the formal potential of the RuIINO+/RuIINO0 couple in these complexes and on the specific rate constant for the liberation of NO (k−NO). In particular, trans-[Ru(NO)(NH3)4imN](BF4)3 administered (500 nmol/kg/day) in BALB/c mice infected with L. major was found to exhibit a significant 98% inhibition on the parasite growth. Furthermore, this complex proved to be at least 66 times more efficient than glucantime in in vivo experiments.204 5.4.2.2. Direct and Indirect Methods of ROS Generation. Kawakami and Orsini et al.205 demonstrated that another nitric oxide (NO) donor complex, cis-[Ru(bpy)2SO3(NO)]PF6, also known as RuNO, showed leishmanicidal activity directly and indirectly on promastigote forms of L. amazonensis. Treatment with RuNO increased NO production by reversing the depletion of NO caused by Leishmania. This compound was incubated with L. amazonensis promastigotes at 30 and 60 μM and significantly inhibited the proliferation of the parasite while remaining nontoxic to cells at the same concentration. RuNO also does not affect the uptake of promastigotes into the macrophages, but in infected macrophages, it actively increases NO production by increasing the expression of inducible nitric oxide synthase (iNOS). These results demonstrated that RuNO was able to kill the parasite by NO release and modulate the transcriptional capacity of the cell. 5.4.2.3. Direct Method of ROS Generation. Iron is a required cofactor in more than 40 proteins involved in biological redox processes belonging to metabolic pathways in most pathogens.206,207 These pathways include respiration and biosynthesis of DNA or amino acids. In macrophages, iron distributes between transferrin, the major iron transport protein in mammalian plasma, and heme, a cofactor for many proteins. Ferrocene itself shows strong binding to hemoglobin, rather than transferrin, and this is usually seen when ionic forms of iron are administered. To carry out necessary biological functions, Leishmania acquire iron from their hosts, as they are unable to produce heme and target macrophages. By targeting iron metabolic pathways, such as binding sites on transferrin, iron complexes and iron-mimicking complexes can be trafficked into the parasite. Fe(III) analogues of ferrocene and substituted ferrocenes have been shown to produce hydroxyl radicals and induce cytotoxicity.208 Ferrocene by itself can cause oxidative stress by generating hydrogen peroxide by auto-oxidation in phosphate-buffered saline. Fe(II) ferrocenyls can also be

Figure 41. Selected selenocynate and diselenide bioscaffolds synthesized by Baquedano et al.201

(diselenodiyldimethanediyl)bis(2-bromothiophene)] were potent inhibitors of trypanothione reductase. 74 did not show any inhibitory activity against TR, indicating that its antileishmanial activity occurs through different mechanistic pathways. Calculated parameters for in silico ADME (absorption, distribution, metabolism, and excretion) for 72 and 74 predict good bioavailbility, and the authors believe that these drugs would make promising candidates for further studies. 5.4.2. Generation of ROS Species. Macrophages are the primary cells infected by Leishmania parasites, and both reactive oxygen species (ROS) and nitric oxide (NO) are important in the control of Leishmania by these cells. When Leishmania parasites are taken up by macrophages, they are able to escape the host defense system by inhibiting certain functions, such as suppressing inducible nitric oxide synthase (iNOS) within the macrophage. The enzyme iNOS is responsible for the production of NO, the major antileishmanial substance. The generation of ROS is hence a method of targeting the intracellular parasites, and this can occur both directly and indirectly. The use of transition-metal-based drugs is also increasing, and many of these complexes have been specifically designed to bind well-defined target sites in different biomolecules. 5.4.2.1. Indirect Method of ROS Generation. One of the studies which explores the indirect method of ROS generation is the latest by Singh and Roy et al.,202 who report that copper salicylaldoxime (CuSal) (Figure 42) targets VL by selectively inhibiting the enzyme leishmanial topoisomerase I. The inhibition of this enzyme causes oxidative stress by generating ROS. The presence of ROS induces the activation of caspaselike proteases, which play a key role in the apoptosis of L. donovani promastigotes. After treatment with 30 μM CuSal, 97% of promastigotes were inhibited at 8 h, and 4 h later, this rose to 100%. With ex vivo amastigotes within macrophages, after 24 h of 30 μM CuSal, 97% of the amastigotes were eliminated. Treatment of mice showed 98% and 99% of parasites were eliminated in the liver and spleen, respectively, at a dosage of 10 mg/kg of body mass. CuSal was found to be nontoxic toward macrophages after treatment with 15, 30, and 45 mM CuSal for 24 h. Kawakami and Orsini et al.203 demonstrated that the release of NO from sodium nitroprusside (Figure 42), an ironcontaining complex, enhanced the in vitro antileishmanial activity in macrophages infected with L. amazonensis. Sodium

Figure 42. Complexes causing indirect generation of ROS to exert antileishmanial effects. AA


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Figure 43. Structures of ferrocenyl derivatives and transition-metal chelates.

Figure 44. Structures of cyclopalladated complexes.

oxidized, resulting in ROS which damage DNA and other biomolecules.209 Quintal et al.206 reported two such ferrocenyl derivatives, 75a and 75b (Figure 43) (IC50 = 5.69 ± 0.22 and 5.73 ± 0.14 μM, respectively). These compounds show higher selectivity for L. infantum promastigotes and amastigotes compared to miltefosine (IC50 = 17 μM) on the basis of their therapeutic indices (SI = 56.4 for 75a; SI = 88.5 for 75b). The ferrocenyl component acts as an ROS producer after in vivo oxidation to Fe(III). Ikram and co-workers210 tested transition-metal complexes 76a−76d derived from 76 (Figure 43). The copper complex 76c (IC50 = 5.86 μM) was more active than the rest of the complexes, and this was due to its high stability. Palladium−NHC complexes have been reported to directly cause oxidative stress due to the intracellular reduction of the NHCs, as well as by redox cycling, which gives rise to free radical species.80 Two studies described below explore the effectiveness of palladium cyclometalated complexes and platinum−NHC compounds. Velásquez et al.211 reported four Pd(IV) cyclometalated compounds, 77a−77d (Figure 44), tested against L. amazonensis and L. infantum promastigotes and intracelluar amastigotes. Compound 77d was found to be the most stable compound, with good activity against L. amazonensis intracellular amastigotes, an IC50 of 9 μM, and a selectivity index of 14.47. The selectivity was better than that of amphotericin B with IC50 = 4.92 μM and SI = 4.70. These cyclopalladated compounds have high thermodynamic stability and lower kinetic lability compared to the other Pd(II) compounds due to the formation of a stable chelate ring. This suggests that palladium cyclometalated compound 77d could selectively target intracellular amastigotes within macrophages. Five CCC-pincer−NHC−Pt(II) complexes, 78a−78e (Figure 45), displayed good antileishmanial activity on Leishmania chagasi, L. major, L. amazonensis, and L. braziliensis with IC50 values of 0.02−3.41 μM.212 The overall order of lipophilicity decreases following the sequence 78e > 78d > 78c > 78b > 78a, which also corresponds to the trend in cytotoxicity. Although 78e has the highest activity against Leishmania, it also has high toxicity. Overall, the presence of the carboxylate group is essential to enhance the cytotoxicities and antileishmanial activities of these complexes. However, as they were not

Figure 45. Structures of platinum−NHC complexes.

selective, the mechanism of action for these compounds was not investigated. The vanadium complex VOSalophen (Figure 46), derived from the stilbene compound H2Salophene (Figure 46), showed

Figure 46. Stilbene-derived compound and its vanadium complex.

strong concentration- and time-dependent antileishmanial activity toward L. amazonensis promastigotes (IC50 = 6.65 μM) and amastigotes (IC50 = 3.51 μM).213 VOSalophen is specific for parasites and displayed no significant toxicity toward human erythrocytes (red blood cells, RBCs) and was 7 times less toxic on macrophages compared to parasites.213 VOSalophen induces antileishmanial activity via ROS and NO production in promastigotes and intracellular amastigotes. In addition, parasites treated with VOSalophen display mitochondrial dysfunction caused by the depolarization of the membrane potential. The transmembrane potential of the mitochondria is the electrical potential difference between the inside of the mitochondria and the outside environment. Maintenance of the mitochondrial transmembrane potential is essential for survival of the cell. Hence, VOSalophen is acting directly to induce ROS production and disrupts the mitochondrial membrane potential, which affects survival of the cell. AB


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iensis (promastigotes, 32−102; amastigotes, 22−35) with murine J744.2 macrophage cells as the cytotoxicity control. These compounds were found to inhibit the mitochondrial Fe− SOD in both Leishmania species, while having little to no effect on the analogous human CuZn−SOD. The inhibition of Fe− SOD results in redox stress, believed to be causing changes in the glucose metabolism pathways. In the presence of compounds 79−84, the levels of excreted metabolites, pyruvate, succinate, acetate, L-alanine, and D-lactate, had changes which led to mitochondrial damage. The authors suggested that further investigatations were necessary for insight into the mechanisms behind their antiparasitic activity and that, due to the different mechanisms of action, combined therapies can be considered for improved efficacy. 5.4.4. Synergistic Metal−Ligand Interactions. A review by Gambino and Otero73 indicates that there have been many studies over the years showing that ruthenium complexes can bind to DNA. Depending on whether the ruthenium center is in the biologically relevant +2 or +3 oxidation state, the metal prefers coordination to sulfur, oxygen, and nitrogen donors, both of which are present in major biomolecules such as DNA, serum proteins, cellular proteins, and enzymes. Biomolecular reducing agents such as glutathione and some enzymes can reduce Ru(III) to Ru(II). Conversely, molecular oxygen and cytochrome oxidase can oxidize Ru(II) to Ru(III). By modifying the coordination environment about the central metal atom, the redox potential of the entire complex can be fine-tuned toward synthesizing ruthenium-based prodrugs that could be activated in hypoxic tumor tissues via reduction and be selective via reoxidation in healthy normal oxygenated cells.

A polymeric vanadium oxido cluster decavanadate, [V10O28]6− (V10), was investigated on Leishmania tarentolae in the form of [NH4]6[V10O28]·6H2O.214 Due to its instability in culture media, enzyme kinetic studies on acid, alkaline, and tyrosine phosphatases and phosphoglycerate mutase were performed instead. Phosphatases catalyze the removal of phosphate groups, which regulates carbohydrate metabolism in metabolic pathways such as glycolysis and gluconeogenesis. V10 strongly inhibits phosphoglucerate mutase. Inhibition of phosphoglucerate mutase indirectly inhibits gluconeogenesis. Leishmania are highly dependent on gluconeogenesis, and inhibition of these enzymes restricts energy production and limits their growth and virulence. Under metabolic stress, the redox balance is damaged.215 This indicates that decavanadate V10 has a role in the inhibition of Leishmania. 5.4.3. Inhibition of Iron Superoxide Dismutase (Fe− ́ SOD). In 2017, Martin-Montes et al.216 synthesized a library of 48 selenium derivatives. Compared to the reference drug meglumine antimonate, six compounds, 79−84 (Figure 47),

Figure 47. Selected selenium complexes with selectivity indice values of >15.

showed a higher range of selectivity indices against L. infantum (promastigotes, 16−190; amastigotes, 17−38) and L. brazil-

Figure 48. Clotrimazole and its ruthenium complexes AM160 and AM162. Structure of ketoconazole (KTZ) and the three complexes derived from KTZ. AC


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Figure 49. Zinc dipicoylamine complexes.

complexes without KTZ are less active and have a lower LD50 of 12−15 μM. The activity of complexes containing both KTZ and Ru together in one compound, 85a−85c (Figure 48), show increased activities (LD50 = 0.8−1.5 μM), 2 times that of KTZ and 10 times that of the analogous Ru complex without KTZ. Furthermore, by coordinating KTZ with Ru, the selectivity index based on human cells significantly increases to 78−150. Compound 85a (Figure 48) is more active than the other two, and it seems that the hydrolysis of one chlorido ligand in the first compound to form a cationic species appears to be a prerequisite for biological activity. The dissociation of KTZ probably occurs upon further interaction of the cationic species with biomolecules within the parasite. As complexes 85b and 85c do not have chlorido ligands, the presence of the more stable chelating ethylenediamine (en) or bipyridine (bipy) ligands most likely plays a role in the lower activity. The en and bipy ligands contain nitrogen, which would be able to form hydrogen bond interactions with DNA218,219 or π-stacking interactions,220,221 respectively. Estrada and Sánchez-Delgado222 reported that these six Ru(II)−KTZ complexes are able to form Ru complex−protein adducts with human serum albumin (HSA) and apotransferrin (ATf), indicating that both HSA and ATf are possible effective transporters for Ru−KTZ antileishmanial complexes. Simpson and Schatzschneider et al. synthesized five manganese(I) tricarbonyl azole complexes derived from ketoconazole, miconazole, and clotrimazole.223 It was found that coordination of the organic azole drugs to the Mn(CO)3 moiety led to complexes with low micromolar IC50 values. Unfortunately, their equally high toxicity on mammalian 293T embryonic kidney cells and J774.1 macrophages meant that these manganese compounds had low selectivity for Leishmania. 5.4.4.2. Quinoline-Functionalized Complexes. Quinoline derivatives are one of the most studied families of organic compounds for leishmanicidal activity due to their easily modulable scaffolds. A set of quinoline-functionalized NHC− gold(I) cationic or neutral complexes were investigated by Paloque et al.,224 but unfortunately, compared to the amphotericin B control (SI = 79), none of the compounds displayed high enough selectivity (SI = 0.09−6.19) even though they displayed very good antileishmanial activity on L. infantum promastigotes and amastigotes. 5.4.4.3. Zinc-Based Complexes. Several modes of action for antileishmanial Zn(II) complexes have been discussed in the literature: inhibition of enzymes essential for parasite carbohydrate metabolism (Embden−Meyerhof pathway); selective recognition of anionic cell surfaces through electrostatic attraction, and specific coordination of cations with phospholipids in the cell membrane. The zinc-based study was conducted by Reddy et al., who in 2017 reported a series of Cu(II) and Zn(II) complexes derived from amino- and iminopyridyl ligands.225 The complexes are well tolerated by mammalian macrophage cells. Zn(II) complexes had good

It is hypothesized that, in synergistic metal−ligand interactions, both the metal and organic compound act as carriers for each other, where the metal stabilizes the organic compound until it reaches the target site, while the organic compound prevents undesirable metal interactions with other biomolecules before the metal ion reaches its secondary target site. Below, a number of metal-based synergistic studies involving azole compounds, organic compounds which have antiparasitic activity, are discussed. Azoles were originally developed as antifungal agents, but their activity on kinetoplastids such as Leishmania has been explored since these parasites also require ergosterol for their metabolism and share this biosynthetic pathway with fungi. The mechanism of action is based on the inhibition of lanosterol demethylase, which leads to the accumulation of 14α-methylsterols. The binding of azoles to such sterol biosynthesis inhibitors to the metal increases the selectivity for Leishmania. 5.4.4.1. Metal−Azole Interactions. Iniguez, Sánchez-Delgado, and co-workers, who have been exploring the potential of synergistic metal−azole interactions, present a series of studies focusing on Ru derivatives of clotrimazole (CTZ) and ketomazole (KTZ), as well as the structure−activity relationship of these complexes. CTZ is a classical imidazole ligand with a single coordination site of N1, capable of binding a metal atom. Eight novel Ru(II) and Ru(III) complexes derived from this compound were prepared.39 These complexes were active against the L. major promastigotes. AM160 (Figure 48) increases the activity of CTZ by a factor of 110 against L. major, with no toxicity against human osteoblasts, which results in nanomolar lethal doses and a therapeutic index of 500.39 This complex also shows significant inhibition on intracellular amastigotes in mice macrophages (IC70 = 29 nM).39 AM162 (Figure 48) showed some effect at a higher concentration (IC40 = 1 μM). Both Ru−clotrimazole compounds AM160 and AM162 were further investigated in in vivo murine studies.217 AM162 reduced the lesion size in mice infected with CL, and both Ru−azole AM160 and AM162 compounds induce an apoptosis-like death in a dose-dependent manner on L. major promastigotes. A follow-up study reported six new ruthenium−ketoconazole (KTZ) complexes.40 Two were octahedral coordination complexes, and four were η6-aryl compounds. Figure 48 shows three of the compounds, 85a−85c, where coordinating the bioactive KTZ with ruthenium resulted in synergistically improved activity and selectivity over those of the individual precursors of KTZ and the Ru constituents, or similar Ru compounds without KTZ. The improved activity was shown by results from the assays on both promastigotes and intracellular amastigotes of L. major. Improved selectivity was shown by assays on human fibroblasts, osteoblasts, and murine and intraperitoneal macrophages. The parent molecule KTZ itself has good in vitro activity and selectivity against L. major promastigotes (LD50 = 1.9 μM, selectivity index of >63). Ru AD


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Figure 50. Au(III), Ag(III), Cu(III), Sb(III), and Bi(III) complexes containing planar nitrogen donor heterocycles.

activity against the L. amazonensis promastigotes, while Cu(II) complexes were unable to inhibit the proliferation of the promastigotes. Compared to the control amphotericin B (IC50 = 0.012 μM), it cannot be said that any of the Zn(II) and Cu(II) complexes had better activity than the control; however, morphological changes in affected parasites could be observed where parasites became round in shape, sometimes swelling or decreasing in size, and lost the flagellum. It was also reported that anionic complexes can differentiate the anionic surface charge of the parasite as opposed to the nearneutral membrane surface charge of healthy mammalian host cells.226 A study by Rice et al.226 used L. major transgenic parasites tagged with a red fluorescent marker, mCherry, which allowed for the direct comparison of fluorescent intensity with parasite viability. Eight cationic zinc dipicoylamine (ZnDPA) complexes, 86a−86h (Figure 49), were tested in vitro against the L. major promastigotes, amastigotes, and mammalian cells. The exact mechanism of action is unknown, but it is hypothesized that the ZnDPA complexes play a role in disrupting the parasite membrane or altering metal cation concentrations within the cytosol. All complexes were active against L. major with EC50 values between 12.7 and 0.3 μM, while showing no toxic effect against mammalian cells. The EC50 is defined as the concentration of the drug at which 50% of its maximum response is observed. Compound 86g (Figure 49) was used as a representative compound in further in vivo studies, with potassium antimony(III) tartrate and saline (no drug) as controls. It was found that mice treated with doses of 86g five times a week gave a progressive loss in fluorescence comparable to that of the standard antimony drug over a 12 day period, even though the dose amount was approximately 50 times lower than that of the antimonial agent. Furthermore, treatment with 86g was also more selective, resulting in less host tissue damage at the treatment site compared to that of the antimonial treatment. 5.4.5. DNA Intercalation as a Mode of Action. DNA intercalation is the insertion of molecules between the planar bases of DNA, which leads to an increase in the viscosity of the DNA when the complex concentration is increased.227 The increase in viscosity is caused by the change in the structure and mechanical properties of DNA when the intercalator, the drug of choice, binds to DNA.228 When this happens, DNA-associated processes such as replication, transcription, and repair are affected.229 The metabolic pathways of parasites are similar to

those of tumor cells; hence, it has been proposed that compounds which have effectively interacted with DNA in an intercalative mode could also show antiparasitic activity.12 DNA intercalating molecules are hence used to complex to metal complexes. These intercalating ligands can be polyaromatic systems with two or more donor atoms in close proximity to chelate metal ions. Not only are they responsible for the interaction of the metal compound with DNA, but they also act as carriers of the metal.30,15 There are several studies described below which have reported compounds which are able to intercalate DNA and exert antileishmanicidal activity on the basis of this pathway. 5.4.5.1. Gold, Silver, and Copper. Navarro et al. reported three studies involving Au(III), Ag(I), and Cu(I) complexes with the polypyridyl compounds dipyrido[3,2a: 2′,3′-c]phenazine (dppz) and dipyrido[3,2-d:2′,3′-f ]quinoxaline (dpq) (Figure 50).230−232 All four compounds [Au(dppz)2]Cl3, [Ag(dppz)2]NO3, [Cu(dppz)2]BF4, and [Ag(dpq)2]NO3 (Figure 50) were extremely effective antileishmanial candidates. [Au(dppz)2]Cl3 has a minimum inhibitory concentration (MIC) value of 3.4 nM and LD26 of 17 nM for 48 h,230 [Ag(dppz)2]NO3 had a leishmanicidal effect at 10 μM (LD23),231 and [Cu(dppz)2]BF4 showed an LD30 of 41 nM,232 after testing on L. mexicana promastigotes under similar conditions. The LD30 is the lethal dose at which 30% of the population is killed in a given period of time. Increasing the concentration of [Au(dppz)2]Cl3 increases the DNA viscosity, indicating that the mechanism of its antileishmanial activity is driven by the interaction of the metal−dppz complex with the parasite DNA.230 Both silver compounds [Ag(dppz)2]NO3 and [Ag(dpq)2]NO3 also have high affinities for DNA.231 The copper compound [Cu(dppz)2]BF4 is able to bind to DNA, and the dppz ligand is able to intercalate between the DNA base pairs.232 5.4.5.2. Antimony and Bismuth. Two dppz complexes involving Sb(III) and Bi(III), [Sb(dppz)Cl3] and [Bi(dppz)Cl3] (Figure 50) were synthesized by Lizararo-Jaimes and Demicheli et al.233 Both [Sb(dppz)Cl3] and [Bi(dppz)Cl3] were equally active against both wild-type and antimony-resistant strains of L. infantum chagasi and L. amazonensis.233 Low micromolar activity was observed for [Bi(dppz)Cl3] against L. infantum chagasi (IC50 = 0.59 μM for WT and 0.61 μM for Sb-R) and L. amazonensis (IC50 = 1.07 μM for WT and 1.12 μM for Sb-R). AE


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Figure 51. Platinum compounds containing pyridines, quinolines, and platinum(II) sterol hydrazones.

tartrate and hence are the most promising compounds from this series. 5.4.5.3. Platinum Group Metals and Other Transition Metals. Platinum group metals consist of six noble precious metallic elements, ruthenium, rhenium, palladium, osmium, iridium, and platinum, and have similar physical and chemical properties. Platinum(II) complexes were found to inhibit TR irreversibly as well as bind double-stranded DNA intercalatively.235 Three Pt(II) complexes derived from 2,2′:6′,2″terpyridine, 87a, 87b, and 88, and their analogues (Figure 51) were found to be extremely effective at inhibiting L. donovani amastigotes at 1 μM (>96% inhibition).121 Visual observations showed a loss in motility, swelling, and cytoplasm vacuolization before cellular lysis was induced.235 In 2011, Carmo et al.236 studied quinoline platinum(II) complexes 89a−89d (Figure 51). Four species of Leishmania were used in the in vitro promastigote assays: L. major, L. braziliensis, L. chagasi, and L. amazonensis. Out of the four platinum(II) quinolines synthesized, only one compound, 89b, displayed effective antileishmanial activity against L. chagasi with an IC50 value of 3.50 μg/mL, and another, 89d, had moderate activity with an IC50 value of 10.71 μg/mL against L. amazonensis and 11.00 μg/mL against L. major promastigotes. The other two complexes, 89a and 89c, displayed no activity against any Leishmania species at all. All complexes were nontoxic against the macrophage cells. The parent quinolines were more active than the derived complexes. Visbal et al. synthesised two platinum complexes, 90a and 90b (Figure 51), derived from sterol hydrazones against L. mexicana promastigotes.237 The structures provided are proposed. 90a results in a significant increase in growth inhibition at 10 μM (71%, p < 0.001), whereas the insignificant leishmanistatic activity displayed by 90b (6%, p > 0.05) could be associated with its instability in solution. Mesa-Valle and co-workers238 showed that two compounds, [H 2 (pentamidine)][Pt IV Br 6 ] and [H 2 (2-piperazinyl-1ethylamine)][PtIVCl6], affected L. donovani (LCR-L 133) DNA. Pentamidine itself is currently used as a second-line antileishmanial drug, and its mode of action involves the interference of DNA synthesis, RNA, and proteins. At 100 and 50 μg/mL, the salt [H2(pentamidine)][PtIVBr6] dramatically inhibits the incorporation of building blocks of DNA [6-3H]-

Similar low micromolar concentrations were observed for [Sb(dppz)Cl3] against L. infantum chagasi (IC50 = 0.62 μM for WT and 0.57 μM for Sb-R) and L. amazonensis (IC50 = 0.95 μM for WT and 0.92 μM for Sb-R). The mechanism of action for these two complexes has not been studied; however, the authors hypothesize that, on the basis of the studies by Navarro et al., the antileishmanial activity of [Sb(dppz)Cl3] and [Bi(dppz)Cl3] would be due to DNA intercalation.230−232 On the basis of the successful result of [Sb(dppz)Cl3], a follow-up study involving the Sb(III) complexes [Sb(dpq)Cl3], [Sb(bipy)Cl3], and [Sb(phen)Cl3] (Figure 50) with the N donor heterocycles dpq, bipyridine (bipy), and phen was published by Lizararo-Jaimes and Demicheli et al.234 Dpq and bipy ligands have extremely high selectivity indices for Sbresistant leishmaniasis, while phen exhibits antileishmanial activity through the chelation of Zn ions in Leishmania enzymes.234 Being small, planar, and nonpolar, dpq, bipy, and phen can cross cell membranes and form complexes with intracellular transition-metal ions, which in turn activates their antileishmanial effect. This factor could contribute toward the ability of the Sb(III) complexes to bypass the mechanisms against antimony for the resistant strains. [Sb(bipy)Cl3] (Figure 50) is more active than bipy, so the ligand most likely acts as an Sb carrier facilitating the delivery of Sb, leading to a synergistic effect of both ligand and metal against the parasite. Complexes [Sb(dpq)Cl3], [SbPh(dpq)Cl2], [Sb(bipy)Cl3], [SbPh(bipy)Cl2], [Sb(phen)Cl3] (Figure 50), and [SbPh(phen)Cl2]·CH3COOH, the ligands, and SbPhCl2 were found to be highly active against both WT and Sb-R L. infantum and L. amazonensis strains. Their IC50 values range from 0.25 to 19 nM, performing better than the potassium antimonyl tartrate control, which has an IC50 range of 86−110 μM against WT and an IC50 value of 3000 μM against antimony-resistant strains. It was suggested that complexes derived from [SbPhCl2] such as [SbPh(phen)Cl2]·CH3COOH and [SbPh(bipy)Cl2] (Figure 50) have both the ligand and the metal contribute toward their bioactivity. When tested on macrophages, however, [SbPhCl2]derived compounds [SbPh(phen)Cl2]·CH3COOH and [SbPh(bipy)Cl2] were also found to be far more toxic compared to the [SbCl3]-derived complexes [Sb(phen)Cl3], [Sb(bipy)Cl3], and [Sb(dpq)Cl3] (Figure 50). [Sb(phen)Cl3] and [Sb(dpq)Cl3] (Figure 50) were more selective than potassium antimonyl AF


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Figure 52. Structures of pentamidine organometallic complexes synthesized by Mbongo and Loiseau et al.242

thymidine and [4,5-3H]leucine, leading to an interruption in DNA synthesis, subsequently affecting the chromatin (DNA and histones) structure. This is visibly observed via the microscope through the disappearance and ruptures in membranes of mitochondria and the nucleus. In vivo testing showed that, when compared to that in the controls, the antileishmanial activity was significantly higher in treated Wistar rats where the parasites were reduced by 88 ± 2.6%, and in the spleen, amastigotes were reduced to 50% per gram of spleen. With [H2(2-piperazinyl-1ethylamine)][PtIVCl6], the mode of action is similar where the chromatin structure, mitochondrial membrane, and endoplasmic reticulum zones are also disrupted, with large vacuoles. Unlike [H2(pentamidine)][PtIVBr6], however, with [H2(2piperazinyl-1-ethylamine)][PtIVCl6], the nucleus of the cell appears unaffected. A study in 2013 by Franco et al.239 reported that three Pd(II) cyclometalated complexes derived from imines were more bioactive against both L. donovani promastigotes and amastigotes (IC50 = 100 mg/mL) and less cytotoxic than the pentamidine control.238 The coordination of the imine to the metal complex further increased the bioactivity of the complex without increasing the cytotoxicity, indicating that the metal ion has a role in the selectivity of the complex toward Leishmania.238 Croft et al. in 1992 tested 27 platinum(II), rhodium(III), and iridium(III) drug complexes against intracellular L. donovani amastigotes.240 Unfortunately, no structures were provided in the report. Eight compounds showed antileishmanial activity: platinum(II) pentamidine (31% inhibition at 30 μM), platinum(II) diaminocyclopentane dipropyl sulfonate succinate (56% inhibition at 10 μM), rhodium(III) mepacrine (69% inhibition at 1 μM), rhodium(III) dicyclohexyl dithiocarbamate (22% inhibition at 10 μM), iridium(III) pyrrolidine dithiocarbamate (99% inhibition at 10 μM), iridium(III) diethyl dithiocarbamate (98% inhibition at 3 μM), iridium(III) dihexyl dithiocarbamate (36% inhibition at 30 μM), and iridium(III) butyl xanthate (40% inhibition at 10 μM). Only three compounds, rhodium(III) mepacrine, iridium(III) pyrolidine dithiocarbamate, and iridium(III) diethyldithiocarbamate had an ED50 < 1 μM. ED50 refers to the median effective dose, which is the dose required to achieve 50% of the desired response in 50% of the population. These two Ir(III) complexes, iridum(III) pyrolidine dithiocarbamate and iridium(III) diethyldithiocarbamate, produced a respective 50% and 30% suppression of L. donovani amastigotes

in the liver of BALB/c mice after subcutaneous administration of 200 mg/kg for five consecutive days. Ultrastructural studies undertaken via electron microscopy showed the primary site of action to be the amastigote kinetoplast−mitochonrion complex.240 Mbongo and Loiseau241 in 1997 designed 15 square-planar organometallic complexes (Figure 52) derived from pentamidine of general formula [M2Y2L]2+·2X− or [M2Y2L]2+·X2− (M = Ir or Rh; Y = 1,5-cyclooctadiene (COD), 1,3,5,7-cyclooctatetraene (COT), or carbon monoxide (CO); L = pentamidine, and X = tetraphenylborate ([B(C6H5)4]−), NO3−, ethyl fumarate, alizarin red, mordant orange, or tetraiodophenolphthalein) and tested them in vitro against L. donovani. Four compounds showed IC50 values of 213.68 μM), the other complexes did not display any activity toward Leishmania. In the second study,124 two oxidovanadium(IV) N-acylhydrazone complexes, 95a and 95b, were tested, and only 95b displayed any activity on L. major promastigotes (IC50 value of 22.1 ± 0.6 μM) and low toxicity on mammalian cells (IC50 > 100 μM). The active

oxidovanadium complexes in both studies, 94a, 94c, and 95b (Figure 53), increased the viscosity of DNA, suggesting that the complexes act by DNA intercalation. 5.4.5.4. Triazolopyrimidines and Their Metal Complexes. Triazolopyrimidines are purine analogues which have found applications as antipyretics, pain relievers, anti-inflammatories, and antitumor, herbicidal, and fungicidal agents.245−249 The biological activity of this family of organic compounds has been investigated through a series of four studies performed by Sánchez-Moreno et al.250−253 In the first study, lanthanide complexes containing 5-methyl1,2,4-triazolo[1,5-α]pyrimidin-7-(4H)-one (HmtpO) (Figure 54) derived complexes [Ln(mtpO)3(H2O)6]·9H2O (Ln = La(III), Nd(III), Eu(III), Gd(III), Tb(III), Dy(III), Er(III)) (see Figure 54 for mtpO−) were evaluated against promastigotes and amastigotes.250 All compounds except [La(mtpO)3(H2O)6]·9H2O (IC50 = 2.8 μM) showed activity similar to that of glucantime on L. infantum promastigotes and amastigotes. [La(mtpO)3(H2O)6]·9H2O was the most active against L. infantum amastigotes and L. braziliensis promastigotes. With L. braziliensis amastigotes, [La(mtpO)3(H2O)6]·9H2O had activity similar to those of the rest of the compounds and the control glucantime. The La(III), Eu(III), Tb(III), Dy(III), and Er(III) complexes had much better selectivity when considering macrophages compared to glucantime. The La(III) complex displayed a high selectivity of SI = 54 toward the promastigotes, while the Tb(III) and Eu(III) complexes showed similar or even greater selectivity against the amastigotes (Tb(III), SI = 60; Eu(III), SI = 79). Hence, lanthanide complexes derived from triazolopyrimidines are very promising antileishmanial candidates due to their high selectivity. In the second study, five Cu(II), Zn(II), and Cd(II) compounds containing unsubstituted (tp), 5,7-dimethylated (dmtp), 7-amine-substituted (7atp) derivatives, and 2,2′bipyrimidine (bpym) (Figure 54) have been tested on L. AH


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infantum and L. braziliensis.251 The accessibility of N donor atoms in these compounds and their resemblance to the DNA nucleobases adenine and guanine allow for interesting pharmacological properties. In all metal complexes, triazolopyrimidines coordinate monodentately via N3, while the versatile binding behavior of bpym leads to mononuclear units [Cd(tp)(bpym)2(H2O)](ClO4)2 and [Cu(dmtp)2(bpym)(H2O)2](ClO4)2·H2O, dinuclear species [Cu2(tp)2(bpym)2(μbpym)(ClO4)2](ClO4)2 and [Zn2(7atp)4(μ-bpym)(H2O)4](ClO4)4·2(7atp), and the helicoidal chainlike complex {[Cd(dmtp)(H2O)(μ-bpym)2Cd(dmtp)2](ClO4)4·dmtp·H2O}n. Testing on L. infantum and L. braziliensis showed little difference between the free parent pyrimidines and the nonCd(II) metal complexes. Only the Zn(II) complex [Zn2(7atp)4(μ-bpym)(H2O)4](ClO4)4·2(7atp) showed any selectivity for the parasites (IC50 = 29.8 ± 2.0 μM on L. infantum and 27.5 ± 1.7 μM on L. braziliensis) compared to the macrophages (IC50 = 864 ± 6.1 μM). This selectivity was even higher than that of the glucantime control. The third study reported six first-row transition-metal complexes of the bioactive molecule dmtp (Figure 54).252 The complexes are in the form of [M(dmtp)2(H2O)4](ClO4)2· 2dmtp·2H2O (M = Mn(II), Fe(II), Co(II), Ni(II), Zn(II)) and [Cu(dmtp)4(H2O)2](ClO4)2·2H2O. On the basis of the IC50 values, with glucantime as a reference (18.0 μM on L. infantum promastigotes, 25.6 μM on L. braziliensis promastigotes; 31.1 μM on L. infantum amastigotes, 38.3 μM on L. braziliensis amastigotes), all complexes showed lower activity against L. infantum (IC50 = 27.7−97.7 μM) and L. braziliensis (IC50 = 10.0−45.1 μM) promastigotes, but similar activity against L. infantum (IC50 = 26.9−40.8 μM) and L. braziliensis (IC50 = 17.0−38.3 μM) amastigotes. However, the complexes showed a wide range of cytotoxicity toward the macrophages (IC50 = 91.0−903.8 μM) compared to the glucantime control (IC50 = 15.2 μM). In particular, the complexes of interest are the three Co(II), Ni(II), and Cu(II) complexes, with extremely high IC50 values of 755.3 ± 31.3, 903.8 ± 63.2, and 558.6 ± 9.8 μM, respectively. As such, the three complexes showed high selectivity indices, with SI = 18.0−23.6 toward L. infantum amastigotes and SI = 20.1−24.0 toward L. braziliensis amastigotes. In vivo studies on murine models showed the efficacy of the compounds to be in the order of Ni(II) > Co(II) > Cu(II). In the fourth and last study, seven nickel(II) triazolopyrimidine complexes derived from Hdmax (Figure 54) were tested against both L. infantum and L. braziliensis promastigotes and amastigotes.253 In general, the in vitro growth rate of Leishmania spp. was reduced, their capacity to infect cells was negatively affected, and the multiplication of the amastigotes decreased. A potential mechanism is at the level of organelle membranes, either by direct action on the microtubules or by their disorganization, leading to vacuolization, degradation, and ultimately cell death. 5.4.5.5. Tin Complexes. There are many studies involving tin complexes due to a growing interest in their ability to interact with DNA. The most recent study by Waseem et al.254 observed that ROS production was one of the mechanisms for the antileishmanial effect for tributyltin(IV) carboxylate complexes (three selected compounds shown in Figure 55). A general idea of the target sites of these complexes was obtained via the molecular target prediction tool SwissTargetPrediction.255 The seven tributyltin(IV) carboxylates were selective for L. tropica promastigotes, and all complexes showed >95% growth

Figure 55. Tributyltin(IV) carboxylate complexes synthesized by Waseem et al.254

inhibition at 20 μg/mL and very low LC50 (0.954−0.078 μg/ mL). The lowest LC50 (0.078 μg/mL) was equivalent to that of amphotericin B (0.044 μg/mL). The LC50 is the lethal concentration required to kill 50% of the population. In terms of the structure−activity relationship, the tributyltin carboxylate complex is highly cytotoxic against promastigotes, and ligand modifications can change the extent of antileishmanial activity. For example, Ch-409 (Figure 55) with phenylenebis(oxy)diacetic acid ligand was least potent among all compounds (LC50 = 0.954 μg/mL), but upon the substitution of ethoxycarbonyl at position 4 on the phenylamino group to give Ch-431 (Figure 55), it was easier to access specific leishmanial proteins, and Ch-431 was 12-fold more potent (LC50 = 0.078 ± 0.002 μg/mL) than Ch-409. A cyclohexyl moiety in another complex, Ch-442 (Figure 55), showed targeted affinity for Leishmania-specific proteins or other biomolecules, allowing selective cytotoxicity behavior with 10.84-fold higher potency than Ch-409 and 1.12-fold lower potency than Ch-431. Ch-409 was identified to bind to membrane receptors, while Ch-431 was identified to predominate enzymes and Ch-442 proteases and other enzymes.254 Compared to the sodium stibogluconate reference, which has IC50 values of 64 and 22 μg/mL against axenic log-phase promastigotes and cellular metacyclic promastigotes, the tin complexes performed better. The antileishmanial activity of the complexes was decreased by 16.38−34.38% in the presence of NaN3, an ROS scavenger for singlet oxygen species, and by 15.0−38.2% with mannitol, which scavenges hydroxyl radicals. This is an indication that the complexes also play a role in the generation of ROS to exert antileishmanial activity since this activity is decreased in the presence of ROS scavengers. A similar mechanism of action could be predicted in the studies conducted by Khan et al.,256 who reported six fivecoordinate triorganotin(IV) 2-maleimidopropanoato complexes, 96a−96f (Figure 56), which showed good antileishmanial activity when tested on L. major, L. major (Pak.), L. tropica, L. mexicana, and L. donovani promastigotes. The complexes [SnR3(OCPCH3(CH)(COCH)2] (96) (R = (a) Me, (b) Et, (c) n-Pr, (d) n-Bu, (e) Ph, (f) Bz) showed IC50 values in the range of 0.04−0.96 mM, while the free acid has an IC50 of 0.97− 1.12 mM across the strains of Leishmania. Shujha et al.257 showed tridentate ONO donor organotin(IV) complexes 97a−97f (Figure 56) intercalating into DNA on the AI


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Figure 56. Tin complexes synthesized by Khan et al.256 and Shujha et al.257 and lapachol, triphenyltin−lapachol complexes, and triphenyltin chloride studied by Rocha and Demicheli et al.258

Figure 57. Tin compounds from three studies reported by Sirajuddin et al.260−262

basis of UV−vis measurements. They were derived from N′-(2hydroxybenzylidene)formohydrazide (Figure 56) with general formula [SnR2L] (97( (R = (a) Ph, (b) Me, (c) Bu, (d) t-Bu, (e) Et, (f) Oct; L = [OC6H4CHNNCHO]. These complexes were tested against L. major promastigotes. Compared to the amphotericin B control with IC 50 = 0.50 μg/mL and pentamidine with IC50 = 5.78 μg/mL, three compounds performed very well: 97e with IC50 = 0.90 μg/mL, 97c with IC50 = 0.96 μg/mL, and 97d with IC50 = 0.98 μg/mL (Figure 56). Unfortunately, as no cytotoxic studies were performed, it was not known how selective they are. Rocha, Demicheli, and co-workers258 focused on varying the complexation of the O donor ligand lapachol (2-hydroxy-3-(3′methyl-2-butenyl)-1,4-naphthoquinone) (Figure 56) with various metals, Sn(IV), Bi(V), and Sb(V). The natural compound lapachol is active in vitro and in vivo against L. braziliensis and L. amazonensis. Tin(IV) complexes [SnPh3(Lp)] (Figure 56) and

[SnPh3Cl] (Figure 56) were the most active compounds, showing IC50 = 0.17 and 0.10 μg/mL against L. amazonensis and SI = 70.65 and 120.35 for HepG2 cells, respectively. Compared to amphotericin B (IC50 = 0.73 μg/mL on L. amazonensis and 644.59 μg/mL on HepG2, SI = 883.00), the tin complexes are slightly more active but are toxic against mice macrophages. On the other hand, the bismuth and antimony analogues were not suitable candidates as antileishmanial drugs due to their low selectivity and inactivity. Another study involving lapachol (Figure 56) by Barbosa et al.259 reported that the complex [RuCl 2 (lapachol)(dppb)], (dppb = 1,4-bis(diphenylphosphino)butane) (Figure 56) was the most potent and selective compound (IC50 = 0.14 μg/mL, SI = 17.5) among four other compounds (SI = 4.7−5.9) toward L. amazonensis, comparable with the control amphotericin B (IC50 = 0.13 μg/ mL). AJ


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Figure 58. Zn complexes synthesized by Uddin and Sirrajuddin et al.264

Sirajuddin et al. reported three studies260−262 showing excellent responses from tin peptide complexes on Leishmania. In these studies, via cyclic voltammetry and molecular docking, there was a focus on showing how these tin complexes exert their antileishmanial activity by acting as potent intercalators of DNA and inserting themselves into the nitrogen-containing bases of DNA. This insertion results in hypochronism (increase in absorbance) and bathochromic shifts (change to longer wavelength/lower frequency), detectable via UV−vis spectroscopy. Both oxidation and reduction behaviors were also observed in the presence of the DNA strand, which may cause the degradation of the genetic material. The first study from Sirajuddin et al.260 tested 14 novel organotin(IV) peptide compounds derived from N-[(2methoxyphenyl)]-4-oxo-4-[oxy]butanamide (LH) (98) (Figure 57), [SnR3L] (99a−99f), [SnR2L2] (100g−100n) [Sn(CH3)3L(bpy)] (101), and [Sn(CH3)3L(phen)] (102), and against L. major promastigotes. All complexes displayed strong antileishmanial activity with a wide IC50 range of 3.90 × 10−5 to 0.0922 μg/mL, more potent than the amphotericin B control (IC50 = 0.56 μg/mL). [Sn(CH3)3L(bpy)] (101) and [Sn(CH3)3L(phen)] (102) had the highest IC50 values of 0.0156 and 0.0922 μg/mL, respectively, followed by the diorganotin(IV) compounds 100g−100n (IC50 range = 5.89 × 10−4 to 1.92 × 10−3 μg/mL) and then by the trisorganotin(IV) compounds 99a−99f (IC50 range = 3.90 × 10−5 to 9.96 × 10−5 μg/mL). It is possible that the trisorganotin(IV) compounds have higher bioactivity than the corresponding diorganotin(IV) compounds due to their greater lipophilicity and permeability through the cell membrane. In the second study, 11 organotin(IV) peptide complexes, 99a−99e, 100h−100n, and 101 (Figure 56), from the previously discussed study,260 underwent further testing on L. tropica promastigotes and intracellular amastigotes. Unfortunately, no information on the exact IC50 values was provided, but from visual inspection of the column graphs given, the complexes generally showed good activity on L. tropica promastigotes (IC50 < 0.1 μg/mL,) and amastigotes (IC50 < 1 μg/mL, Glucantime 5.5 μg/mL), while retaining nontoxicity for macrophages (LD50 > 100 μg/mL). The third study from Sirajuddin et al.262 investigated 10 organotin(IV) carboxylates derived from HL = N-[(2-methoxy5-nitrophenyl)]-4-oxo-4-[oxy]butanamide (103) (Figure 57): R3SnL (104) (R = (a) CH3, (b) C2H5, (c) C4H9, (d) C6H5, (e)

C6H11) and R2SnL2 (105) (R = (f) CH3, (g) C4H9, (h) C6H5, (j) C(CH3)3, (k) C8H17). Compound 105k was the most potent complex against promastigote forms of L. major, exhibiting an IC50 value of 0.98 ± 0.06 μM as compared to amphotericin B (IC50 = 0.29 ± 0.05 μM). The trisorganotin(IV) complexes 104a−104e (Figure 57) displayed an IC50 range of 3.23 ± 0.28 to 5.12 ± 0.44 μM, while the diorganotin(IV) complexes 105f− 105j (Figure 57) showed slightly lower IC50 values in the range of 1.23 ± 0.07 to 2.26 ± 0.08 μM. Compounds 104a−104e and 105f−105k (Figure 56) tested with kidney fibroblast assays showed a range of IC50 values, 1.24 ± 0.25 to 3.29 ± 0.33 μM, respectively. As there is little difference between the toxicity on L. major promastigotes and fibroblast cells, this indicates that these complexes are not selective for Leishmania. Early studies showed that tin peptide complexes could be bound to the zinc metalloprotease leishmanolysin GP63 receptor.261,263 This receptor is the most abundant protein on the surface of the Leishmania promastigote. This binding most likely resulted in the formation of a receptor−mediator inlet of the synthetic peptide derivatives into the parasite cells, where they were then bound to DNA. This led to a redox reaction between DNA and the above compounds tested in Sirajuddin’s studies, leading to the degradation of DNA and thus apoptosis. On the basis of measurement with UV−vis spectroscopy, the synthesized compounds show hypochromism and minor red shift upon interaction with DNA, indicating that they can intercalate and insert themselves into the nitrogenous bases of DNA. 5.4.5.6. Zinc and Mercury. Uddin and Sirrajuddin et al.264 conducted additional studies showing that Zn complexes were able to intercalate with DNA as a mechanism of action. Six zinc(II) and mercury(II) carboxylate complexes, 106a−106f (Figure 58), were tested on L. major promastigotes, and it was shown that the Zn complexes 106a (LD50 = 1.25 μg/mL), 106c (LD50 = 0.95 μg/mL), and 106d (LD50 = 0.38 μg/mL) (Figure 58) had higher activity compared with amphotericin B (LD50 = 3.42 μg/mL). Furthermore, addition of 2,2′-bipyridine and 1,10-phenanthroline improved the biological properties of the complexes, with biological activity in the order 106d > 106c > 106a. This could also be observed in the mercury(II) species, with the most active species 106f (LD50 = 9.63 μg/mL) > 106e (LD50 = 12.35 μg/mL) > 106b (LD50 = 14.83 μg/mL). This observed phenomenon may be due to the better binding affinity of the aromatic coligands, which allow stacking between the AK


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Figure 59. Set of Au(III), Pd(II), and Re(V) compounds synthesized by Fricker et al.118

Figure 60. Palladacycle complex DPPE 1.2 and organotellurane complexes RT-01 synthesized by Lima and Cunha et al.266 and RF07 synthesized by Pimental and Cunha et al.267

In another study, Paladi et al.265 reported a palladacycle complex, DPPE 1.2 (Figure 60), whose mode of action is the inhibition of cysteine protease activity of amastigotes, as well as cathepsin B activity. This complex eliminated axenic L. amazonensis promastigotes at nanomolar concentrations (IC50 = 2.13 nM), while intracellular parasites were killed (IC50 = 128.35 nM), and the drug displayed 10-fold less toxicity to macrophages (IC50 = 1267 nM). After one month in murine models, a significant decrease in the size of lesions on affected animals and a decrease of 97% of the parasite burden when compared to the controls indicated that this compound is effective in vivo and in vitro. Within the past 10 years, organotellurane compounds have been shown to play a role in the inhibition of specific cysteine proteases, such as cathepsin B.268,269 On this basis, two organotellurane complexes (Figure 60) have been developed in two separate studies. In the first study, Lima and Cunha et al.266 synthesized the organotellurane (IV) compound RT-01 (Figure 60) by reacting tellurium tetrachloride with propargyl alcohol and triethylbenzylammonium chloride. In vitro screening against L. amazonensis promastigotes showed the IC50 value after 24 h incubation to be 2 μg/mL, with the RT-01-treated promastigotes losing their ability to proliferate. Screening with extracellular amastigotes exposed to 2 μg/mL RT-01 for 48 h completely prevented the amastigotes from transforming into their promastigote form. In vivo studies on L. amazonensisinfected mice showed intralesional administration of 720 μg/kg/

DNA base pairs. These aromatic moieties in turn have greater lipophilic character, which ensures cell penetration, association with cellular sites, and reaching the target after crossing the cell membrane. 5.4.6. Cathepsin B as the Target of Interest. Some studies have reported that thiol-containing cysteine proteases such as cathepsin B are targets of interest. This is due to two main reasons: cysteine protease knockouts of L. mexicana have been shown to display a loss in infectivity in both macrophage and in vivo models of cutaneous leishmaniasis, and inhibition of the cathepsin B-like cysteine protease of L. major leads to the inhibition of parasite growth in vitro, resulting in the complete eradication of pathology in in vivo mice models.118 Fricker et al.118 reported the activity of six Au(III) (107a− 107f), six Pd(II) (108a−108f), and six Re(V) (109a−1099f) complexes (Figure 59) on cathepsin B from L. major. The Au(III) complexes from this series appear to be highly active (0.18−1.29 μM). The rhenium(V) compounds 109a−109f were very strong inhibitors of cathepsin B but were cytotoxic. Only the palladium compound 108e was extremely effective upon testing at 10 μM against L. major, L. mexicana, and L. donovani promastigotes, showing 100% of the promastigotes were eliminated after 5 days of culture. Complete inhibition of promastigote growth (100% for L. major and L. mexicana after 4 days and 99% for L. donovani at 8 days post-treatment) and a reduction in intracellular amastigotes could be observed at 1 μM 108e in all three Leishmania species. AL


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Figure 61. Tris-substituted, bis-substituted, and monosubstituted bismuth thiocarboxylates.

amazonensis. A 10 mg/mL concentration of ARAGAL−VO and 25 mg/mL GMPOLY−VO and XGJ−VO led to increases of 562%, 1054%, and 523% for IL-1β, respectively. For IL-6 at the same concentration, the levels increased by 539% and 794% for ARAGAL−VO and GMPOLY−VO, respectively. Both the polysaccharides and complexes also show activity against amastigotes and promastigotes of L. amazonensis, which was better than the reference glucantime (300 μg/mL for 60% inhibition on promastigotes). XGJ−VO showed the lowest IC50 value (6.2 mg/mL; 0.07 mg/mL vanadium); that for ARAGAL− VO was 6.5 mg/mL (0.21 mg/mL vanadium), and that for GMPOLY−VO was 7.3 mg/mL (0.06 mg/mL vanadium).

day of RT-01 delayed the onset of lesion development and showed a reduced parasite tissue burden 11 times lower compared to that for untreated mice. This result was comparable to that of treatment with the reference drug meglumine antimonate. In the second study, Pimental and Cunha et al.267 synthesized another organotellurane(IV) complex, RF07 (Figure 60), through reaction of (p-methoxyphenyl)tellurium with 1ethynyl-1-cyclohexanol. In vitro studies with L. infantum chagasi amastigotes showed a low IC50 value of 0.5 μM and an IC50 value of 5.4 μM toward the macrophages. In vivo studies with hamsters infected with L. infantum chagasi showed a reduction of the parasite burden by 99.6% after one month of intraperitoneal multidose treatment. Spectrofluorometric assay results suggested that RF07 inhibits cathepsin B by incubating increasing concentrations of RF07 with cathepsin-like cysteine protease substrates with extracts of L. infantum chagasi amastigotes in the presence of the reducing agent dithiothreitol (DTT). 5.4.7. Interleukin-1β. Interleukin-1β (IL-1β) is a proinflammatory cytokine playing important roles in immunity against Leishmania infection and the outcome of the disease. It facilitates the expression of nitric oxide synthase 2 (NOS2), another enzyme that is required for NO-mediated restriction of Leishmania replication in macrophages.270 IL-1β signaling indirectly determines the severity of disease in humans. Polymorphism within the human IL1B gene is associated with severity of the disease.271,272 The regulation of IL-1β can lead to either the development of severe cases of visceral leishmaniasis in patients infected with L. infantum chagasi or uncontrolled diffuse forms of cutaneous leishmaniasis in patients infected with L. mexicana.271,272 When activated, macrophages can release mediators such as superoxide anions, nitric oxide, and proinflammatory interleukin such as IL-1β, which can culminate in the death of parasites. Being hosts to Leishmania parasites, the macrophages are hence targets for activation. Adriazola and Noleto et al. in 2014273 reported that the polysaccharide galactomannan (GALMAN-A) and its oxidovanadium (IV/V) complex GALMAN-A−VO2+/ VO3+ both promote a significant increase in IL-1β production and also showed activity against L. amazonensis amastigotes, reaching 60% activity at 100 and 25 μg/mL, respectively. The polysaccharides are activators of IL-1β and IL-6, and this was further increased in the presence of vanadium complexes. At 25 μg/mL, GALMAN-A increased IL-1β production by 448%, which is 5.5 times higher than that of the control, while the vanadium complex at 10 μg/mL increased IL-1β production by 727%. GALMAN-A and GALMAN-A−VO2+/VO3+ (IC50 = 74.4 μg/mL) are 3 and 12 times more active, respectively, when compared against the glucantime control. Amaral and Noleto et al.274 continued their study by investigating the leishmaniacidal effects of three polysaccharides, arabinogalactan (ARAGAL), galactomannan (GMPOLY), and xyoglucan (XGJ), and their oxidovanadium(IV/V) complexes ARAGAL−VO, GMPOLY− VO, and XGJ−VO on intracellular amastigotes of L.

5.5. Bismuth in Medicine

The current antileishmanial drugs are antimony-based and are highly effective but are toxic. In some areas where antimony resistance is prevalent, they cannot be used. Another metal, bismuth, has similar chemical properties due to being in the same group (group 15). It is known as the least toxic heavy metal and is readily available in the United States as Pepto-Bismol, an oral suspension or tablet of bismuth subsalicylate used to treat diarrhea and stomach upsets, as well as stomach ulcers. Furthermore, no reports of bismuth resistance are known, which makes bismuth an ideal target to study as an antileishmanial candidate. The mechanism of action of these bismuth compounds has not yet been investigated; however, it is believed that they act in a manner similar to that of the current antimonial drugs. In 2011, Andrews and co-workers275 explored the bis- and triscarboxylatobismuth(III) complexes [BiPhL2] and [BiL3] derived from simple substituted benzoic acids, and the triscarboxylatobismuth(III) complexes from NSAIDs. In vitro studies on L. major promastigotes and human fibroblasts suggested that, in general, the toxicity of Bi complexes was both ligand and metal dependent. The NSAIDs and their bismuth complexes showed no activity against Leishmania at concentrations of 100 μM, while AM


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Figure 62. Bismuth(III) monophenyl and tris(heterocyclic thiol)s.

Figure 63. Bismuth(III) α-hydroxcarboxylates tested on L. major.

selectivity for Leishmania, with the lowest IC50 value of 0.17 μM, and expresses nontoxicity toward the fibroblast cells at the same concentration. Another study by Loh and Andrews et al.279 in 2015 reported the synthesis and in vitro assay results of four bismuth(III) αhydroxycarboxylates: [Bi(H2-tar)(H3-tar)] (Figure 63) derived from tartaric acid, [Bi(man)(H-man)(H2O)] (Figure 63) derived from mandelic acid, and [Bi(gly)(H-gly)] and [Bi(gly)(NO3)(H2O)] (Figure 63) derived from glycolic acid. These complexes were found to be nontoxic against both the L. major promastigotes and human fibroblast cells. With amastigote studies, however, the two glycolate complexes [Bi(gly)(H-gly)] and [Bi(gly)(NO3)(H2O)] showed good selective toxicity toward amastigotes at 50 μM. [Bi(gly)(H-gly)] reduced the percentage viability of infected macrophages to 7.5 ± 3.8%, and [Bi(gly)(NO3)(H2O)] reduced the percentage even further to 1.8 ± 0.9%. The displacement of a glycolate group with nitrate from [Bi(gly)(H-gly)] results in [Bi(gly)(NO3)(H2O)], which is shown to provide better antiparasitic activity, and this result is comparable to that of amphotericin B at a similar concentration of 0.54 μM. So far, most of the studies from Andrews et al. have mainly focused on the Bi(III) complexes as the active reagent. More recently, there was a shift toward a focus on the Bi(V) compounds as prodrugs, which presumably would then be reduced to the more active Bi(III) compounds in vitro. The mechanism of action of bismuth on the leishmanial parasite is not yet known nor understood, with only the mechanisms from first-line antimony treatments to extrapolate from. Other Bi(V) studies by Islam and Demicheli et al.280 suggested that organometallic salts such as [BiPh3CO3] are also able to play a role in antileishmanial activity. The

110b and 110b were insoluble and were not tested. The low IC50 value of 0.39 μM for the bis-substituted compounds 111c and 111e suggested that the presence of the phenyl moiety, presence of Bi3+/BiO+ ions, and degree of substitution with the thiocarboxylate ligands play a role in the higher activity of bissubstituted compounds. However, despite the high bioactivity of both monosubstituted and bis-substituted compounds, they are poorly selective and are toxic to the mammalian fibroblast cells. In 2014, Andrews et al.277 performed a number of in vitro assays with bismuth(III) tris-substituted β-thioxoketonates and their parent compounds on L. major promastigotes and fibroblasts. Although β-thioxoketonates themselves were excellent candidates for antileishmanial drugs, the coordination to the bismuth center unfortunately did not improve their selectivity. In fact, the bismuth thioxoketonate complexes were less bioactive compared to the β-thioxoketones. The complexes also displayed toxicity to both the promastigotes and the fibroblasts in a dose-dependent manner. The parent βthioxoketones were selective for the L. major promastigotes and nontoxic to the fibroblasts cells. Two β-thioxoketones, [C6H5C(O)CH2C(S)C6H5] and [C5H4NC(O)CH2C(S)C6H5] eliminated approximately 80% of the L. major promastigotes at 25 μM (6.0 μg/mL), and this was comparable to that of amphotericin B. In 2015, Luqman and Andrews et al.278 tested heterocyclic thiols and their four bismuth(III) analogues on L. major promastigotes. The monophenyl derivatives [BiPh(MBT)2] and [BiPh(4-BrMTD)2] (Figure 62), derived from 4-phenylthiazole-2-thiol and 4-(4-bromophenyl)thiazole-2-thiol (Figure 62), respectively, are more active than their tris-thiolato analogues [Bi(MBT)3] (Figure 62) and [Bi(4-BrMTD)3] (Figure 62). Only [BiPh(MBT)2] shows some form of AN


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Figure 64. Selectivity trends across the library of trisarylbismuth(V) dicarboxylates synthesized by Ong and Andrews et al.197,198

human fibroblast cells. In particular, two complexes, [Bi(oTol)3(L8)2] and [Bi(m-Tol)3(L11)2] (HL8 = diflunisal; HL11 = aspirin) (Figure 64), had selectivity ratios of 114 and 838 at 6.12 μM, which were far higher than the usual range of 20−60 shown by the rest of the complexes. [Bi(o-Tol)3(L8)2] and [Bi(m-Tol)3(L11)2] also showed low IC50 values of 0.57 ± 0.02 and 0.76 ± 0.02 μM, respectively, on L. major promastigotes. Stability studies on two representative compounds from the phenyl and tolyl complexes showed that their stability in D2O and d6-DMSO did not extend to cell culture media (half-life of approximately 1.2 h), with glucose being a contributing factor in the reduction to BiPh3 and Bi(Tol)3, respectively.

antileishmanial activities of three Bi(V) compounds, [BiPh3CO3], [BiPh3(asp)2], and [BiPh3(ace)2] (aspH = aspirin; aceH = 3-acetoxybenzoic acid) toward L. infantum and L. amazonensis promastigotes were studied. All the bismuth complexes showed promising antileishmanial activity. [BiPh3CO3] was the most active compound with IC50 values of 1.1 ± 0.37 and 2.7 ± 0.34 μM for L. infantum and L. amazonensis, respectively; the parent acids themselves showed no antileishmanial activity. Compared to potassium antimony tartrate (TA),233 which is a source of Sb(III), the bismuth complexes have performed much better than the control. Two Bi(V) studies carried out over 2014−2015197,198 by Ong and Andrews et al. studied the structure−activity relationship of a series of pentavalent trisarylbismuth(V) dicarboxylates (aryl = phenyl and o-, m-, and p-tolyl). The bismuth complexes (Figure 64) displayed a range of IC50 values, 0.57−1.11 μM, comparable to that of the reference amphotericin B (IC50 = 1.02 μM). Selectivity ratios [SI (selectivity index) = IC50 of fibroblasts/ IC50 of promastigotes] were calculated, and the parent compounds Bi(o-Tol)3 and Bi(p-Tol)3 displayed significant antileishmanial activities (IC50 = 0.85 and 0.98 μM) and selectivity indices (13.0 and 29.0). This suggested that the aryl group controlled the nontoxicity toward the human fibroblasts, and the carboxylates controlled activity toward the promastigotes. The phenyl and p-tolyl analogues were the least selective complexes (SI < 7), followed by the best performing o- and mtolyl complexes with SI values of 11−20. At concentrations above 12.5 μM, many complexes showed their toxicity toward the fibroblast cells. Below 10 μM, the complexes were more discriminating between the leishmania promastigotes and the

5.6. Encapsulation as a Mode of Delivery

5.6.1. Background on Types of Encapsulation. There are many types of encapsulation possible, depending on the physical properties of the compound to be encapsulated, and these are known as disperse systems. Disperse systems consist of the disperse phase, made up of particles or droplets dispersed through the continuous phase. These phases may be colloidal dispersions (1 nm to 1 μm), such as surfactant micelles or coarse dispersions, e.g., emulsions, suspensions, foams, and aerosols.281 Colloids can be broadly classified as lyophobic (solvent hating = hydrophobic in aqueous systems) or lyophilic (= hydrophilic in aqueous systems). Emulsions are usually dispersions of oil in water or water in oil.281 They are stabilized by an interfacial film of surfactant or hydrophilic polymer around the dispersed droplets.281 Being unstable systems, the emulsion will separate into two phases if droplet growth is not controlled. Suspensions may by stabilized by controlling the aggregation of the dispersed particles by addition of electrolytes or ionic surfactants.281 AO


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target cells. In vitro tests demonstrated a 2.5−3-fold higher antiparasitic activity of Sb(V) nanohybrid hydrosols, when compared to a solution of meglumine antimonate (glucantime). A similar comparison for in vivo treatment of experimental cutaneous leishmaniasis with Sb(V) nanohybrids showed a more effective decrease in the lesions by 1.75−1.85-fold. Microimages of tissue fragments confirmed the presence of nanoparticles (NPs) inside the cytoplasm of infected macrophages. Sb2O5 NPs penetrate directly into the affected cells, creating a high local concentration of the drug, a precondition to overcoming the parasite resistance to molecular forms of pentavalent antimonials. The nanohybrids are more effective at a lower dose, when compared to glucantime. It is suggested that the new form of treatment has the potential to reduce and simplify the course of cutaneous leishmaniasis treatment. At the same time, Sb2O5·nH2O hydrosols provide an opportunity to avoid toxic antimony(V) spreading throughout the body. In 2013, Fernandes, Demicheli, and co-workers285 synthesized two amphiphilic nanoassemblies involving Sb(V) complexes [SbL8] and [SbL10] derived from the alkylmethylglucamides N-octanoyl-N-methylglucamide, [L8], and N-decanoylN-methylglucamide, [L10], with carbon chains of 8 and 10, respectively (Figure 66). These were targeted as orally administered drug candidates for leishmaniasis. [SbL8] and [SbL10] were administered orally to mice infected with L. infantum at a dosage of 200 mg of Sb/kg of body mass/day for 20 days, and glucantime was used as comparison. Both compounds gave a similar extent of parasite suppression (>99.96%) similar to that of glucantime administered via intraperitoneal injection at 80 mg of Sb/kg/day. There was a significant reduction in the liver and spleen parasite burdens as compared to that in mice of the control group treated with saline. It was also found that complexation of the toxic N-decanoyl-N-methylglucamide, [L8], to Sb(V) gave rise to reduced toxicity of the complex [SbL8]. It is assumed that the antileishmanial action of [SbL8] is derived from the reduction of Sb(V) to Sb(III), a known and accepted model for the mechanism of action of the Sb(V) complexes. These amphiphilic antimony(V) complexes are hence the most promising candidates for the oral treatment of VL. From the previous work,285 Lanza and Demicheli et al.286 introduced a new concept of the “polarity-sensitive nanocarrier” and investigated its influence on the oral bioavailability of Sb to optimize an oral formulation of [SbL8] for the treatment of cutaneous leishmaniasis. By interfering in the structural organization of these nanoassemblies, the structural organization of [SbL8] nanoassemblies was manipulated through addition of propylene glycol (PG) to the aqueous dispersion of [SbL8]. The presence of 50% (v/v) PG resulted in the loss of the hydrophobic microenvironment, as evidenced by fluorescence probing. However, nanostructures were still present, as demonstrated by dynamic light scattering, small-angle X-ray scattering, and atomic force microscopy (AFM). A remarkable property of these nanoassemblies, as revealed by AFM analysis, is the flexibility of their supramolecular organization, which

Above the critical micelle concentration (CMC) of surfactants, micelles form. Micellar solutions are stable dispersions within the true colloidal size range (1 nm to 1 μm).281 Unlike the other colloidal dispersions, there is a dynamic equilibrium between the micelles and the free surfactant molecules in solution. The micelles continuously break down and re-form in solution. Generally, micelles have an interior core similar to a liquid hydrocarbon, and this is where poorly soluble drug compounds can be located and solubilized.281 5.6.2. Studies Involving Encapsulation. The following studies in this section are targeting various encapsulated forms of the compounds to decrease cytotoxicity and improve selectivity. For example, liposomal amphotericin B displays a significant reduction in toxicity and improvement in potency (i.e., lower dose for the same treatment effect) compared to nonliposomal amphotericin B.173,282 Some of the encapulsation reagents also work in a synergistic manner as they themselves exert antileishmanial activity, thus improving activity when coupled with the drug itself. The studies included are metal complexes delivered as various types of encapsulations. Antimisiaris, Iannou, and Loiseau283 in 2003 prepared four arsonoliposome formulations: two arsenic(V) lipids with C12 and C16 acyl chains (Figure 65), with two types of formulations

Figure 65. C12 and C16 arsenic(V) liposomal formulations synthesized by Antimisiaris, Iannou, and Loiseau.283

for each, phosphotidylcholine (PC) and cholesterol and just cholesterol alone. It was shown that the arsonoliposomes with the higher acyl chain number (C16) had a higher activity compared to the C12 analogue. It was necessary to have the arsonolipids in the form of arsonoliposomes, as the unformulated C12 and C16 arsonolipids in a DMSO solution have very little biological activity (IC50 > 100 μM). After 72 h of incubation, the IC50 ranges for the liposomes are 4.72−11.60 μM on the L. donovani DD8 wild-type strain, 0.81−2.33 μM on the L. donovani DD8 amphotericin B-resistant strain, 0.40−2.31 μM on the L. donovani L82 wild-type strain, and 0.21−1.70 μM on the L. donovani L82 miltefosine-resistant strain. This indicates that the prepared formulations were more potent against the resistant strains. In vivo studies on BALB/c mice with 200 μL/0.54 mg of arsonolipid showed an accumulation of high amounts of arsenic in the liver, which is favorable for combating visceral leishmaniasis, where the parasites are located mainly in the liver. Franco and Grafova et al.284 decided to encapsulate Sb2O5 in the form of nanoscaled hydrosols to enhance therapeutic potency and to increase the Sb(V) concentration within the

Figure 66. Two parent compounds of the Sb(V) amphiphilic nanoassemblies.285,286 AP


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Figure 67. Structures of a few organic antifilarial drugs.

Figure 68. Ruthenium complexes of paa, pbp, bbp, tptz, and bppz ligands. paa = pyridine-2-carbaldehyde azine, pbp = p-phenylenebis(picoline)aldimine, bbp = p-biphenylenebis(picoline)aldimine, tptz = 2,4,6-tris(2-pyridyl)-1,3,5-triazine, and bppz = 2,3-bis(2-pyridyl)pyrazine.

6. LYMPHATIC FILARIASIS

showed changes as a function of the solvent and substrate polarities. The formulation of [SbL8] in 1:1 water−PG given orally to mice promoted significantly higher and more sustained serum levels of Sb, when compared to SbL8 in water. The new formulation, when given as repeated doses (200 mg of Sb/kg/ day) to BALB/c mice infected with L. amazonensis, was significantly more effective in reducing the lesion parasite burden, compared to [SbL8] in water, and even the conventional drug glucantime given intraperitoneally at the same dose. Last but not least, Frézard and Demicheli et al.287 demonstrated that heating a meglumine antimonate (MA)−βcyclodextrin (CD) mixture still produced significantly lower serum Sb levels. This in turn induced depolymerization of MA from high molecular weight Sb complexes into a 1:1 Sb− meglumine complex, resulting in an enhanced oral bioavailability of Sb. The ability of the MA−CD composition to act as a sustained release system of the antimonial drug MA was also discussed, suggesting that this property may result in a change of the drug absorption site in the gastrointestinal tract.

6.1. Introduction and Main Challenges for Treatment of Lymphatic Filariasis

Lymphatic filariasis (LF), commonly known as elephantiasis, is one of the most common mosquito-borne diseases worldwide.288 The infection occurs when filarial parasites are transmitted to humans through mosquitoes and causes lymphatic damage and swelling that leads to abnormal enlargement of body parts, causing pain and permanent or long-term disability. According to WHO, currently 856 million people in 52 countries require urgent chemotherapy to prevent the spread of this infection.289 Current antifilarial drugs used for the treatment of LF are diethylcarbamazine (DEC), ivermectin (IVM), albendazole (ALB), levamisole hydrochloride, suramin, and moxidectin (MOX). (Figure 67) These organic drugs are mainly targeted at microfilaremia (mf) and associated with low macrofilaricidal activity. During treatment with these organic drugs, the macroparasites survived and reappeared after several months of treatment. It is therefore necessary to develop a new drug delivery system to target adult parasites. In a review, Singh et al. summarized the current status of antifilarial agents and AQ


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their activity and modes of action.288 There are only a few papers on inorganic antifilarial agents in the literature.

infected blackflies of the genus Simulium.293,294 It affects over 37 million people and is a risk in populations of over 120 million, mainly in tropical countries of sub-Saharan Africa, Yemen, and parts of Latin America. The main symptoms of the disease are skin irritations and eye lesions, which can ultimately lead to blindness. No vaccine or medications are yet available to prevent infection with O. volvulus. The only available drug in the market against microfilaricidal onchocerciasis is ivermectin (Figure 67), and no current drug is effective against macrofilariae.


Pandey and co-workers reported a series of mono- and binuclear ruthenium(II) polypyridyl and pyridylazine complexes of formulas [RuH(CO)(PPh3)2(L)]+, [RuH(CO)(PPh3)2(μ-L)RuH(CO)(PPh3)2]2+, and [RuH(CO)(PPh3)2(L)]+ [L = pyridine-2-carbaldehyde azine (paa), p-phenylenebis(picoline)aldimine (pbp), p-biphenylenebis(picoline)aldimine (bbp), 2,4,6-tris(2-pyridyl)-1,3,5-triazine (tptz), and 2,3-bis(2pyridyl)pyrazine (bppz)] (Figure 68). They described the DNA topoisomerase II (topo II) inhibition activity of these complexes in vitro against filarial parasite Setaria cervi.290 The results suggest that the filarial parasite inhibition activity of these complexes depends upon the number and type of coordinated and uncoordinated donor nitrogen atoms present in the pyridyl or azine group. In complex 113f (Figure 68), the “tptz” group has six nitrogen atoms, of which only two are coordinated to the metal center and the other four remain uncoordinated. This complex showed higher activity (95% inhibition) compared to other complexes. A moderate DNA binding ability of all the complexes was observed. Loiseau et al. investigated the potential antifilarial activity of several iridium, rhodium, ruthenium, palladium, and platinum organometallic complexes in vitro against two models: infective larvae of Molinema dessetae and the adult female of Brugia pahangi.291 The biological results were compared with those of several standard organic antifilarial drugs. Ir(I)−COD− pentamidine tetraphenylborate (Figure 69) was found to be


In order to develop novel antionchocercal drug candidates which could work against both microfilaricidal parasites and adult parasites, Mainsah et al. reported several Cu(II) and Zn(II) complexes of N′-(3-methoxybenzylidene)isonicotinoylhydrazone (L1) and N′-(4-methoxybenzylidene)isonicotinoylhydrazone (L2).295 All compounds were studied against Onchocerca ochengi parasite at a concentration of 20 μg/ mL. The organic ligands and Zn(II) complexes did not show any antionchocercal activity, while Cu complexes CuIIL1 (IC50 = 5.0 μg/mL) and CuIIL2 (IC50 = 10 μg/mL) (Figure 70) were found

Figure 70. Cu compound of ligands N′-(3-methoxybenzylidene)isonicotinoylhydrazone (L1) and N′-(4-methoxybenzylidene)isonicotinoylhydrazone (L2).

to be more active among the series and showed significant antimicrofilaricidal activity. Unfortunately, the complexes were not well-characterized. Both complexes were nontoxic to monkey kidney epithelial (LLCMK2) cells and showed a selectivity index greater than 2. These two active complexes were assayed against adult worms of O. ochengi. At a concentration 20 μg/mL, complex CuIIL2 was inactive, while complex CuIIL1 showed 100% inhibition at a concentration of 10 μg/mL.

Figure 69. Structure of iridium(I) 1,5-cyclooctadiene pentamidine tetraphenylborate.

more active (EC50 = 6 ± 1 μM) among the series against infective larvae of M. dessetae after a 7 day incubation period, although this compound remained 5-fold less active compared with the reference drug pentamidine isethionate. In the 2aminobenzothiazole series, the ruthenium complex ruthenium(III) 2-aminobenzothiazole was found to be a more potent (EC50 = 14 ± 1 μM) antifilarial agent than the iridium complex iridium(III) 2-aminobenzothiazole (EC50 = 111 ± 12 μM) and the standard drug 2-aminobenzothiazole (EC50 = 35 ± 3 μM). In vitro evaluation on B. pahangi adult worms was performed at a concentration of 20 mM in 100% DMSO solution. Among all the complexes, a few platinum complexes (Pt−DDH−Nacetylleucine and Pt−diminazene) were found to kill the adult parasite B. pahangi after 4 days of incubation.

8. SCHISOTOSOMIASIS Schistosomiasis, a parasitic disease caused through infection by flatworms, is also known as bilharzia or bilharziosis in many countries. It was named after the German physician Theodor Bilharz, who, in 1851, first identified it as the cause of a certain type of urinary infection.296 The World Health Organization (WHO) regards the disease as a neglected tropical disease, with an estimated 732 million people being vulnerable to infection worldwide. The majority of patients are school-aged children and young adults.297 It is estimated that 218 million people required preventive treatment for schistosomiasis in 2016, while only 88 million people were reported to have received preventive treatment.298 This disease is an intravascular debilitating disease, and infection occurs when the larval forms of the parasite, known as cercariae, are released from aquatic freshwater snails (their intermediate host) and penetrate the skin during water contact. Once inside a human host, cercariae transform into schistosomula and are transported to the portal circulation of the liver, where they mature and mate in the bloodstream.

7. ONCHOCERCIASIS (RIVER BLINDNESS) 7.1. Introduction and Main Challenges for Treatment of Onochocerciasis

Onchocerciasis (river blindness) is one of the NTDs caused by the filarial worm Onchocerca volvulus.292 The infection is commonly transmitted to humans through the bite of parasiteAR


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Human schistosomiasis is caused by five species of parasitic worms: Schistosoma hematobium, Schistosoma intercalatum, Schistosoma japonicum, Schistosoma mansoni, and Schistosoma mekongi. The distribution of the different species depends on the snail hosts. S. mansoni is transmitted by Biomphalaria snails and causes intestinal and hepatic schistosomiasis in Africa, the Arabian peninsula, and South America.299 S. hematobium is transmitted by Bulinus snails and causes urinary schistosomiasis in Africa and the Arabian peninsula. S. japonicum is transmitted by the amphibian snail Oncomelania and causes intestinal and hepatosplenic schistosomiasis in China, the Philippines, and Indonesia.

can infect the human host within 72 h (Figure 71), entering the human by skin contact with water. The cercariae then migrate into the blood via the liver and lungs, differentiating into the form known as “schistosomula” or immature worms. Male and female schistosomula mature within 4−6 weeks within the portal vein, couple together, and then migrate to either the perivesicular or mesenteric venous plexus to start the cycle again (Figure 71). 8.2. Pathology

Acute schistosomiasis, otherwise known as Katayama fever, is a systemic hypersensitive reaction to the migrating schistosomulae. It occurs from a few weeks to months after the primary infection. This is characterized by symptoms such as fever, fatigue, myalgia, cough, and increased levels of white blood cells. This disease can heal spontaneously within 2−10 weeks, but there is also the chance of developing more serious symptoms such as weight loss, difficulty with breathing, diarrhea, diffuse abdominal pain, blood toxicity, swelling of the liver and spleen, and rash. Chronic schistosomiasis is comprised of urinary, intestinal, hepatic, and ectopic schistosomiasis, where the symptoms include abdominal pain, enlarged liver, blood in the stool or in urine, and problems passing urine. There is a possibility that chronic schistosomiasis can increase the risk of bladder cancer.

8.1. Life Cycle of Schistosoma

The life cycle of the schistosomula parasite consists of two stages: mature schistosomes and cercarial larvae.300 The mature schistosomes are gray or white worms about 7−20 mm in length.301 Unique to this trematode, they exist as two sexes permanently coupled together (Figure 71). The longer and

8.3. Main Challenges in the Current Treatment for Schistosomiasis

The current first-line treatment is praziquantel (PZQ; Figure 72), the sole drug currently used in all affected countries. PZQ is an acylated quinoline−pyrazine active against all schistosome species. The mechanism of action is not fully known; however, it is believed that PZQ targets the voltage-gated calcium channels in the parasite membrane, allowing calcium influx.303,304 It is marketed as 600 mg tablets, with a recommended regimen of 40 mg/kg of body mass in one dose. PZQ acts within 1 h after ingestion by paralyzing the worms and damaging the outer body covering. Side effects are mild and include nausea, vomiting, and abdominal pain. PZQ has low toxicity and no long-term side effects, being safe for treatment with young children and pregnant women. Unfortunately, PZQ has little effect on eggs and immature worms. Corticosteriods can be used in conjunction with PZQ to suppress the hypersensitivity reaction from acute schistosomiasis. This treatment is repeated in 4−6 weeks to ensure the previously immature worms are eliminated. In cases of failure of treatment with PZQ, oxamniquine (OXA; Figure 72) is used; however, it is only effective against S. mansoni. This drug is as effective as PZQ; however, it has side effects such as drowsiness, sleep induction, and epileptic seizures. Resistance against OXA meant that it was used only until 2010, leaving PZQ as the sole remaining treatment. It was found that artemisinin derivatives, such as artemether (Figure 72), an antimalarial drug, are effective against immature stages of S. japoniucum, S. mansoni,

Figure 71. Life cycle of S. mansoni and S. hematobium. Created with data taken from ref 302.

thinner female is gripped by the male in a groovelike structure along the length of its body. For S. hemotobium, the schistosomes live in the perivesicular venous plexus next to the urinary bladder and, for S. mansoni and S. japonicum, in the mesenteric venous plexus next to the intestines. Female schistosomes can produce hundreds to thousands of eggs per day, and each individual egg contains the form of the larvae known as “miracidium” (Figure 71). These eggs move to the bladder or the intestine and are subsequently excreted in feces or urine where they can remain alive for up to 7 days. When the eggs are in the presence of freshwater, the miracidium form of the larvae is released and locates and penetrates the freshwater snail intermediate host, which inhabits calm or slow-moving freshwater bodies (Figure 71). The miracidia undergo asexual reproduction, producing multicellular sporocytes which develop to cercarial larvae (Figure 71). After 4−6 weeks, the cercariae leave the snail and

Figure 72. Current drugs used for treatment of schistosomiasis. AS


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and perhaps S. hematobium.302 It is recommended to use multiple doses of artemisinin in combination with PZQ over 1− 2 weeks to prevent schistosomiasis.302 However, widespread use is not recommended in areas endemic for malaria, as artemisinin resistance in malaria parasites could develop.302 Since only PZQ is currently available to treat schistosomiasis, and there are already occasional reports of its failure in treatment, there is an urgent need to develop a broader suite of alternative treatments. As highlighted by Hess et al.,305 and explained below, metal complexes have the potential to play a pivotal role in the discovery of new lead compounds against schisotosomiasis. With this in mind, most follow-up studies have been based upon developing drug candidates either derived from currently used drugs PZQ and OXA or derived from modified antifungal agents and/or antimalarial agents.

8.4.2. Compounds Derived from Praziquantel. A series of studies by Keiser and Gasser and co-workers have been published over the past few years detailing the systematic development of organometallic compounds derived from PZQ. Three strategies (Scheme 1) to modify the molecular structure of PZQ were designed and explored in two studies published in 2012307 and 2013.308 (Figure 76). The idea behind this work was that the presence of ferrocene in PZQ, like in ferroquine the ferrocene derivative of chloroquine309 would be able to increase the intrinsic antischistosomal activity of PZQ and bypass resistance mechanisms through different metal-specific modes of action.296 Strategies I and II focused on the modification of the cyclohexyl moiety, while strategy III focused on modification of the aromatic part. Furthermore, in both studies, representative compounds typical of their analogues were tested and found to be stable in human plasma at 37 °C in each of the studies. In 2012, Patra et al.307 synthesized and evaluated 18 ferrocenyl derivatives of PZQ. These compounds were designed utilizing strategies I and II. These complexes were found to be generally nontoxic toward MRC-5 mammalian fibroblast cells. Upon in vitro screening against adult S. mansoni, only four active compounds (114a, 115a−115c; Figure 74) displayed IC50 values of 25.6−68 μM, which were significantly higher than that for PZQ (0.1 μM). From these disappointing results, an alternative approach, strategy III (Scheme 1), was taken to modify the aromatic region of PZQ instead. In the following study, two chromium tricarbonyl−PZQ racemate derivatives, 116 and 117, were synthesized (Figure 74).308 The compounds were prepared in a one-step reaction by heating PZQ with [Cr(CO)6] at 140 °C to yield the diastereomeric mixture of 116 and 117 in 77% combined yield. The {Cr(CO)3} moiety was selected for coordination to the aromatic ring of PZQ for two reasons: first, preparation of such chromium derivatives is facile, forming airand water-stable products; second, attachment of the organometallic {Cr(CO)3} moiety has the potential to improve lipophilicity, increase metabolic stability, and alter the structural and electronic properties of the aromatic part of PZQ.308 Furthermore, it is important to note that previous compounds


8.4.1. Gold Compounds. Through the evaluation of the gold complex auranofin (Figure 73), Kuntz et al.306 reported

Figure 73. Structure of auranofin.

that the S. mansoni-specific multifunctional enzyme thioredoxin glutathione reductase (TGR) is essential for parasite redox processes, and this is now recognized as one of the key targets for the future development of drug candidates. Furthermore, the authors found that auranofin was the most potent inhibitor of TGR, with IC50 values in the low nanomolar range, and there was a significant decrease in cultured worms and worm burden in infected mice treated with auranofin (59−63%).

Scheme 1. Structure of Praziquantel (PZQ) and Its Derivatives with Organometallic Moieties Designed with Three Different Strategiesa

a

Adapted with permission from ref 308. Copyright 2013 Wiley. AT


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to the stability of the Cr−PZQ compounds in human plasma, where little to no release of PZQ was observed, the antischistosomal activity was assumed to be directly due to the Cr−PZQ compounds and not to PZQ. The highly promising activity of these two compounds308 gave rise to two further studies.316,317 The first study explored the role of PZQ enantiomers in antischistosomial activity,316 and the second study located the compound 116 within the worms via imaging techniques.317 These studies are discussed below. The first study was conducted on the premise that PZQ is given to patients as a racemic mixture, although only the Renantiomer shows promising activity in vitro but not in vivo.318 The R-enantiomer also leads to fewer side effects than the Senantiomer. For these reasons, four diastereomers of the chromium−PZQ complexes, (R,Rp)-116, (S,Sp)-116, (S,Rp)117, and (R,Sp)-117, were prepared to identify whether the Rdiastereomers are more active than the S-diasteromers. A strong antischistosomal activity was only observed for (R,Rp)-116 and (R,S p)-117 (Figure 3), which contain the active PZQ enantiomer. These two complexes were found to be highly active in vitro against adult S. mansoni (IC50 = 0.08−0.13 μM), whereas both S-enantiomers were found to be inactive. This strongly suggests that the R-enantiomers of the chromium complexes have the same target as the parent PZQ compound. Further in vivo studies resulted in some disappointing results. A racemic mixture of 116 and 117 delivered to mice infected with adult S. mansoni resulted in worm burden reductions of 24% and 29% at 400 mg/kg, which is low compared to that of the control PZQ (94.1% for racemic PZQ). The reasoning behind the second study was to discover the mode of action of compound 116. As discussed above, even though millions of doses of PZQ have been delivered, the exact mode of action of this drug is still not determined.303 One hypothesis suggests that PZQ interacts with tegumental phospholipids, and this was recently supported using mass spectrometry.297 X-ray fluorescence (XRF) and IR absorption

Figure 74. Four ferrocenyl derivatives of PZQ synthesized in 2012 and two chromium tricarbonyl−PZQ racemates (116 and 117) synthesized in 2013 by Patra et al.308

containing {Cr(CO)3} have proved to be useful in the field of receptorology and, more recently, in diverse areas of medicinal chemistry, including antimicrobial, anti-inflammatory, and antimalarial agents.310−315 Both Cr−PZQ racemates 116 and 117 (Figure 74) showed in vitro IC50 values of 0.25 and 0.27 μM, respectively, on adult S. mansoni worms.308 These values are comparable to that of the parent PZQ, which has an IC50 value of 0.1 μM. Furthermore, 116 and 117 were completely nontoxic toward MRC-5 human fibroblasts cells, indicating their selectivity for the parasite. Due

Figure 75. Ferrocenyl, ruthenocenyl, and benzyl derivatives from OXA. AU


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Figure 76. Antimalarial drugs (candidates) repurposed for antischistosomal screening.

reference OXA (IC50 > 90 μM). On the adult S. mansoni after incubation for 72 h, compound 118a was extremely potent again and killed 100% of worms by 24 h, while the rest of the ferrocenyl compounds, 118b−118d, showed only mild toxicity (worm viability of 24.3−40.5%). In mice, only OXA and 118a at a dose of 200 mg/kg showed 100% elimination of worms from the host. On the basis of these results, two other analogues of 118a were designed: a ruthenocenyl analogue, 118e, and a benzyl analogue, 118f, shown in Figure 75. To assess whether ironmediated redox is relevant to antischistosomal activity, a ruthenocenyl center was chosen for 118e since Ru(II) displays different electrochemical behaviors compared to Fe(II), while benzyl was used to assess the relevance of the metallocenyl functionality within 108e (ferrocenyl analogue) and 118e (ruthenocenyl analogue). At 100 mg/kg, compounds 118a, 118e, and 118f (Figure 75) demonstrated 76.1−93.7% worm burden reduction, comparable to that of OXA with 99.2% reduction. All three compounds showed high selectivity indices (>73.8), indicating selectivity for the parasite. Very interestingly, during in vitro testing, compounds 118e and 118f were found to be lethal to not only S. mansoni but also S. hematobium adults. Compared to OXA, which is only effective against S. mansoni, the additional effectiveness of 118a, 118e, and 118f against S. hemotobium indicates that these compounds work via a different/additional mode of action, and further structure− activity relationship (SAR) studies are currently under way. 8.4.4. Compounds Derived from Chloroquine. In 2014, Biot, Keiser, Gasser, and co-workers331 screened ferroquine (FQ), ruthenoquine (RQ), hydroxylferroquine (FQ-OH), and the reference compounds chloroquine (CQ) and mefloquine (MQ) (Figure 76) in vitro and in vivo against S. mansoni adult worms and newly transformed schistosomula (NTS). These are known antimalarial compounds. Ferroquine is the ferrocenyl analogue of CQ and an antimalarial currently in late-stage drug development. FQ acts via two primary modes of action: the inhibition of hemozoin and the generation of OH radicals under oxidizing conditions.309 FQ shares the same 4-aminoquinoline scaffold with basic centers with CQ. This similarity is responsible for its high lipophilicity, which allows FQ to cross membranes and accumulate within the digestive vacuole.332 The presence of FQ or CQ within the digestive vacuole prevents the biomineralization of hemozoin, which is ultimately fatal since the cell is unable to precipitate the toxic products of hemoglobin digestion. Through the generation of OH radicals, FQ is able to induce the breakdown of the parasite digestive vacuole membrane, and this is not seen in RQ or CQ. The OH radicals may also play a role in the oxidation of glutathione, which is

spectromicroscopy (IR) were used in combination to directly locate compound 116 within the schistosome.317 The CO (IR) and Cr (XRF) signatures indicated a preferential accumulation of the compound in the worm’s tegument (outer skin covering), where biological targets for PZQ are believed to be located. 8.4.3. Compounds Derived from Oxamniquine. Introduced in 1972, oxamniquine (OXA; Figure 75) is another commercially available antischistosomal drug.319 Although effective in eliminating worm burden in both animals and humans, OXA is active only on S. mansoni but not other species of schistosomiasis affecting humans.320,321 In 2006, PicaMattoccia, Cioli, and co-workers showed that OXA is a prodrug, which is activated upon binding to a S. mansoni-specific sulfotransferase. This sulfotransferase transfers sulfate groups from the universal sulfate donor 3′-phosphoadenosine 5′phosphosulfate (PAPS) to the hydroxyl group in OXA.322 In a 2013 study, Valentim, Cioli, and colleagues323 confirmed this through the solid-state structure determination of sulfotransferase bound with OXA and PAPS. They also compared sulfotransferases from S. mansoni with that of S. hemotobium and found only 3 differences out of the 16 amino acid residues interacting with DNA. Only one of the three differing amino acid residues was considered to have an impact on binding due to its effect on the polarity and size of the active site. The mutation in this gene was homologous to the sulfotransferase responsible for the resistance observed to OXA in OXA-resistant parasites. Through this study, insight into the exact mode of action of oxamniquine and the genetic basis for the difference in speciesspecific activity of OXA was provided. In 2017, new metallocene derivatives from oxamniquine (Figure 75) were reported by Keiser, Gasser, and co-workers.324 Conjugating metallocenyl moieties to OXA was aimed at overcoming species-specific resistance, improve the ability to modulate the properties, and opening up the antischistosomal activity displayed by the parent drug OXA to species other than S. mansoni. This strategy has proven to be extremely successful in the development of other antiparasitic drugs such as monepantel325−327 and chloroquine.328−330 Initially, four ferrocenyl compounds, 118a−118d (Figure 75), with varying degrees of N-alkylation and N-acylation, were tested in vitro on S. mansoni larval and adult stages and in vivo in mice models infected with S. mansoni. Incubation of the compounds at 100 μM over 72 h with larval S. mansoni showed 118a killing 100% of worms, 118b killing 76%, and 118c and 118d killing [RuCl(η 6 -p-cymene)(MCZ)2]Cl > [Ru(η6-p-cymene)(MCZ)3](PF6)2. Incubation with lower concentrations (1 and 10 μg/mL) of compounds [RuCl 2 (η 6 -p-cymene)(MCZ)] and [RuCl(η 6 -p-cymene)(MCZ)2]Cl resulted in decreased activities of adult S. mansoni worms. Sex-specific activity was documented for [Ru(η6-pcymene)(MCZ)3](PF6)2, where female worms incubated at 100 μg/mL for 72 h showed slightly decreased motility, whereas all male worms had died.

involved in heme detoxification. In contrast, RQ cannot produce reactive oxygen species (ROS). FQ-OH produces hydroxyl radicals and provides reduced cytotoxic effects compared to FQ. This difference in redox activity was assumed to be, at least in part, responsible for the greater antimalarial activity of FQ over RQ. Although they displayed moderate activity against larval and adult S. mansoni in vitro after 72 h of incubation, FQ, RQ, and FQ-OH were unfortunately not active during in vivo screening. Low total worm burden reductions of 0−36% were observed following oral administration of 200−800 mg/kg of the ferroquine derivatives to S. mansoni-infected mice. Of note, all metallocenes displayed moderate cytotoxicity (IC50 range of 21.9−24.4 μM) toward MRC-5 mammalian cells and higher toxicity toward HeLa cancer cells (IC50 range of 8.8−16.8 μM). 8.4.5. Compounds Derived from Epiisopiloturine. Portes et al.333 synthesized copper and zinc complexes of epiisopiloturine (EPI): [Cu(EPI)4](ClO4)2 and [Zn(EPI)2Cl2] (Figure 77). EPI is an imidazole alkaloid, a byproduct from the production of pilocarpine, a treatment for dry mouth and ocular hypertension. It was found that coordination with copper(II) improved the activity of free EPI, while coordination to zinc(II) decreased the activity. The authors speculated that copper acts as a carrier of EPI into the parasite, further providing a synergistic effect. They further show that when the EPI ligand was coordinated to zinc(II), the resulting complex was not active against parasites. All complexes were not toxic to mammalian cells. No IC50 values were provided in this study; however, as an overall measure of the antischistosomal activity of the complexes, tegumental (outer covering) modifications, oviposition (egg-laying ability), and reduction in motor mobility and AW


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Scheme 2. Proposed Speciation Equilibrium between [(η6-p-cymene)RuCl2(L)] and [(η6-p-cymene)RuCl2(DMSO)] in DMSO by Patra, Joshi, and Gasser et al.335

Figure 79. Mono- or bisquinoline derivatives of tetraazamacrocycles and their metallocenyl analogues.

with rigid cross-bridged and side-bridged tetraazamacrocyclic ligands are effective antimalarial agents. In 2016, as an extension to their current work, Khan et al.342 screened 26 tetraazamacrocyclic derivatives and their metal complexes for antischistosomal activity, first in vitro against newly transformed schistosomula (NTS) of harvested S. mansoni cercariae, then against adult worms, and finally in vivo using the mouse model. From this study, it was realized that the highly lipophilic heteroaromatic mono- or bisquinoline derivatives of tetraazamacrocycles were more effective against S. mansoni larvae. Five compounds, 119−123 (Figure 79), demonstrated complete inhibition of viability of NTS after 72 h of incubation at 10 μM with IC50 values of 0.87 ± 0.91 to 9.7 ± 0.95 μM, which are comparable to that of the parent drug PZQ (IC50 = 2.20 ± 0.9 μM). Upon further screening against adult S. mansoni-infected worms, only compounds 121−123 (Figure 79) demonstrated strong activity of 87.5−100% elimination at low IC50s values ranging from 1.34 ± 0.87 to 4.12 ± 0.91 μM. On the basis of the cytotoxicity test with L6 mammalian muscle cells, calculated selectivity indices for these three compounds range from 0.14 to 2.9 for parasites and from 1.34 to 4.12 for worms. This is extremely low compared to PZQ SI values of 43.6 on parasites and 960 on worms, indicating that although the compounds are extremely active against the schistosoma parasites, they are not selective. In vivo, the worm burden reductions were 12.3%, 88.4%, and 74.5%, respectively, at a single oral dose of 400 mg/ kg of body mass.

At this point, it is important to mention a problem highlighted by Patra, Joshi, and Gasser et al. about the potential instability of compounds investigated during biological studies.335 These authors published stability studies, using 1H NMR spectral data, on Ru(II) complexes showing that monoazole piano-stool complexes with the general formula [Ru(η6-arene)Cl2(L)] undergo ligand exchange with DMSO to give [Ru(η6-arene)Cl2(DMSO)]. On the contrary, bis- and trisazole analogues were stable in DMSO. As DMSO is the common vehicle for the delivery of drug in biological studies, this would indicate that the previously reported biological activity of monoazole [Ru(η6arene)Cl2(L)] complexes would not be completely accurate. Very importantly, similar conclusions were drawn on cisplatin.335 On the basis of the coordinated organic ligand, either a complete dissociation of the ligand from the metal center occurs to form the free ligand, or a mixture of different species was formed (Scheme 2). In vitro biological assays demonstrated that there was little difference in biological activity between a freshly prepared DMSO stock solution of the complex and an equimolar solution of the ligand and [Ru(η6-arene)Cl2(DMSO)]. Overall, this study clearly shows that it is important to take into account the stability of a complex in DMSO and also that mixing the [RuCl2(η6-p-cymene)(DMSO)] with the target ligand is sufficient for an improvement in the biological activity of the ligand in solution. This can be a preliminary screening method for biological activity before embarking upon the often time-consuming and rigorous preparation of new monoazole [RuCl2(η6-p-cymene)(L)] (L = N-heterocyclic ligands) type complexes. We also note that the less coordinating ligand DMF can potentially replace DMSO.335 Within the past decade, macrocyclic polyamines, such as cyclen (1,4,7,10-tetraazacyclododecane) and cyclam (1,4,8,11tetraazacyclotetradecane), have become important structural moieties for various diagnostic and therapeutic agents.336,337 Metal complexes derived from macrocyclic polyamines were found to have antimalarial properties and to have application against HIV via CXCR4 inhibition.338−340 In one example, Khan and co-workers341 showed that metal complexes coordinated

9. HUMAN AFRICAN TRYPANOSOMIASIS (SLEEPING SICKNESS) Human African trypanosomiasis (HAT), or sleeping sickness, is a disease occurring only in rural sub-Saharan Africa.17 It is caused by subspecies of the parasite Trypanosoma brucei brucei: Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. This parasite is transmitted by the Glossina tsetse fly. Humans, wild animals, and domestic animals can be hosts and reservoirs of infection for the tsetse fly vectors. T. cruzi causes Chagas disease and is discussed within its respective AX


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section within this review. With T. brucei gambiense and T. brucei rodesiense, the clinical stages and symptoms are extensively discussed by Vincendeau and Bouteille,343 Ponte-Sucre,344 and Kennedy345 and so are only summarized briefly below. There are two clear clinical stages of trypanosomiasis. In the first stage, the parasite remains in the systemic circulation. The second stage begins when the parasite infects the central nervous system (CNS) by crossing the blood−brain barrier. The rate of progression from the first stage to the second stage depends on the subspecies, although without treatment, infection with either T. brucei gambiense or T. brucei rhodesiense will lead to coma and death. 9.1. Symptoms of T. brucei gambiense

T. brucei gambiense causes HAT in western and central Africa, representing the majority of the reported cases (>90%) of sleeping sickness. It progresses slowly, causing chronic infection where the symptoms do not emerge for months or even years until the patient is in the second stage where the CNS is infected. Patients may have mild symptoms of intermittent fevers, headaches, muscle and joint aches, and malaise. Itching of the skin, swollen lymph nodes, and weight loss are also possible. After 1−2 years, as the disease advances, the CNS becomes involved, with neurological signs such as changes in personality, daytime sleepiness with night-time sleep disturbances, progressive confusion, partial paralysis, or problems with balance or walking, and hormonal imbalances. This disease is usually fatal in three years, and untreated infections rarely last more than 6−7 years.

Figure 80. Life cycle of the trypanosoma parasite and its various forms within different hosts. Adapted with permission from ref 347. Copyright 2006 Springer Nature.

trypanosomiasis in the world, where “the major challenge in developing a new drug that can ensure sustainable disease control will be to find a safe and affordable, orally administered drug that is effective against both forms of the disease, in both disease stages, and that does not require any particular skills or care to administer...” In 2018, 10 years later, this challenge still remains relevant and current for all drug candidates. Indeed, Sutherland’s report in The Lancet Global Health in January 2017349 reported that, in particular, short or single-dose oral treatments could greatly improve the goal of achieving elimination of sleeping sickness as a public health problem by 2020. With this in mind, we turn our attention to review the current treatments available. The type of treatment administered is based on whether the patient has been infected by T. brucei gambiense or T. brucei rhodesiense and the progression of the disease. The first-line treatment for T. brucei gambiense infections is pentamidine. Alternative drugs such as suramin, melarsoprol, eflornithine, and nifurtimox (Figure 81) are available. Table 1, with data taken from The Lancet, gives a good summary of each treatment and their adverse side effects. The corresponding chemical structure for each compound is included in Figure 81. Suramin and pentamidine (Figure 81) are delivered intramuscularly in the first (early hemolympathic) stage of disease, while melarsoprol and eflornithine (Figure 81) are delivered intravenously in the second (meningoencephalitis) stage. Sumarin (Figure 81) is a polysulfonated symmetrical naphthalene derivative. It was first used in 1922, and it binds strongly to serum proteins, such as low-density lipoprotein, forming a complex.351,352 Trypanosomes have a receptor for this complex, and it has been suggested that the uptake of suramin occurs via the accumulation of the complex. Pentamidine (Figure 81) is an aromatic diamidine. It is effective only toward the early-stage T. brucei gambiense form of HAT. Pentamidine enters T. brucei via a P2 aminopurine transporter. It acts by inhibiting type II topoisomerase in the mitochondria, which results in the disruption of circular mitochrondrial DNA. Melarsoprol (Figure 81) is a highly toxic arsenic-based drug that is effective against both T. brucei gambiense and T. brucei rhodesiense. Before implementation of what is known as nifurtimox/eflornithine combined therapy, melarsoprol was

9.2. Symptoms of T. brucei rhodesiense

T. brucei rhodesiense occurs in eastern and southern Africa, representing 35. However, the low SI value of [RuCp(PPh3)2(CTZ)](CF3SO3) (SI = 3) indicated that the complex had low selectivity for T. brucei brucei and therefore is not a good candidate for further studies. Loiseau et al.367 investigated analogues of spiroarsorane I, testing spiroarsoranes I, II, and III (Figure 86) in murine T.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. Phone: +61 3 9905 5509. *E-mail: [email protected]. Phone: +33 1 44 27 56 02. Web site: www.gassergroup.com. Figure 86. Structures of spiroarsoranes I, II, and III.

ORCID

Yih Ching Ong: 0000-0003-0411-1114 Saonli Roy: 0000-0003-2605-8449 Philip C. Andrews: 0000-0002-3971-7311 Gilles Gasser: 0000-0002-4244-5097

brucei CNS models. Dreyfuss et al. in 1988 showed that subcutaneous administration of spiroarsorane I (75 μmol/kg) was effective against both stages of the disease in infected sheep. Spiroarsoranes are lipophilic trypanocidal arsenic(V) prodrugs designed to cross the blood−brain barrier (BBB). The aim was to understand the compound’s lipophilicity and SAR, to optimimse its ability to cross the blood−brain barrier, and to determine if this factor was essential for its antitrypanocidal activity. However, the result of spiroarsorane I effecting a permanent cure in sheep by passing the BBB was not observed in the mice models. In fact, the respective mice treated topically with spiroarsoranes I, II, and III showed signs of relapse with varying periods of aparasitemia. Intraperitoneal administration was also attempted; however, the results were also disappointing.

Author Contributions ∥

Y.C.O. and S.R. contributed equally to this work.

Notes

The authors declare no competing financial interest. Biographies Yih Ching Ong completed her Ph.D. studies in 2017 on the solutionand solid-state chemistry of antileishmanial bismuth complexes under the supervision of Prof. Phil Andrews and Dr. Kellie Tuck at Monash University, Melbourne. She is currently undertaking a postdoctoral fellowship in the group of Prof. Gilles Gasser at Chimie ParisTech, PSL University (Paris, France), synthesizing metallocenyl compounds targeted toward parasitic diseaes. Her research interests include the development of metal-based complexes for biological applications and exploring the reactivity of unstable main-group-metal complexes.

10. CONCLUSION Many efforts have focused on developing metal complexes as treatments for Chagas disease, dengue, echinococcosis, leishmaniasis, lymphatic filariasis, onchocerciasis, schistosomiaBC


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REFERENCES

Saonli Roy completed her M.Sc. in chemistry from the Indian Institute of Technology Roorkee (IIT-R), India. She performed doctoral research in the area of physical organic chemistry under the mentorship of Prof. Wolfram Sander, Organic Chemistry II, Ruhr University Bochum, Germany (2008−2013). After continuing as a postdoctoral researcher in the same research group until 2014, she joined the group of Dr. Sugumar Venkataramani, IISER Mohali, India, as a posdoc (2015−2016). Afterward, Dr. Roy joined the group of Prof. Gilles Gasser, Department of Chemistry, University of Zurich, Switzerland, to acquire postdoctoral training in the area of medicinal organometallic chemistry (2016−2017).

(1) World Health Organization (WHO). Neglected Tropical Diseases. http://www.who.int/neglected_diseases/diseases/en/ (accessed Mar 11, 2018). (2) World Health Organization (WHO). Why Are Some Tropical Diseases Called “Neglected”? http://www.who.int/features/qa/58/ en/ (accessed Mar 11, 2018). (3) Barry, N. P. E.; Sadler, P. J. Exploration of the Medical Periodic Table: Towards New Targets. Chem. Commun. 2013, 49, 5106−5131. (4) Gasser, G.; Metzler-Nolte, N. The Potential of Organometallic Complexes in Medicinal Chemistry. Curr. Opin. Chem. Biol. 2012, 16, 84−91. (5) Hartinger, C. G.; Metzler-Nolte, N.; Dyson, P. J. Challenges and Opportunities in the Development of Organometallic Anticancer Drugs. Organometallics 2012, 31, 5677−5685. (6) Ronconi, L.; Sadler, P. J. Using Coordination Chemistry to Design New Medicines. Coord. Chem. Rev. 2007, 251, 1633−1648. (7) Gielen, M.; Tiekink, E. R. T. Metallotherapeutic Drugs and MetalBased Diagnostic Agents: The Use of Metals in Medicine; John Wiley & Sons, Ltd., 2005. (8) Sessler, J. L. Medicinal Inorganic Chemistry; American Chemical Society, 2005. (9) Thompson, K. H.; Orvig, C. Boon and Bane of Metal Ions in Medicine. Science 2003, 300, 936−939. (10) Bratso, I.; Gianferrara, T.; Alessio, E.; Hartinger, C. G.; Jakupec, M. A.; Keppler, B. K. Ruthenium and Other Non-Platinum Anticancer Compounds. Bioinorg. Med. Chem. 2011, 151−174. (11) Torres-Guerrero, E.; Quintanilla-Cedillo, M. R.; RuizEsmenjaud, J.; Arenas, R. Leishmaniasis: A Review. F1000Research 2017, 6, 750. (12) Sigel, A.; Sigel, H.; Sigel, R. K. O. Interrelations between Essential Metal Ions and Human Diseases; Springer Netherlands, 2013. (13) Caballero, A. B.; Salas, J. M.; Sánchez-Moreno, M. Metal-Based Therapeutics for Leishmaniasis. In LeishmaniasisTrends in Epidemiology, Diagnosis and Treatment; InTech, 2014; pp 465−493. (14) Navarro, M. Gold Complexes as Potential Anti-Parasitic Agents. Coord. Chem. Rev. 2009, 253, 1619−1626. (15) Tahghighi, A. Importance of Metal Complexes for Development of Potential Leishmanicidal Agents. J. Organomet. Chem. 2014, 770, 51−60. (16) Gambino, D.; Otero, L. Design of Prospective Antiparasitic Metal-Based Compounds Including Selected Organometallic Cores. Inorg. Chim. Acta 2018, 472, 58−75. (17) Njoroge, M.; Njuguna, N. M.; Mutai, P.; Ongarora, D. S. B.; Smith, P. W.; Chibale, K. Recent Approaches to Chemical Discovery and Development Against Malaria and the Neglected Tropical Diseases Human African Trypanosomiasis and Schistosomiasis. Chem. Rev. 2014, 114, 11138−11163. (18) Ong, Y. C.; Kedzierski, L.; Andrews, P. C. Do Bismuth Complexes Hold Promise as Antileishmanial Drugs? Future Med. Chem. 2018, 10, 1721−1733. (19) World Health Organization (WHO). Neglected Tropical DiseasesA Summary. http://www.who.int/neglected_diseases/ diseases/en/ (accessed Apr 25, 2018). (20) Clayton, J. Chagas Disease: Pushing through the Pipeline. Nature 2010, 465, S12−S15. (21) Schofield, C. J.; Jannin, J.; Salvatella, R. The Future of Chagas Disease Control. Trends Parasitol. 2006, 22, 583−588. (22) Cavalli, A.; Bolognesi, M. L. Neglected Tropical Diseases: MultiTarget-Directed Ligands in the Search for Novel Lead Candidates against Trypanosoma and Leishmania. J. Med. Chem. 2009, 52, 7339− 7359. (23) Maya, J. D.; Cassels, B. K.; Iturriaga-vásquez, P.; Ferreira, J.; Faúndez, M.; Galanti, N.; Ferreira, A.; Morello, A. Mode of Action of Natural and Synthetic Drugs against Trypanosoma Cruzi and Their Interaction with the Mammalian Host. Comp. Biochem. Physiol., Part A: Mol. Integr. Physiol. 2007, 146, 601−620.

Phil Andrews graduated from the University of Strathclyde in Glasgow in 1992, having completed his Ph.D. studies on alkali-metal organometallic complexes under the supervision of Prof. Robert Mulvey. He then took up a Royal Society Postdoctoral Fellowship at Griffith University in Queensland (1993−1994), working with Prof. Colin Raston, before moving to Phillips University in Marburg on the Alexander von Humboldt Fellowship (1994−1995), working with Prof. Gernot Boche. Dr. Andrews then moved back to Australia, this time to Monash University in Melbourne, as a postdoctoral research fellow and was awarded an Australian Research Council QEII Fellowship in 1997. He took up an ongoing academic teaching and research position at Monash in 2004 and is currently Professor and Deputy Head in the School of Chemistry. His research interests include discovering new bioactive metal compounds as anti-inflammatory, antitumor, and antimicrobial agents, development of new antimicrobial materials, synthesis of homo and heterobimetallic metal cages for medical imaging and therapeutics, and exploring metal-mediated anion rearrangements in main-group organometallic complexes. Gilles Gasser was born, raised, and educated in the French-speaking part of Switzerland. After a Ph.D. thesis on supramolecular chemistry with Prof. Helen Stoeckli-Evans (University of Neuchâtel, Switzerland), Dr. Gasser undertook two postdocs, first with the late Prof. Leone Spiccia (Monash University, Australia) in bioinorganic chemisty and then as an Alexander von Humboldt Fellow with Prof. Nils Metzler Nolte (Ruhr-University Bochum, Germany) in bioorganometallic chemistry. In 2010, Dr. Gasser started his independent scientific career at the University of Zurich as a Swiss National Science Foundation (SNSF) Ambizione Fellow before obtaining an SNSF Assistant Professorship in 2011. In 2016, Dr. Gasser moved to Chimie ParisTech, PSL University (Paris, France), to take a PSL Chair of Excellence. Dr. Gasser was the recipient of several fellowships and awards, including the Alferd Werner Award from the Swiss Chemical Society, an ERC Consolidator Grant, the Thieme Chemistry Journal Award, the Jucker Award for his contribution to cancer research, and recently the European Biological Inorganic Chemistry (EuroBIC) medal. Dr. Gasser’s research interests lie in the use of metal complexes in different areas of medicinal and biological chemistry.

ACKNOWLEDGMENTS This work was financially supported by the Swiss National Science Foundation (Grant Sinergia CRSII5_173718, Professorship Nos. PP00P2_133568 and PP00P2_157545 to G.G.) and has received support under the program “Investissements d’Avenir” launched by the French Government and implemented by the ANR with the reference ANR-10-IDEX-0001-02 PSL (G.G.). We gratefully acknowledge Monash University and the Australian Research Council (Grant DP110103812/ DP170103624) for financial support of this work. BD


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(24) Maya, J. D.; Orellana, M.; Ferreira, J.; Kemmerling, U.; LopezMunoz, R.; Morello, A. Chagas Disease: Present Status of Pathogenic Mechanisms and Chemotherapy. Biol. Res. 2010, 43, 323−331. (25) Castro, J. A.; de Mecca, M. M.; Bartel, L. C. Toxic Side Effects of Drugs Used to Treat Chagas’ Disease (American Trypanosomiasis). Hum. Exp. Toxicol. 2006, 25, 471−479. (26) Sánchez-Delgado, R. A.; Anzellotti, A. Metal Complexes as Chemotherapeutic Agents Against Tropical Diseases: Trypanosomiasis, Malaria and Leishmaniasis. Mini-Rev. Med. Chem. 2004, 4, 23−30. (27) Magalhaes Moreira, D. R.; Lima Leite, A.; Santos, R. R.; Soares, M. Approaches for the Development of New Anti-Trypanosoma Cruzi Agents. Curr. Drug Targets 2009, 10, 212−231. (28) Brown, R. W.; Hyland, C. J. T. Medicinal Organometallic Chemistry − an Emerging Strategy for the Treatment of Neglected Tropical Diseases. MedChemComm 2015, 6, 1230−1243. (29) Camarada, M. B.; Echeverria, C.; Ramirez-Tagle, R. Medicinal Organometallic Compounds with Anti-Chagasic Activity. MedChemComm 2016, 7, 1307−1315. (30) Navarro, M.; Gabbiani, C.; Messori, L.; Gambino, D. MetalBased Drugs for Malaria, Trypanosomiasis and Leishmaniasis: Recent Achievements and Perspectives. Drug Discovery Today 2010, 15, 1070− 1078. (31) de Souza, W.; Rodrigues, J. C. F. Sterol Biosynthesis Pathway as Target for Anti-Trypanosomatid Drugs. Interdiscip. Perspect. Infect. Dis. 2009, 2009, 1−19. (32) Kessler, R. L.; Soares, M. J.; Probst, C. M.; Krieger, M. A. Trypanosoma Cruzi Response to Sterol Biosynthesis Inhibitors: Morphophysiological Alterations Leading to Cell Death. PLoS One 2013, 8, e55497. (33) Yuzo, Y.; Yuri, A. Interaction of Azole Antifungal Agents with Cytochrome P-45014DM Purified from Saccharomyces Cerevisiae Microsomes. Biochem. Pharmacol. 1987, 36, 229−235. (34) Urbina, J. A.; Lazardi, K.; Aguirre, T.; Piras, M. M.; Piras, R. Antiproliferative Synergism of the Allylamine SF 86−327 and Ketoconazole on Epimastigotes and Amastigotes of Trypanosoma (Schizotrypanum) Cruzi. Antimicrob. Agents Chemother. 1988, 32, 1237−1242. (35) Sánchez-Delgado, R. A.; Lazardi, K.; Rincón, L.; Urbina, J. A.; Hubert, A. J.; Noels, A. N. Toward a Novel Metal-Based Chemotherapy against Tropical Diseases. 1. Enhancement of the Efficacy of Clotrimazole against Trypanosoma Cruzi by Complexation to Ruthenium in RuCl2(Clotrimazole)2. J. Med. Chem. 1993, 36, 2041− 2043. (36) Sánchez-Delgado, R. a.; Navarro, M.; Lazardi, K.; Atencio, R.; Capparelli, M.; Vargas, F.; Urbina, J. a.; Bouillez, A.; Noels, A. F.; Masi, D. Toward a Novel Metal Based Chemotherapy against Tropical Diseases 4. Synthesis and Characterization of New Metal-Clotrimazole Complexes and Evaluation of Their Activity against Trypanosoma Cruzi. Inorg. Chim. Acta 1998, 275−276, 528−540. (37) Navarro, M.; Lehmann, T.; Cisneros-Fajardo, E. J.; Fuentes, A.; Sánchez-Delgado, R. A.; Silva, P.; Urbina, J. A. Toward a Novel MetalBased Chemotherapy against Tropical Diseases.: Part 5. Synthesis and Characterization of New Ru(II) and Ru(III) Clotrimazole and Ketoconazole Complexes and Evaluation of Their Activity against Trypanosoma Cruzi. Polyhedron 2000, 19, 2319−2325. (38) Navarro, M.; Cisneros-Fajardo, E. J.; Lehmann, T.; SanchezDelgado, R. A.; Atencio, R.; Silva, P.; Lira, R.; Urbina, J. A. Toward a Novel Metal-Based Chemotherapy against Tropical Diseases. 6. Synthesis and Characterization of New Copper(II) and Gold(I) Clotrimazole and Ketoconazole Complexes and Evaluation of Their Activity against Trypanosoma Cruzi. Inorg. Chem. 2001, 40, 6879− 6884. (39) Martínez, A.; Carreon, T.; Iniguez, E.; Anzellotti, A.; Sánchez, A.; Tyan, M.; Sattler, A.; Herrera, L.; Maldonado, R. A.; Sánchez-Delgado, R. A. Searching for New Chemotherapies for Tropical Diseases: Ruthenium-Clotrimazole Complexes Display High in Vitro Activity against Leishmania Major and Trypanosoma Cruzi and Low Toxicity toward Normal Mammalian Cells. J. Med. Chem. 2012, 55, 3867−3877.

(40) Iniguez, E.; Sánchez, A.; Vasquez, M. A.; Martínez, A.; Olivas, J.; Sattler, A.; Sánchez-Delgado, R. A.; Maldonado, R. A. Metal-Drug Synergy: New Ruthenium(II) Complexes of Ketoconazole Are Highly Active against Leishmania Major and Trypanosoma Cruzi and Nontoxic to Human or Murine Normal Cells. JBIC, J. Biol. Inorg. Chem. 2013, 18, 779−790. (41) Arce, E. R.; Sarniguet, C.; Moraes, T. S.; Vieites, M.; Tomaz, A. I.; Medeiros, A.; Comini, M. A.; Varela, J.; Cerecetto, H.; González, M.; et al. A New Ruthenium Cyclopentadienyl Azole Compound with Activity on Tumor Cell Lines and Trypanosomatid Parasites. J. Coord. Chem. 2015, 68, 2923−2937. (42) Bautista Rodriguez, J. WC-9 a Lead Drug with Great Prospects for American Trypanosomiasis and Toxoplasmosis. Mini-Rev. Med. Chem. 2016, 16, 1195−1200. (43) Chao, M. N.; Storey, M.; Li, C.; Rodríguez, M. G.; Di Salvo, F.; Szajnman, S. H.; Moreno, S. N. J.; Docampo, R.; Rodriguez, J. B. Selenium-Containing Analogues of WC-9 Are Extremely Potent Inhibitors of Trypanosoma Cruzi Proliferation. Bioorg. Med. Chem. 2017, 25, 6435−6449. (44) Magalhaes Moreira, D. R.; De Oliveira, A. D. T.; Teixeira De Moraes Gomes, P. A.; De Simone, C. A.; Villela, F. S.; Ferreira, R. S.; Da Silva, A. C.; Dos Santos, T. A. R.; Brelaz De Castro, M. C. A.; Pereira, V. R. A.; et al. Conformational Restriction of Aryl Thiosemicarbazones Produces Potent and Selective Anti-Trypanosoma Cruzi Compounds Which Induce Apoptotic Parasite Death. Eur. J. Med. Chem. 2014, 75, 467−478. (45) Leite, A. C.; Moreira, D. R. d. M.; Cardoso, M. V. d. O.; Hernandes, M. Z.; Alves Pereira, V. R.; Silva, R. O.; Kiperstok, A. C.; Lima, M. d. S.; Soares, M. B. Synthesis, Cruzain Docking, and in Vitro Studies of Aryl-4-Oxothiazolylhydrazones against Trypanosoma Cruzi. ChemMedChem 2007, 2, 1339−1345. (46) Donnici, C. L.; Araújo, M. H.; Oliveira, H. S.; Moreira, D. R. M.; Pereira, V. R. A.; de Assis Souza, M.; de Castro, M. C. A. B.; Leite, A. C. L. Ruthenium Complexes Endowed with Potent Anti-Trypanosoma Cruzi Activity: Synthesis, Biological Characterization and StructureActivity Relationships. Bioorg. Med. Chem. 2009, 17, 5038−5043. (47) Bogdan, C. Nitric Oxide and the Immune Response. Nat. Immunol. 2001, 2, 907−916. (48) Napoli, C.; Ignarro, L. J. Nitric Oxide-Releasing Drugs. Annu. Rev. Pharmacol. Toxicol. 2003, 43, 97−123. (49) Bocedi, A.; Gradoni, L.; Menegatti, E.; Ascenzi, P. Kinetics of Parasite Cysteine Proteinase Inactivation by NO-Donors. Biochem. Biophys. Res. Commun. 2004, 315, 710−718. (50) Silva, J. S.; Vespa, G. N.; Cardoso, M. A.; Aliberti, J. C.; Cunha, F. Q. Tumor Necrosis Factor Alpha Mediates Resistance to Trypanosoma Cruzi Infection in Mice by Inducing Nitric Oxide Production in Infected Gamma Interferon-Activated Macrophages. Tumor Necrosis Factor Alpha Mediates Resistance to Trypanosoma Cruzi Infection. Infect. Immun. 1995, 63, 4862−4867. (51) Silva, J. J.; Osakabe, A. L.; Pavanelli, W. R.; Silva, J. S.; Franco, D. W. In Vitro and in Vivo Antiproliferative and Trypanocidal Activities of Ruthenium NO Donors. Br. J. Pharmacol. 2007, 152, 112−121. (52) Silva, J. J.; Guedes, P. M.; Zottis, A.; Balliano, T. L.; Nascimento Silva, F. O.; Franca Lopes, L. G.; Ellena, J.; Oliva, G.; Andricopulo, A. D.; Franco, D. W.; et al. Novel Ruthenium Complexes as Potential Drugs for Chagas’s Disease: Enzyme Inhibition and in Vitro/in Vivo Trypanocidal Activity. Br. J. Pharmacol. 2010, 160, 260−269. (53) Tfouni, E.; Truzzi, D. R.; Tavares, A.; Gomes, A. J.; Figueiredo, L. E.; Franco, D. W. Biological Activity of Ruthenium Nitrosyl Complexes. Nitric Oxide 2012, 26, 38−53. (54) Toledo, J. C.; dos Santos Lima Neto, B.; Franco, D. W. Mutual Effects in the Chemical Properties of the Ruthenium Metal Center and Ancillary Ligands upon Coordination. Coord. Chem. Rev. 2005, 249, 419−431. (55) Borges, S. da S. S.; Davanzo, C. U.; Castellano, E. E.; ZSchpector, J.; Silva, S. C.; Franco, D. W. Ruthenium Nitrosyl Complexes with N-Heterocyclic Ligands. Inorg. Chem. 1998, 37, 2670−2677. BE


Chemical Reviews

Review

Carboxaldehyde Semicarbazone Derivatives. Farmaco 1998, 53, 89− 94. (72) Aguirre, G.; Boiani, L.; Cerecetto, H.; Fernández, M.; González, M.; Denicola, A.; Otero, L.; Gambino, D.; Rigol, C.; Olea-Azar, C.; et al. In Vitro Activity and Mechanism of Action against the Protozoan Parasite Trypanosoma Cruzi of 5-Nitrofuryl Containing Thiosemicarbazones. Bioorg. Med. Chem. 2004, 12, 4885−4893. (73) Gambino, D.; Otero, L. Perspectives on What Ruthenium-Based Compounds Could Offer in the Development of Potential Antiparasitic Drugs. Inorg. Chim. Acta 2012, 393, 103−114. (74) Otero, L.; Noblia, P.; Gambino, D.; Cerecetto, H.; González, M.; Ellena, J. A.; Piro, O. E. Synthesis and Characterization of New Ruthenium Complexes with Active Ligands against Chagas’ Disease. Inorg. Chim. Acta 2003, 344, 85−94. (75) Otero, L.; Aguirre, G.; Boiani, L.; Denicola, A.; Rigol, C.; OleaAzar, C.; Maya, J. D.; Morello, A.; González, M.; Gambino, D.; et al. Nitrofurylsemicarbazone Rhenium and Ruthenium Complexes as AntiTrypanosomal Agents. Eur. J. Med. Chem. 2006, 41, 1231−1239. (76) Otero, L.; Smircich, P.; Vieites, M.; Ciganda, M.; Severino, P. C.; Terenzi, H.; Cerecetto, H.; Gambino, D.; Garat, B. DNA Conformational Changes and Cleavage by Ruthenium(II) Nitrofurylsemicarbazone Complexes. J. Inorg. Biochem. 2007, 101, 74−79. (77) Pagano, M.; Demoro, B.; Toloza, J.; Boiani, L.; González, M.; Cerecetto, H.; Olea-Azar, C.; Norambuena, E.; Gambino, D.; Otero, L. Effect of Ruthenium Complexation on Trypanocidal Activity of 5Nitrofuryl Containing Thiosemicarbazones. Eur. J. Med. Chem. 2009, 44, 4937−4943. (78) Vieites, M.; Otero, L.; Santos, D.; Toloza, J.; Figueroa, R.; Norambuena, E.; Olea-Azar, C.; Aguirre, G.; Cerecetto, H.; González, M.; et al. Platinum(II) Metal Complexes as Potential AntiTrypanosoma Cruzi Agents. J. Inorg. Biochem. 2008, 102, 1033−1043. (79) Otero, L.; Folch, C.; Barriga, G.; Rigol, C.; Opazo, L.; Vieites, M.; Gambino, D.; Cerecetto, H.; Norambuena, E.; Olea-Azar, C. ESR, Electrochemical and Reactivity Studies of Antitrypanosomal Palladium Thiosemicarbazone Complexes. Spectrochim. Acta, Part A 2008, 70, 519−523. (80) Otero, L.; Vieites, M.; Boiani, L.; Denicola, A.; Rigol, C.; Opazo, L.; Olea-Azar, C.; Maya, J. D.; Morello, A.; Krauth-Siegel, R. L.; et al. Novel Antitrypanosomal Agents Based on Palladium Nitrofurylthiosemicarbazone Complexes: DNA and Redox Metabolism as Potential Therapeutic Targets. J. Med. Chem. 2006, 49, 3322−3331. (81) Vieites, M.; Otero, L.; Santos, D.; Olea-Azar, C.; Norambuena, E.; Aguirre, G.; Cerecetto, H.; Gonzalez, M.; Kemmerling, U.; Morello, A.; et al. Platinum-Based Complexes of Bioactive 3-(5-Nitrofuryl)Acroleine Thiosemicarbazones Showing Anti-Trypanosoma Cruzi Activity. J. Inorg. Biochem. 2009, 103, 411−418. (82) Demoro, B.; Rossi, M.; Caruso, F.; Liebowitz, D.; Olea-Azar, C.; Kemmerling, U.; Maya, J. D.; Guiset, H.; Moreno, V.; Pizzo, C.; et al. Potential Mechanism of the Anti-Trypanosomal Activity of Organoruthenium Complexes with Bioactive Thiosemicarbazones. Biol. Trace Elem. Res. 2013, 153, 371−381. (83) Mason, R. P.; Holtzman, J. L. The Role of Catalytic Superoxide Formation in the O2inhibition of Nitroreductase. Biochem. Biophys. Res. Commun. 1975, 67, 1267−1274. (84) Paes, M. C.; Cosentino-Gomes, D.; de Souza, C. F.; Nogueira, N. P.; Meyer-Fernandes, J. R. The Role of Heme and Reactive Oxygen Species in Proliferation and Survival of Trypanosoma Cruzi. J. Parasitol. Res. 2011, 2011, 174614. (85) Piacenza, L.; Irigoin, F.; Alvarez, M. N.; Peluffo, G.; Taylor, M. C.; Kelly, J. M.; Wilkinson, S. R.; Radi, R. Mitochondrial Superoxide Radicals Mediate Programmed Cell Death in Trypanosoma Cruzi: Cytoprotective Action of Mitochondrial Iron Superoxide Dismutase Overexpression. Biochem. J. 2007, 403, 323−334. (86) Cipriani, M.; Toloza, J.; Bradford, L.; Putzu, E.; Vieites, M.; Curbelo, E.; Tomaz, A. I.; Garat, B.; Guerrero, J.; Gancheff, J. S.; et al. Effect of the Metal Ion on the Anti T. Cruzi Activity and Mechanism of Action of 5-Nitrofuryl-Containing Thiosemicarbazone Metal Complexes. Eur. J. Inorg. Chem. 2014, 2014, 4677−4689.

(56) Gomes, M. G.; Davanzo, C. U.; Silva, S. C.; Lopes, L. G. F.; Santos, P. S.; Franco, D. W. Cis- and TransNitrosyltetraammineruthenium(II). Spectral and Electrochemical Properties and Reactivity. J. Chem. Soc., Dalton Trans. 1998, 4, 601− 608. (57) Toledo, J. C.; Silva, H. A. S.; Scarpellini, M.; Mori, V.; Camargo, A. J.; Bertotti, M.; Franco, D. W. Ruthenium Tetraammines as a Model of Nitric Oxide Donor Compounds. Eur. J. Inorg. Chem. 2004, 2004, 1879−1885. (58) Silva, J. J.; Pavanelli, W. R.; Pereira, J. C.; Silva, J. S.; Franco, D. W. Experimental Chemotherapy against Trypanosoma Cruzi Infection Using Ruthenium Nitric Oxide Donors. Antimicrob. Agents Chemother. 2009, 53, 4414−4421. (59) Verlinde, C. L. M. J.; Hannaert, V.; Blonski, C.; Willson, M.; Périé, J. J.; Fothergill-Gilmore, L. A.; Opperdoes, F. R.; Gelb, M. H.; Hol, W. G. J.; Michels, P. A. M. Glycolysis as a Target for the Design of New Anti-Trypanosome Drugs. Drug Resist. Updates 2001, 4, 50−65. (60) Souza, D. H. F.; Garratt, R. C.; Araújo, A. P. U.; Guimarães, B. G.; Jesus, W. D. P.; Michels, P. A. M.; Hannaert, V.; Oliva, G. Trypanosoma Cruzi Glycosomal Glyceraldehyde-3-Phosphate Dehydrogenase: Structure, Catalytic Mechanism and Targeted Inhibitor Design. FEBS Lett. 1998, 424, 131−135. (61) Guedes, P. M. M.; Oliveira, F. S.; Gutierrez, F. R. S.; da Silva, G. K.; Rodrigues, G. J.; Bendhack, L. M.; Franco, D. W.; Do Valle Matta, M. A.; Zamboni, D. S.; da Silva, R. S.; et al. Nitric Oxide Donor Trans[RuCl([15]AneN(4))NO](2+) as a Possible Therapeutic Approach for Chagas’ Disease. Br. J. Pharmacol. 2010, 160, 270−282. (62) Bastos, T. M.; Barbosa, M. I. F.; da Silva, M. M.; Júnior, J. W. d. C.; Meira, C. S.; Guimaraes, E. T.; Ellena, J.; Moreira, D. R. M.; Batista, A. A.; Soares, M. B. P. Nitro/Nitrosyl- Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma Cruzi Agents Causing Autophagy and Necrotic Parasite Death. Antimicrob. Agents Chemother. 2014, 58, 6044−6055. (63) Docampo, R.; Mason, R. P.; Mottley, C.; Muniz, R. P. A. Generation of Free Radicals Induced by Nifurtimox in Mammalian Tissues. J. Biol. Chem. 1981, 256, 10930−10933. (64) Moreno, S. N. J.; Docampo, R.; Mason, R. P.; Leon, W.; Stoppani, A. O. M. Different Behaviors of Benznidazole as Free Radical Generator with Mammalian and Trypanosoma Cruzi Microsomal Preparations. Arch. Biochem. Biophys. 1982, 218, 585−591. (65) Maya, J. D.; Cassels, B. K.; Iturriaga-Vásquez, P.; Ferreira, J.; Faúndez, M.; Galanti, N.; Ferreira, A.; Morello, A. Mode of Action of Natural and Synthetic Drugs against Trypanosoma Cruzi and Their Interaction with the Mammalian Host. Comp. Biochem. Physiol., Part A: Mol. Integr. Physiol. 2007, 146, 601−620. (66) Silva, J. J. N.; Pavanelli, W. R.; Salazar Gutierrez, F. R.; Lima, F. C. A.; da Silva, A. B. F.; Silva, J. S.; Franco, D. W. Complexation of the AntiTrypanosoma Cruzi Drug Benznidazole Improves Solubility and Efficacy. J. Med. Chem. 2008, 51, 4104−4114. (67) Sesti-Costa, R.; Carneiro, Z. A.; Silva, M. C.; Santos, M.; Silva, G. K.; Milanezi, C.; da Silva, R. S.; Silva, J. S. Ruthenium Complex with Benznidazole and Nitric Oxide as a New Candidate for the Treatment of Chagas Disease. PLoS Neglected Trop. Dis. 2014, 8, e3207. (68) Cheng, G.; Sa, W.; Cao, C.; Guo, L.; Hao, H.; Liu, Z.; Wang, X.; Yuan, Z. Quinoxaline 1,4-Di-N-Oxides: Biological Activities and Mechanisms of Actions. Front. Pharmacol. 2016, 7, 64. (69) Urquiola, C.; Vieites, M.; Aguirre, G.; Marín, A.; Solano, B.; Arrambide, G.; Noblía, P.; Lavaggi, M. L.; Torre, M. H.; González, M.; et al. Improving Anti-Trypanosomal Activity of 3-Aminoquinoxaline-2Carbonitrile N1,N4-Dioxide Derivatives by Complexation with Vanadium. Bioorg. Med. Chem. 2006, 14, 5503−5509. (70) Moreno, S. N. J.; Mason, R. P.; Docampos, R.; Carolina, N. Reduction of Nifurtimox and Nitrofurantoin to Free Radical Metabolites by Rat Liver Mitochondria. J. Biol. Chem. 1984, 259, 6298−6305. (71) Cerecetto, H.; Di Maio, R.; Ibarruri, G.; Seoane, G.; Denicola, A.; Peluffo, G.; Quijano, C.; Paulino, M. Synthesis and Anti-Trypanosomal Activity of Novel 5-Nitro-2-Furaldehyde and 5-Nitrothiophene-2BF


Chemical Reviews

Review

(87) Sarniguet, C.; Toloza, J.; Cipriani, M.; Lapier, M.; Vieites, M.; Toledano-Magaña, Y.; García-Ramos, J. C.; Ruiz-Azuara, L.; Moreno, V.; Maya, J. D.; et al. Water-Soluble Ruthenium Complexes Bearing Activity Against Protozoan Parasites. Biol. Trace Elem. Res. 2014, 159, 379−392. (88) Fernández, M.; Arce, E. R.; Sarniguet, C.; Morais, T. S.; Tomaz, A. I.; Azar, C. O.; Figueroa, R.; Diego Maya, J.; Medeiros, A.; Comini, M.; et al. Novel Ruthenium(II) Cyclopentadienyl Thiosemicarbazone Compounds with Antiproliferative Activity on Pathogenic Trypanosomatid Parasites. J. Inorg. Biochem. 2015, 153, 306−314. (89) Olea-Azar, C.; Rigol, C.; Mendizabal, F.; Morello, A.; Diego Maya, J.; Moncada, C.; Cabrera, E.; di Maio, R.; González, M.; Cerecetto, H. ESR Spin Trapping Studies of Free Radicals Generated from Nitrofuran Derivative Analogues of Nifurtimox by Electrochemical and Trypanosoma Cruzi Reduction. Free Radical Res. 2003, 37, 993−1001. (90) Olea-Azar, C.; Atria, A. M.; di Maio, R.; Seoane, G.; Cerecetto, H. Electron Spin Resonance and Cyclic Voltammetry Studies of Nitrofurane and Nitrothiophene Analogues of Nifurtimox. Spectrosc. Lett. 1998, 31, 849−857. (91) Arancibia, R.; Klahn, A. H.; Buono-Core, G. E.; Contreras, D.; Barriga, G.; Olea-Azar, C.; Lapier, M.; Maya, J. D.; Ibañez, A.; Garland, M. T. Organometallic Schiff Bases Derived from 5-Nitrothiophene and 5-Nitrofurane: Synthesis, Crystallographic, Electrochemical, ESR and AntiTrypanosoma Cruzi Studies. J. Organomet. Chem. 2013, 743, 49− 54. (92) Arancibia, R.; Klahn, A. H.; Buono-Core, G. E.; GutierrezPuebla, E.; Monge, A.; Medina, M. E.; Olea-Azar, C.; Maya, J. D.; Godoy, F. Synthesis, Characterization and Anti-Trypanosoma Cruzi Evaluation of Ferrocenyl and Cyrhetrenyl Imines Derived from 5Nitrofurane. J. Organomet. Chem. 2011, 696, 3238−3244. (93) Turrens, J. F.; Newton, C. L.; Zhong, L.; Hernandez, F. R.; Whitfield, J.; Docampo, R. Mercaptopyridine- N -Oxide, an NADHFumarate Reductase Inhibitor, Blocks Trypanosoma Cruzi Growth in Culture and in Infected Myoblasts. FEMS Microbiol. Lett. 1999, 175, 217−221. (94) Sun, P. J.; Fernando, Q.; Freiser, H. Structure and Behavior of Organic Analytical Reagents. Formation Constants of Transition Metal Complexes of 2-Hydroxypyridine-1-Oxide and 2-Mercaptopyridine-1Oxide. Anal. Chem. 1964, 36, 2485−2488. (95) Higes-Rolando, F. J.; Pérez-Florindo, A.; Valenzuela-Calahorro, C. Thermal Studies on 1-Hydroxypyridine-2-Thione Complexes of VO(IV), Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II). Thermochim. Acta 1991, 186, 43−52. (96) Chen, X.; Hu, Y.; Wu, D.; Weng, L.; Kang, B. Syntheses and Electrochemistry of Some Transition Metal Complexes with 2Mercaptopyridine N-Oxide and Crystal Structure of Bis(2-Mercaptopyridine N-Oxide)Nickel(II). Polyhedron 1991, 10, 2651−2657. (97) Machado, I.; Marino, L. B.; Demoro, B.; Echeverría, G. A.; Piro, O. E.; Leite, C. Q. F.; Pavan, F. R.; Gambino, D. Bioactivity of Pyridine2-Thiolato-1-Oxide Metal Complexes: Bi(III), Fe(III) and Ga(III) Complexes as Potent Anti-Mycobacterium Tuberculosis Prospective Agents. Eur. J. Med. Chem. 2014, 87, 267−273. (98) Ravindran Durai Nayagam, B.; Jebas, S. R.; Schollmeyer, D. Cis -Bis(2-Sulfidopyridine N -Oxide)Platinum(II). Acta Crystallogr., Sect. E: Struct. Rep. Online 2008, 64, m425−m425. (99) Vieites, M.; Smircich, P.; Parajón-Costa, B.; Rodríguez, J.; Galaz, V.; Olea-Azar, C.; Otero, L.; Aguirre, G.; Cerecetto, H.; González, M.; et al. Potent in Vitro Anti-Trypanosoma Cruzi Activity of Pyridine-2Thiol N-Oxide Metal Complexes Having an Inhibitory Effect on Parasite-Specific Fumarate Reductase. JBIC, J. Biol. Inorg. Chem. 2008, 13, 723−735. (100) Vieites, M.; Smircich, P.; Guggeri, L.; Marchán, E.; GómezBarrio, A.; Navarro, M.; Garat, B.; Gambino, D. Synthesis and Characterization of a Pyridine-2-Thiol N-Oxide Gold(I) Complex with Potent Antiproliferative Effect against Trypanosoma Cruzi and Leishmania Sp. Insight into Its Mechanism of Action. J. Inorg. Biochem. 2009, 103, 1300−1306.

(101) Parajón-Costa, B. S.; González-Baró, A. C.; Baran, E. J. Electrochemical and Spectroscopic Behaviour of Bis(2-Mercaptopyridine-N-Oxide)Oxovanadium(IV). Z. Anorg. Allg. Chem. 2002, 628, 1419−1424. (102) Gambino, D. Potentiality of Vanadium Compounds as AntiParasitic Agents. Coord. Chem. Rev. 2011, 255, 2193−2203. (103) Salas, J. M.; Caballero, A. B.; Esteban-Parra, G. M.; MéndezArriaga, J. M. Leishmanicidal and Trypanocidal Activity of Metal Complexes with 1,2,4-Triazolo[1,5-a]Pyrimidines: Insights on Their Therapeutic Potential against Leishmaniasis and Chagas Disease. Curr. Med. Chem. 2017, 24, 2796−2806. (104) Boutaleb-Charki, S.; Marin, C.; Maldonado, C.; Rosales, M.; Urbano, J.; Guitierrez-Sanchez, R.; Quiros, M.; Salas, J.; SanchezMoreno, M. Copper (II) Complexes of [1,2,4]Triazolo [1,5a]Pyrimidine Derivatives as Potential Anti-Parasitic Agents. Drug Metab. Lett. 2009, 3, 35−44. (105) Widler, L.; Jaeggi, K. A.; Glatt, M.; Muller, K.; Bachmann, R.; Bisping, M.; Born, A. R.; Cortesi, R.; Guiglia, G.; Jeker, H.; et al. Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa). J. Med. Chem. 2002, 45, 3721−3738. (106) Sanders, J. M.; Song, Y.; Chan, J. M.; Zhang, Y.; Jennings, S.; Kosztowski, T.; Odeh, S.; Flessner, R.; Schwerdtfeger, C.; Kotsikorou, E.; et al. Pyridinium-1-Yl Bisphosphonates Are Potent Inhibitors of Farnesyl Diphosphate Synthase and Bone Resorption. J. Med. Chem. 2005, 48, 2957−2963. (107) Montalvetti, A.; Bailey, B. N.; Martin, M. B.; Severin, G. W.; Oldfield, E.; Docampo, R. Bisphosphonates Are Potent Inhibitors of Trypanosoma Cruzi Farnesyl Pyrophosphate Synthase. J. Biol. Chem. 2001, 276, 33930−33937. (108) Demoro, B.; Caruso, F.; Rossi, M.; Benitez, D.; Gonzalez, M.; Cerecetto, H.; Parajon-Costa, B.; Castiglioni, J.; Galizzi, M.; Docampo, R.; et al. Risedronate Metal Complexes Potentially Active against Chagas Disease. J. Inorg. Biochem. 2010, 104, 1252−1258. (109) Martin, M. B.; Grimley, J. S.; Lewis, J. C.; Heath, H. T., 3rd; Bailey, B. N.; Kendrick, H.; Yardley, V.; Caldera, A.; Lira, R.; Urbina, J. A.; et al. Bisphosphonates Inhibit the Growth of Trypanosoma Brucei, Trypanosoma Cruzi, Leishmania Donovani, Toxoplasma Gondii, and Plasmodium Falciparum: A Potential Route to Chemotherapy. J. Med. Chem. 2001, 44, 909−916. (110) Supuran, C. T. Special Issue: Sulfonamides. Molecules 2017, 22, 1642−1646. (111) Chohan, Z. H.; Shad, H. A. Structural Elucidation and Biological Significance of 2-Hydroxy-1-Naphthaldehyde Derived Sulfonamides and Their First Row d-Transition Metal Chelates. J. Enzyme Inhib. Med. Chem. 2008, 23, 369−379. (112) Supuran, C. T. Structure-Based Drug Discovery of Carbonic Anhydrase Inhibitors. J. Enzyme Inhib. Med. Chem. 2012, 27, 759−772. (113) Chohan, Z. H.; Hernandes, M. Z.; Sensato, F. R.; Moreira, D. R.; Pereira, V. R. A.; Neves, J. K.; de Oliveira, A. P.; de Oliveira, B. C.; Leite, A. C. L. Sulfonamide-Metal Complexes Endowed with Potent AntiTrypanosoma Cruzi Activity. J. Enzyme Inhib. Med. Chem. 2014, 29, 230−236. (114) Batista, D. da G. J.; da Silva, P. B.; Stivanin, L.; Lachter, D. R.; Silva, R. S.; Felcman, J.; Louro, S. R. W.; Teixeira, L. R.; Soeiro, M. de N. C. Co(II), Mn(II) and Cu(II) Complexes of Fluoroquinolones: Synthesis, Spectroscopical Studies and Biological Evaluation against Trypanosoma Cruzi. Polyhedron 2011, 30, 1718−1725. (115) Martins, D. A.; Gouvea, L. R.; Muniz, G. S.; Louro, S. R.; Batista, D. d. G. J.; Soeiro, M. d. N. C.; Teixeira, L. R. Norfloxacin and N-Donor Mixed-Ligand Copper(II) Complexes: Synthesis, Albumin Interaction, and Anti-Trypanosoma Cruzi Activity. Bioinorg. Chem. Appl. 2016, 2016, 5027404. (116) Gouvea, L. R.; Martins, D. A.; Batista, D. d. G. J.; Soeiro, M. d. N. C.; Louro, S. R.; Barbeira, P. J.; Teixeira, L. R. Norfloxacin Zn(II)Based Complexes: Acid Base Ionization Constant Determination, DNA and Albumin Binding Properties and the Biological Effect against Trypanosoma Cruzi. BioMetals 2013, 26, 813−825. BG


Chemical Reviews

Review

(117) Navarro-Ranniger, C.; López-Solera, I.; Pérez, J. M.; Rodríguez, J.; García-Ruano, J. L.; Raithby, P. R.; Masaguer, J. R.; Alonso, C. Analysis of Two Cycloplatinated Compounds Derived from N-(4Methoxyphenyl)-α-Benzoylbenzylidenamine. Comparison of the Activity of These Compounds with Other Isostructural Cyclopalladated Compounds. J. Med. Chem. 1993, 36, 3795−3801. (118) Fricker, S. P.; Mosi, R. M.; Cameron, B. R.; Baird, I.; Zhu, Y.; Anastassov, V.; Cox, J.; Doyle, P. S.; Hansell, E.; Lau, G.; et al. Metal Compounds for the Treatment of Parasitic Diseases. J. Inorg. Biochem. 2008, 102, 1839−1845. (119) Farrell, N. P.; Williamson, J.; McLaren, D. J. M. Trypanocidal and Antitumour Activity of Platinum-Metal and Platinum-Metal-Drug Dual-Function Complexes. Biochem. Pharmacol. 1984, 33, 961−971. (120) Jennette, K. W.; Lippard, S. J.; Vassiliades, G. A.; Bauer, W. R. Metallointercalation Reagents. 2-Hydroxyethanethiolato(2,2’,2’-Terpyridine)-Platinum(II) Monocation Binds Strongly to DNA by Intercalation. Proc. Natl. Acad. Sci. U. S. A. 1974, 71, 3839−3843. (121) Lowe, G.; Droz, A. S.; Vilaivan, T.; Weaver, G. W.; Tweedale, L.; Pratt, J. M.; Rock, P.; Yardley, V.; Croft, S. L. Cytotoxicity of (2,2’:6’,2Terpyridine)Platinum(II) Complexes to Leishmania Donovani, Trypanosoma Cruzi, and Trypanosoma Brucei. J. Med. Chem. 1999, 42, 999−1006. (122) Benítez, J.; Guggeri, L.; Tomaz, I.; Arrambide, G.; Navarro, M.; Costa Pessoa, J.; Garat, B.; Gambino, D. Design of Vanadium MixedLigand Complexes as Potential Anti-Protozoa Agents. J. Inorg. Biochem. 2009, 103, 609−616. (123) Benítez, J.; Guggeri, L.; Tomaz, I.; Pessoa, J. C.; Moreno, V.; Lorenzo, J.; Avilés, F. X.; Garat, B.; Gambino, D. A Novel Vanadyl Complex with a Polypyridyl DNA Intercalator as Ligand: A Potential Anti-Protozoa and Anti-Tumor Agent. J. Inorg. Biochem. 2009, 103, 1386−1394. (124) Benítez, J.; Cavalcanti De Queiroz, A.; Correia, I.; Alves, M. A.; Alexandre-Moreira, M. S.; Barreiro, E. J.; Lima, L. M.; Varela, J.; González, M.; Cerecetto, H.; et al. New Oxidovanadium(IV) NAcylhydrazone Complexes: Promising Antileishmanial and Antitrypanosomal Agents. Eur. J. Med. Chem. 2013, 62, 20−27. (125) Bincoletto, C.; Tersariol, I. L. S.; Oliveira, C. R.; Dreher, S.; Fausto, D. M.; Soufen, M. A.; Nascimento, F. D.; Caires, A. C. F. Chiral Cyclopalladated Complexes Derived from N,N-Dimethyl-1-Phenethylamine with Bridging Bis(Diphenylphosphine)Ferrocene Ligand as Inhibitors of the Cathepsin B Activity and as Antitumoral Agents. Bioorg. Med. Chem. 2005, 13, 3047−3055. (126) Matsuo, A. L.; Silva, L. S.; Torrecilhas, A. C.; Pascoalino, B. S.; Ramos, T. C.; Rodrigues, E. G.; Schenkman, S.; Caires, A. C.; Travassos, L. R. In Vitro and in Vivo Trypanocidal Effects of the Cyclopalladated Compound 7a, a Drug Candidate for Treatment of Chagas’ Disease. Antimicrob. Agents Chemother. 2010, 54, 3318−3325. (127) Guzman, M. G.; Halstead, S. B.; Artsob, H.; Buchy, P.; Farrar, J.; Gubler, D. J.; Hunsperger, E.; Kroeger, A.; Margolis, H. S.; Martí-nez, E.; et al. Dengue: A Continuing Global Threat. Nat. Rev. Microbiol. 2010, 8, S7−S16. (128) Rodenhuis-Zybert, I. A.; Wilschut, J.; Smit, J. M. Dengue Virus Life Cycle: Viral and Host Factors Modulating Infectivity. Cell. Mol. Life Sci. 2010, 67, 2773−2786. (129) Gubler, D. J.; Suharyono, W.; Tan, R.; Abidin, M.; Sie, A. Viraemia in Patients with Naturally Acquired Dengue Infection. Bull. World Health Organ. 1981, 59, 623−630. (130) Mukhopadhyay, S.; Kuhn, R. J.; Rossmann, M. G. A Structural Perspective of the Flavivirus Life Cycle. Nat. Rev. Microbiol. 2005, 3, 13−22. (131) Li, L.; Lok, S. M.; Yu, I. M.; Zhang, Y.; Kuhn, R. J.; Chen, J.; Rossmann, M. G. The Flavivirus Precursor Membrane-Envelope Protein Complex: Structure and Maturation. Science 2008, 319, 1830−1834. (132) Yu, I. M.; Zhang, W.; Holdaway, H. A.; Li, L.; Kostyuchenko, V. A.; Chipman, P. R.; Kuhn, R. J.; Rossmann, M. G.; Chen, J. Structure of the Immature Dengue Virus at Low PH Primes Proteolytic Maturation. Science 2008, 319, 1834−1837.

(133) Centers for Disease Control and Prevention (CDC). Epidemiology of Dengue. https://www.cdc.gov/dengue/ epidemiology/index.html (accessed Apr 18, 2018). (134) Cavicchioli, M.; Massabni, A. C.; Heinrich, T. A.; Costa-Neto, C. M.; Abrão, E. P.; Fonseca, B. A. L.; Castellano, E. E.; Corbi, P. P.; Lustri, W. R.; Leite, C. Q. F. Pt(II) and Ag(I) Complexes with Acesulfame: Crystal Structure and a Study of Their Antitumoral, Antimicrobial and Antiviral Activities. J. Inorg. Biochem. 2010, 104, 533−540. (135) Saini, A. K.; Kumari, P.; Sharma, V.; Mathur, P.; Mobin, S. M. Varying Structural Motifs in the Salen Based Metal Complexes of Co(II), Ni(II) and Cu(II): Synthesis, Crystal Structures, Molecular Dynamics and Biological Activities. Dalton Trans 2016, 45, 19096− 19108. (136) de Aguiar, I.; Rocha dos Santos, E.; Mafud, A. C.; Annies, V.; Navarro-Silva, M. A.; Rodrigues dos Santos Malta, V.; do Prado Gambardella, M. T.; de Assis Marques, F.; Carlos, R. M. Synthesis and Characterization of Mn(I) Complexes and Their Larvicidal Activity against Aedes Aegypti, Vector of Dengue Fever. Inorg. Chem. Commun. 2017, 84, 49−55. (137) Dutta, S.; Celestine, M. J.; Khanal, S.; Huddleston, A.; Simms, C.; Arca, J. F.; Mitra, A.; Heller, L.; Kraj, P. J.; Ledizet, M.; et al. Coordination of Different Ligands to Copper(II) and Cobalt(III) Metal Centers Enhances Zika Virus and Dengue Virus Loads in Both Arthropod Cells and Human Keratinocytes. Biochim. Biophys. Acta, Gen. Subj. 2018, 1862, 40−50. (138) Moro, P.; Schantz, P. M. Echinococcosis: A Review. Int. J. Infect. Dis. 2009, 13, 125−133. (139) Hemphill, A.; Walker, M. Drugs Against Echinococcosis. Drug Des. Rev.–Online 2004, 1, 325−332. (140) Eckert, J.; Deplazes, P. Biological, Epidemiological, and Clinical Aspects of Echinococcosis, a Zoonosis of Increasing Concern. Clin. Microbiol. Rev. 2004, 17, 107−135. (141) Schweiger, A.; Ammann, R. W.; Candinas, D.; Clavien, P.-A.; Eckert, J.; Gottstein, B.; Halkic, N.; Muellhaupt, B.; Prinz, B. M.; Reichen, J.; et al. Human Alveolar Echinococcosis after Fox Population Increase, Switzerland. Emerging Infect. Dis. 2007, 13, 878−882. (142) Smego, R. A.; Bhatti, S.; Khaliq, A. A.; Beg, M. A. Percutaneous Aspiration-Injection-Reaspiration Drainage Plus Albendazole or Mebendazole for Hepatic Cystic Echinococcosis: A Meta-Analysis. Clin. Infect. Dis. 2003, 37, 1073−1083. (143) Kadry, Z.; Renner, E. C.; Bachmann, L. M.; Attigah, N.; Renner, E. L.; Ammann, R. W.; Clavien, P. A. Evaluation of Treatment and Long-Term Follow-up in Patients with Hepatic Alveolar Echinococcosis. Br. J. Surg. 2005, 92, 1110−1116. (144) Hemphill, A.; Stadelmann, B.; Rufener, R.; Spiliotis, M.; Boubaker, G.; Müller, J.; Müller, N.; Gorgas, D.; Gottstein, B. Treatment of Echinococcosis: Albendazole and Mebendazole − What Else? Parasite 2014, 21, 70. (145) Qu, B.; Guo, L.; Sheng, G.; Yu, F.; Chen, G.; Wang, Y.; Shi, Y.; Zhan, H.; Yang, Y.; Du, X. Management of Advanced Hepatic Alveolar Echinococcosis: Report of 42 Cases. Am. J. Trop. Med. Hyg. 2017, 96, 680−685. (146) Lacey, E. Mode of Action of Benzimidazoles. Parasitol. Today 1990, 6, 112−115. (147) Aksit, D.; Yalinkilinc, H. S.; Sekkin, S.; Boyacioğlu, M.; Cirak, V. Y.; Ayaz, E.; Gokbulut, C. Comparative Pharmacokinetics and Bioavailability of Albendazole Sulfoxide in Sheep and Goats, and Dose-Dependent Plasma Disposition in Goats. BMC Vet. Res. 2015, 11, 124. (148) Küster, T.; Lense, N.; Barna, F.; Hemphill, A.; Kindermann, M. K.; Heinicke, J. W.; Vock, C. A. A New Promising Application for Highly Cytotoxic Metal Compounds: η 6-Areneruthenium(II) Phosphite Complexes for the Treatment of Alveolar Echinococcosis. J. Med. Chem. 2012, 55, 4178−4188. (149) Bates, P. A. Transmission of Leishmania Metacyclic Promastigotes by Phlebotomine Sand Flies. Int. J. Parasitol. 2007, 37, 1097−1106. BH


Chemical Reviews

Review

(150) Bates, P. A.; Rogers, M. E. New Insights into the Developmental Biology and Transmission Mechanisms of Leishmania. Curr. Mol. Med. 2004, 4, 601−609. (151) Cao, T. Atlas of Diagnostic Parasitology. http://www.tuyenlab. net/2016/09/parasitology-atlas-of-diagnostic.html (accessed July 20, 2017). (152) World Health Organization (WHO). LeishmaniasisEpidemiological Situation. http://www.who.int/leishmaniasis/burden/en/ (accessed July 20, 2017). (153) World Health Organization (WHO). Leishmaniasis. http:// www.who.int/leishmaniasis/en/ (accessed July 21, 2017). (154) World Health Organization (WHO). Clinical Forms of the Leishmaniases. http://www.who.int/leishmaniasis/clinical_forms_ leishmaniases/en/index1.html (accessed July 21, 2017). (155) Maroli, M.; Rossi, L.; Baldelli, R.; Capelli, G.; Ferroglio, E.; Genchi, C.; Gramiccia, M.; Mortarino, M.; Pietrobelli, M.; Gradoni, L. The Northward Spread of Leishmaniasis in Italy: Evidence from Retrospective and Ongoing Studies on the Canine Reservoir and Phlebotomine Vectors. Trop. Med. Int. Health 2008, 13, 256−264. (156) Frézard, F.; Demicheli, C.; Ribeiro, R. R. Pentavalent Antimonials: New Perspectives for Old Drugs. Molecules 2009, 14, 2317−2336. (157) Sundar, S.; Chakravarty, J. Antimony Toxicity. Int. J. Environ. Res. Public Health 2010, 7, 4267−4277. (158) Haldar, A. K.; Sen, P.; Roy, S. Use of Antimony in the Treatment of Leishmaniasis: Current Status and Future Directions. Mol. Biol. Int. 2011, 2011, 571242. (159) Do Prado, B. R.; Islam, A.; Frézard, F.; Demicheli, C. Organometallic Compounds in Chemotherapy against Leishmania. In Drug Discovery for Leishmanias; Rivas, L., Gil, C., Eds.; RSC Drug Discovery Series; The Royal Society of Chemistry, 2018; Chapter 10, pp 199−223. (160) Croft, S. L.; Olliaro, P. Leishmaniasis Chemotherapy  Challenges and Opportunities. Clin. Microbiol. Infect. 2011, 17, 1478− 1483. (161) Croft, S. L.; Neame, K. D.; Homewood, C. A. Accumulation of 125-Sb Sodium Stibogluconate by Leishmania Mexicana Amazonesis and Leishmania Donovani in Vitro. Comp. Biochem. Physiol., C: Comp. Pharmacol. 1981, 68C, 95−98. (162) Matoussi, N.; Ameur, H. B.; Amor, S. B.; Fitouri, Z.; Becher, S. B. Toxicité Cardiaque de l’antimoniate de Méglumine (Glucantime®). À Propos d’une Observation. Médecine Mal. Infect. 2007, 37, S257− S259. (163) Gasser, R. A.; Magill, A. J.; Oster, C. N.; Franke, E. D.; Grögl, M.; Berman, J. D. Pancreatitis Induced by Pentavalent Antimonial Agents during Treatment of Leishmaniasis. Clin. Infect. Dis. 1994, 18, 83−90. (164) Zaghloul, I.; Al-Jasser, M. Effect of Renal Impairment on the Pharmacokinetics of Antimony in Hamsters. Ann. Trop. Med. Parasitol. 2004, 98, 793−800. (165) McConville, M. J.; Ralph, S. a. Chronic Arsenic Exposure and Microbial Drug Resistance. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 19666−19667. (166) Perry, M. R.; Wyllie, S.; Raab, A.; Feldmann, J.; Fairlamb, A. H. Chronic Exposure to Arsenic in Drinking Water Can Lead to Resistance to Antimonial Drugs in a Mouse Model of Visceral Leishmaniasis. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 19932−19937. (167) Perry, M.; Wyllie, S.; Prajapati, V.; Menten, J.; Raab, A.; Feldmann, J.; Chakraborti, D.; Sundar, S.; Boelaert, M.; Picado, A.; et al. Arsenic, Antimony, and Leishmania: Has Arsenic Contamination of Drinking Water in India Led to Treatment- Resistant Kala-Azar? Lancet 2015, 385, S80. (168) Berman, J. D.; Grogl, M. Leishmania Mexicana: Chemistry and Biochemistry of Sodium Stibogluconate (Pentostam). Exp. Parasitol. 1988, 67, 96−103. (169) Croft, S. L.; Sundar, S.; Fairlamb, A. H. Drug Resistance in Leishmaniasis. Clin. Microbiol. Rev. 2006, 19, 111−126.

(170) Roberts, W. L.; Mcmurray, W. J.; Rainey, P. M. Characterization of the Antimonial Antileishmanial Agent Meglumine Antimonate (Glucantime). Antimicrob. Agents Chemother. 1998, 42, 1076−1082. (171) Treiger Borborema, S. E.; Schwendener, R. A.; Osso Junior, J. A.; De Andrade Junior, H. F.; Do Nascimento, N. Uptake and Antileishmanial Activity of Meglumine Antimoniate-Containing Liposomes in Leishmania (Leishmania) Major-Infected Macrophages. Int. J. Antimicrob. Agents 2011, 38, 341−347. (172) Demicheli, C.; Ochoa, R.; da Silva, J. B. B.; Falcão, C. A. B.; Rossi-Bergmann, B.; de Melo, A. L.; Sinisterra, R. D.; Frézard, F. Oral Delivery of Meglumine Antimoniate-Beta-Cyclodextrin Complex for Treatment of Leishmaniasis. Antimicrob. Agents Chemother. 2004, 48, 100−103. (173) Tiphine, M.; Letscher-Bru, V.; Herbrecht, R. Amphotericin B and Its New Formulations: Pharmacologic Characteristics, Clinical Efficacy, and Tolerability. Transplant Infect. Dis. 1999, 1, 273−283. (174) Krauth-siegel, R. L.; Meiering, S. K.; Schmidt, H. The ParasiteSpecific Trypanothione Metabolism of Trypanosoma and Leishmania. Biol. Chem. 2003, 384, 539−549. (175) Sindermann, H.; Engel, J. Development of Miltefosine as an Oral Treatment for Leishmaniasis. Trans. R. Soc. Trop. Med. Hyg. 2006, 100, S17−S20. (176) Dorlo, T. P. C.; Balasegaram, M.; Beijnen, J. H.; de vries, P. J. Miltefosine: A Review of Its Pharmacology and Therapeutic Efficacy in the Treatment of Leishmaniasis. J. Antimicrob. Chemother. 2012, 67, 2576−2597. (177) Jhingran, A.; Chawla, B.; Saxena, S.; Barrett, M. P.; Madhubala, R. Paromomycin: Uptake and Resistance in Leishmania Donovani. Mol. Biochem. Parasitol. 2009, 164, 111−117. (178) Maarouf, M.; Adeline, M. T.; Solignac, M.; Vautrin, D.; RobertGero, M. Development and Characterisation of ParomomycinResistant Leishmania Donovani Promastigotes. Parasite 1998, 5, 167−173. (179) Garnier, T.; Brown, M. B.; Lawrence, M. J.; Croft, S. L. In-Vitro and in-Vivo Studies on a Topical Formulation of Sitamaquine Dihydrochloride for Cutaneous Leishmaniasis. J. Pharm. Pharmacol. 2006, 58, 1043−1054. (180) Basselin, M.; Lawrence, F.; Robert-Gero, M. Promastigotes and Axenic Amastigotes. Biochem. J. 1996, 315, 631−634. (181) Kandpal, M.; Fouce, R. B.; Pal, A.; Guru, P. Y.; Tekwani, B. L. Kinetics and Molecular Characteristics of Arginine Transport by Leishmania Donovani Promastigotes. Mol. Biochem. Parasitol. 1995, 71, 193−201. (182) Khan, M. O. F. Trypanothione Reductase: A Viable Chemotherapeutic Target for Antitrypanosomal and Antileishmanial Drug Design. Drug Target Insights 2007, 2, 129−146. (183) Oza, S. L.; Shaw, M. P.; Wyllie, S.; Fairlamb, A. H. Trypanothione Biosynthesis in Leishmania Major. Mol. Biochem. Parasitol. 2005, 139, 107−116. (184) Yan, S.; Li, F.; Ding, K.; Sun, H. Reduction of Pentavalent Antimony by Trypanothione and Formation of a Binary and Ternary Complex of Antimony(III) and Trypanothione. JBIC, J. Biol. Inorg. Chem. 2003, 8, 689−697. (185) Baiocco, P.; Colotti, G.; Franceschini, S.; Ilari, A. Molecular Basis of Antimony Treatment in Leishmaniasis. J. Med. Chem. 2009, 52, 2603−2612. (186) Parish, R. V.; Buckley, R. G.; Fricker, S. P.; Mack, J.; Hargreaves, L.; Wright, J. P.; Elsome, A. M.; Theobald, B. R. C. Chemical and Biological Reactions of Diacetato[2-(Dimethylaminomethyl)-Phenyl Gold(III), [Au(O2CMe)2(Dmamp)]. J. Chem. Soc., Dalton Trans. 1996, 69−74. (187) Singh, A. M. P.; Mishra, M.; Khan, A. B.; Ramdas, S. L.; Panjiyar, S. Gold Treatment For Kala-Azar. Br. Med. J. 1989, 299, 1318. (188) Ilari, A.; Baiocco, P.; Messori, L.; Fiorillo, A.; Boffi, A.; Gramiccia, M.; Di Muccio, T.; Colotti, G. A Gold-Containing Drug against Parasitic Polyamine Metabolism: The X-Ray Structure of Trypanothione Reductase from Leishmania Infantum in Complex with Auranofin Reveals a Dual Mechanism of Enzyme Inhibition. Amino Acids 2012, 42, 803−811. BI


Chemical Reviews

Review

Ruthenium(II)Tetraammine Nitrosyl Complexes. Eur. J. Med. Chem. 2010, 45, 4180−4187. (205) Orsini, T. M.; Kawakami, N. Y.; Panis, C.; Thomazelli, A. P. F. d. S.; Tomiotto-Pellissier, F.; Cataneo, A. H. D.; Kian, D.; Yamauchi, L. M.; Junior, F. S. G.; Lopes, L. G. d. F.; et al. Antileishmanial Activity and Inducible Nitric Oxide Synthase Activation by RuNO Complex. Mediators Inflammation 2016, 2016, 2631625. (206) Quintal, S.; Morais, T. S.; Matos, C. P.; Paula Robalo, M.; Piedade, M. F. M.; Villa De Brito, M. J.; Helena Garcia, M.; Marques, M.; Maia, C.; Campino, L.; et al. Synthesis, Structural Characterization and Leishmanicidal Activity Evaluation of Ferrocenyl N-Heterocyclic Compounds. J. Organomet. Chem. 2013, 745−746, 299−311. (207) Mittra, B.; Laranjeira-Silva, M. F.; Perrone Bezerra de Menezes, J.; Jensen, J.; Michailowsky, V.; Andrews, N. W. A Trypanosomatid Iron Transporter That Regulates Mitochondrial Function Is Required for Leishmania Amazonensis Virulence. PLoS Pathog. 2016, 12, e1005340. (208) Tabbì, G.; Cassino, C.; Cavigiolio, G.; Colangelo, D.; Ghiglia, A.; Viano, I.; Osella, D. Water Stability and Cytotoxic Activity Relationship of a Series of Ferrocenium Derivatives. ESR Insights on the Radical Production during the Degradation Process. J. Med. Chem. 2002, 45, 5786−5796. (209) Tamura, H.; Miwa, M. DNA Cleaving Activity and Cytotoxic Activity of Ferricenium Cations. Chem. Lett. 1997, 26, 1177−1178. (210) Ikram, M.; Rehman, S.; Jamal, Q.; Shah, A. Activity on Leishmania Tropica of Metal Complexes with NNOO Tetradentate Schiff Base Ligand: Kinetic and Thermodynamic Studies from TGDTA Analysis. J. Chem. Soc. Pakistan 2015, 37, 869−878. (211) Velásquez, A. M. A.; de Souza, R. A.; Passalacqua, T. G.; Ribeiro, A. R.; Scontri, M.; Chin, C. M.; de Almeida, L.; Del Cistia, M. L.; Rosa, J. A. Da; Mauro, A. E.; et al. Antiprotozoal Activity of the Cyclopalladated Complexes against Leishmania Amazonensis and Trypanosoma Cruzi. J. Braz. Chem. Soc. 2016, 27, 1032−1039. (212) Tabrizi, L.; Chiniforoshan, H. New Platinum(II) Complexes of CCC-Pincer N-Heterocyclic Carbene Ligand: Synthesis, Characterization, Cytotoxicity and Antileishmanial Activity. J. Organomet. Chem. 2016, 818, 98−105. (213) Machado, P. de A.; Mota, V. Z.; Cavalli, A. C. de L.; de Carvalho, G. S. G.; Da Silva, A. D.; Gameiro, J.; Cuin, A.; Coimbra, E. S. High Selective Antileishmanial Activity of Vanadium Complex with Stilbene Derivative. Acta Trop. 2015, 148, 120−127. (214) Turner, T. L.; Nguyen, V. H.; McLauchlan, C. C.; Dymon, Z.; Dorsey, B. M.; Hooker, J. D.; Jones, M. A. Inhibitory Effects of Decavanadate on Several Enzymes and Leishmania Tarentolae in Vitro. J. Inorg. Biochem. 2012, 108, 96−104. (215) Zhao, Y.; Hu, X.; Liu, Y.; Dong, S.; Wen, Z.; He, W.; Zhang, S.; Huang, Q.; Shi, M. ROS Signaling under Metabolic Stress: Cross-Talk between AMPK and AKT Pathway. Mol. Cancer 2017, 16, 79. (216) Martín-Montes, Á .; Plano, D.; Martín-Escolano, R.; Alcolea, V.; Díaz, M.; Pérez-Silanes, S.; Espuelas, S.; Moreno, E.; Marín, C.; Gutiérrez-Sánchez, R.; et al. Library of Seleno-Compounds as Novel Agents against Leishmania Species. Antimicrob. Agents Chemother. 2017, 61, e02546-16. (217) Iniguez, E.; Varela-Ramirez, A.; Martinez, A.; Torres, C. L.; Sanchez-Delgado, R. A.; Maldonado, R. A. Ruthenium-Clotrimazole Complex Has Significant Efficacy in the Murine Model of Cutaneous Leishmaniasis. Acta Trop. 2016, 164, 402−410. (218) Chen, H.; Parkinson, J. A.; Morris, R. E.; Sadler, P. J. Highly Selective Binding of Organometallic Ruthenium Ethylenediamine Complexes to Nucleic Acids: Novel Recognition Mechanisms. J. Am. Chem. Soc. 2003, 125, 173−186. (219) Habtemariam, A.; Melchart, M.; Fernández, R.; Parsons, S.; Oswald, I. D. H.; Parkin, A.; Fabbiani, F. P. A.; Davidson, J. E.; Dawson, A.; Aird, R. E.; et al. Structure-Activity Relationships for Cytotoxic Ruthenium(II) Arene Complexes Containing N,N-, N,O-, and O,OChelating Ligands. J. Med. Chem. 2006, 49, 6858−6868. (220) Lincoln, P.; Norden, B. DNA Binding Geometries of Ruthenium(II) Complexes with 1,10-Phenanthroline and 2,2’-Bipyridine Ligands Studied with Linear Dichroism Spectroscopy. Borderline Cases of Intercalation. J. Phys. Chem. B 1998, 102, 9583−9594.

(189) Mota, V. Z.; De Carvalho, G. S. G.; Da Silva, A. D.; Costa, L. A. S.; De Almeida Machado, P.; Coimbra, E. S.; Ferreira, C. V.; Shishido, S. M.; Cuin, A. Gold Complexes with Benzimidazole Derivatives: Synthesis, Characterization and Biological Studies. BioMetals 2014, 27, 183−194. (190) Segura, D. F.; Netto, A. V. G.; Frem, R. C. G.; Mauro, A. E.; Da Silva, P. B.; Fernandes, J. A.; Paz, F. A. A.; Dias, A. L. T.; Silva, N. C.; De Almeida, E. T.; et al. Synthesis and Biological Evaluation of Ternary Silver Compounds Bearing N,N-Chelating Ligands and Thiourea: XRay Structure of [{Ag(Bpy)(μ-Tu)}2](NO3)2 (Bpy = 2,2’-Bipyridine; Tu = Thiourea). Polyhedron 2014, 79, 197−206. (191) Rauf, M. K.; Yaseen, S.; Badshah, A.; Zaib, S.; Arshad, R.; Imtiaz-Ud-Din; Tahir, M. N.; Iqbal, J. Synthesis, Characterization and Urease Inhibition, in Vitro Anticancer and Antileishmanial Studies of Ni(II) Complexes with N,N,N’-Trisubstituted Thioureas. JBIC, J. Biol. Inorg. Chem. 2015, 20, 541−554. (192) Yaseen, S.; Rauf, M. K.; Zaib, S.; Badshah, A.; Tahir, M. N.; Ali, M. I.; Imtiaz-Ud-Din; Shahid, M.; Iqbal, J. Synthesis, Characterization and Urease Inhibition, in Vitro Anticancer and Antileishmanial Studies of Co(III) Complexes with N,N,N’-Trisubstituted Acylthioureas. Inorg. Chim. Acta 2016, 443, 69−77. (193) Portas, A. D. S.; Miguel, D. C.; Yokoyama-Yasunaka, J. K. L.; Uliana, S. R. B.; Espósito, B. P. Increasing the Activity of Copper(II) Complexes against Leishmania through Lipophilicity and pro-Oxidant Ability. JBIC, J. Biol. Inorg. Chem. 2012, 17, 107−112. (194) Da Silva Maffei, R.; Yokoyama-Yasunaka, J. K. U.; Miguel, D. C.; Uliana, S. R. B.; Espósito, B. P. Synthesis, Characterization and Evaluation of Antileishmanial Activity of Copper(II) with Fluorinated α-Hydroxycarboxylate Ligands. BioMetals 2009, 22, 1095−1101. (195) Khan, M. I.; Gul, S.; Hussain, I.; Khan, M. A.; Ashfaq, M.; Inayat-Ur-Rahman; Ullah, F.; Durrani, G. F.; Baloch, I. B.; Naz, R. In Vitro Anti-Leishmanial and Anti-Fungal Effects of New Sb III Carboxylates. Org. Med. Chem. Lett. 2011, 1, 2. (196) Ali, M. I.; Rauf, M. K.; Badshah, A.; Kumar, I.; Forsyth, C. M.; Junk, P. C.; Kedzierski, L.; Andrews, P. C. Anti-Leishmanial Activity of Heteroleptic Organometallic Sb(v) Compounds. Dalton Trans 2013, 42, 16733−16741. (197) Ong, Y. C.; Blair, V. L.; Kedzierski, L.; Andrews, P. C. Stability and Toxicity of Heteroleptic Organometallic Bi(V) Complexes towards Leishmania Major. Dalton Trans 2014, 43, 12904−12916. (198) Ong, Y. C.; Blair, V. L.; Kedzierski, L.; Tuck, K. L.; Andrews, P. C. Stability and Toxicity of Tris-Tolyl Bismuth(v) Dicarboxylates and Their Biological Activity towards Leishmania Major. Dalton Trans 2015, 44, 18215−18226. (199) Mushtaq, R.; Rauf, M. K.; Bond, M.; Badshah, A.; Ali, M. I.; Nadhman, A.; Yasinzai, M.; Tahir, M. N. A Structural Investigation of Heteroleptic Pentavalent Antimonials and Their Leishmanicidal Activity. Appl. Organomet. Chem. 2016, 30, 465−472. (200) Gomes, M. L.; DeFreitas-Silva, G.; dos Reis, P. G.; Melo, M. N.; Frézard, F.; Demicheli, C.; Idemori, Y. M. Synthesis and Characterization of Bismuth(III) and Antimony(V) Porphyrins: High Antileishmanial Activity against Antimony-Resistant Parasite. JBIC, J. Biol. Inorg. Chem. 2015, 20, 771−779. (201) Baquedano, Y.; Alcolea, V.; Toro, M. Á .; Gutiérrez, K. J.; Nguewa, P.; Font, M.; Moreno, E.; Espuelas, S.; Jiménez-Ruiz, A.; Palop, J. A.; et al. Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents. Antimicrob. Agents Chemother. 2016, 60, 3802−3812. (202) Singh, M. K.; Bhaumik, S. K.; Karmakar, S.; Paul, J.; Sawoo, S.; Majumder, H. K.; Roy, A. Copper Salisylaldoxime (CuSAL) Imparts Protective Efficacy against Visceral Leishmaniasis by Targeting Leishmania Donovani Topoisomerase IB. Exp. Parasitol. 2017, 175, 8−20. (203) Kawakami, N. Y.; Tomiotto-Pellissier, F.; Cataneo, A. H. D.; Orsini, T. M.; Thomazelli, A. P. F. D. S.; Panis, C.; Conchon-Costa, I.; Pavanelli, W. R. Sodium Nitroprusside Has Leishmanicidal Activity Independent of INOS. Rev. Soc. Bras. Med. Trop. 2016, 49, 68−73. (204) Melo Pereira, J. C.; Carregaro, V.; Costa, D. L.; Santana Da Silva, J.; Cunha, F. Q.; Franco, D. W. Antileishmanial Activity of BJ


Chemical Reviews

Review

(221) Song, H.; Kaiser, J. T.; Barton, J. K. Crystal Structure of Δ[Ru(Bpy)2dppz]2+ Bound to Mismatched DNA Reveals Side-by-Side Metalloinsertion and Intercalation. Nat. Chem. 2012, 4, 615−620. (222) Estrada, J. G.; Sánchez-Delgado, R. A. Spectroscopic Study of the Interactions of Ruthenium-Ketoconazole Complexes of Known Antiparasitic Activity with Human Serum Albumin and Apotransferrin. J. Mex. Chem. Soc. 2013, 57, 169−174. (223) Simpson, P. V.; Nagel, C.; Bruhn, H.; Schatzschneider, U. Antibacterial and Antiparasitic Activity of Manganese(I) Tricarbonyl Complexes with Ketoconazole, Miconazole, and Clotrimazole Ligands. Organometallics 2015, 34, 3809−3815. (224) Paloque, L.; Hemmert, C.; Valentin, A.; Gornitzka, H. Synthesis, Characterization, and Antileishmanial Activities of Gold(I) Complexes Involving Quinoline Functionalized N -Heterocyclic Carbenes. Eur. J. Med. Chem. 2015, 94, 22−29. (225) Reddy, A.; Sangenito, L. S.; Guedes, A. de A.; Branquinha, M. H.; Kavanagh, K.; McGinley, J.; dos Santos, A. L. S.; Velasco-Torrijos, T. Glycosylated Metal Chelators as Anti-Parasitic Agents with Tunable Selectivity. Dalton Trans 2017, 46, 5297−5307. (226) Rice, D. R.; Vacchina, P.; Norris-Mullins, B.; Morales, M. A.; Smith, B. D. Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania Major. Antimicrob. Agents Chemother. 2016, 60, 2932−2940. (227) Lerman, L. S. S. Structural Considerations in the Interaction of DNA and Acridines. J. Mol. Biol. 1961, 3, 18−30. (228) Koster, D. A.; Palle, K.; Bot, E. S. M.; Bjornsti, M.-A.; Dekker, N. H. Antitumour Drugs Impede DNA Uncoiling by Topoisomerase I. Nature 2007, 448, 213−217. (229) Biebricher, A. S.; Heller, I.; Roijmans, R. F. H.; Hoekstra, T. P.; Peterman, E. J. G.; Wuite, G. J. L. The Impact of DNA Intercalators on DNA and DNA-Processing Enzymes Elucidated through ForceDependent Binding Kinetics. Nat. Commun. 2015, 6, 7304. (230) Navarro, M.; Cisneros-Fajardo, E. J.; Fernandez-Mestre, M.; Arrieche, D.; Marchan, E. Synthesis, Characterization, DNA Binding Study and Biological Activity against Leishmania Mexicana of [Cu(Dppz)2]BF4. J. Inorg. Biochem. 2003, 97, 364−369. (231) Navarro, M.; Cisneros-Fajardo, E. J.; Marchan, E. New Silver Polypyridyl Complexes: Synthesis, Characterization and Biological Activity on Leishmania Mexicana. Arzneim. Forsch. 2006, 56, 600−604. (232) Navarro, M.; Hernández, C.; Colmenares, I.; Hernández, P.; Fernández, M.; Sierraalta, A.; Marchán, E. Synthesis and Characterization of [Au(Dppz)2]Cl3. DNA Interaction Studies and Biological Activity against Leishmania (L.) Mexicana. J. Inorg. Biochem. 2007, 101, 111−116. (233) Lizarazo-Jaimes, E. H.; Monte-Neto, R. L.; Reis, P. G.; Fernandes, N. G.; Speziali, N. L.; Melo, M. N.; Frézard, F.; Demicheli, C. Improved Antileishmanial Activity of Dppz through Complexation with Antimony(III) and Bismuth(III): Investigation of the Role of the Metal. Molecules 2012, 17, 12622−12635. (234) Lizarazo-Jaimes, E. H.; Reis, P. G.; Bezerra, F. M.; Rodrigues, B. L.; Monte-Neto, R. L.; Melo, M. N.; Frézard, F.; Demicheli, C. Complexes of Different Nitrogen Donor Heterocyclic Ligands with SbCl3 and PhSbCl2 as Potential Antileishmanial Agents against SbIIISensitive and -Resistant Parasites. J. Inorg. Biochem. 2014, 132, 30−36. (235) Bonse, S.; Richards, J. M.; Ross, S. A.; Lowe, G.; Krauth-Siegel, R. L. (2,2’:6’,2’-Terpyridine)Platinum(II) Complexes Are Irreversible Inhibitors of Trypanosoma Cruzi Trypanothione Reductase but Not of Human Glutathione Reductase. J. Med. Chem. 2000, 43, 4812−4821. (236) Carmo, A. M. L.; Silva, F. M. C.; Machado, P. A.; Fontes, A. P. S.; Pavan, F. R.; Leite, C. Q. F.; Leite, S. R. de A.; Coimbra, E. S.; Da Silva, A. D. Synthesis of 4-Aminoquinoline Analogues and Their Platinum(II) Complexes as New Antileishmanial and Antitubercular Agents. Biomed. Pharmacother. 2011, 65, 204−209. (237) Visbal, G.; Marchán, E.; Maldonado, A.; Simoni, Z.; Navarro, M. Synthesis and Characterization of Platinum-Sterol Hydrazone Complexes with Biological Activity against Leishmania (L.) Mexicana. J. Inorg. Biochem. 2008, 102, 547−554. (238) Mesa-Valle, C. M.; Rodriguez-Cabezas, M. N.; MoraledaLindez, V.; Craciunescu, D.; Sanchez-Moreno, M.; Osuna, A. In Vitro

and in Vivo Activity of Two Pt(IV) Salts against Leishmania Donovani. Pharmacology 1998, 57, 160−172. (239) Franco, L. P.; De Góis, E. P.; Codonho, B. S.; Pavan, A. L. R.; De Oliveira Pereira, I.; Marques, M. J.; De Almeida, E. T. Palladium(II) Imine Ligands Cyclometallated Complexes with a Potential Leishmanicidal Activity on Leishmania (L.) Amazonensis. Med. Chem. Res. 2013, 22, 1049−1056. (240) Croft, S. L.; Neal, R. A.; Craciuunescu, D. G.; Certad-Fombona, G. The Activity of Platium, Iridum and Rhodium Drug Complexes against Leishmania Donovani. Trop. Med. Parasitol. 1992, 43, 24−28. (241) Mbongo, N.; Loiseau, P. M.; Lawrence, F.; Bories, C.; Craciunescu, D. G.; Robert-Gero, M. In Vitro Sensitivity of Leishmania Donovani to Organometallic Derivatives of Pentamidine. Parasitol. Res. 1997, 83, 515−517. (242) Loiseau, P. M.; Mbongo, N.; Bories, C.; Boulard, Y.; Craciunescu, D. G. In Vivo Antileishmanial Action of Ir-(COD)Pentamidine Tetraphenylborate on Leishmania Donovani and Leishmania Major Mouse Models. Parasite 2000, 7, 103. (243) Yadav, M. K.; Rajput, G.; Srivastava, K.; Singh, R. K.; Mishra, R.; Drew, M. G. B.; Singh, N. Anti-Leishmanial Activity of Ni(II), Pd(II) and Pt(II) β-Oxodithioester Complexes. New J. Chem. 2015, 39, 6358− 6366. (244) Benítez, J.; Becco, L.; Correia, I.; Leal, S. M.; Guiset, H.; Pessoa, J. C.; Lorenzo, J.; Tanco, S.; Escobar, P.; Moreno, V.; et al. Vanadium Polypyridyl Compounds as Potential Antiparasitic and Antitumoral Agents: New Achievements. J. Inorg. Biochem. 2011, 105, 303−312. (245) Magán, R.; Marín, C.; Rosales, M. J.; Barrera, M. A.; Salas, J. M.; Sánchez-Moreno, M. Activities of Pt(II) and Ru(III) TriazolePyrimidine Complexes against Trypanosoma Cruzi and T. Brucei Brucei. Pharmacology 2004, 70, 83−90. (246) Navarro, J. A. R.; Salas, J. M.; Romero, M. A.; Vilaplana, R.; Gonzalez-Vílchez, F.; Faure, R. Cis-[PtCl2 (4, 7-H-5-Methyl-7-Oxo [1, 2, 4] Triazolo [1, 5-a] Pyrimidine) 2]: A Sterically Restrictive New Cisplatin Analogue. Reaction Kinetics with Model Nucleobases, DNA Interaction Studies, Antitumor Activity, and Structure-Activity Relationships. J. Med. Chem. 1998, 41, 332−338. (247) Łakomska, I.; Fandzloch, M.; Muzioł, T.; Lis, T.; Jezierska, J. Synthesis, Characterization and Antitumor Properties of Two Highly Cytotoxic Ruthenium(III) Complexes with Bulky Triazolopyrimidine Ligands. Dalton Trans 2013, 42, 6219−6226. (248) Velders, A. H.; Bergamo, A.; Alessio, E.; Zangrando, E.; Haasnoot, J. G.; Casarsa, C.; Cocchietto, M.; Zorzet, S.; Sava, G. Synthesis and Chemical - Pharmacological Characterization of the Antimetastatic NAMI-A-Type Ru (III) Complexes (Hdmtp)[TransRuCl 4 (Dmso-S)(Dmtp)], (Na)[Trans-RuCl4(Dmso-S)(Dmtp)], and 5,7-Dimethyl[1,2,4]Triazolo[1,5-α]Pyrimidine). J. Med. Chem. 2004, 47, 1110−1121. (249) Zhang, N.; Ayral-Kaloustian, S.; Nguyen, T.; Afragola, J.; Hernandez, R.; Lucas, J.; Gibbons, J.; Beyer, C. Synthesis and SAR of [1,2,4]Triazolo[1,5-α]Pyrimidines, a Class of Anti-Cancer Agents with a Unique Mechanism of Tubulin Inhibition. J. Med. Chem. 2007, 50, 319−327. (250) Caballero, A. B.; Rodríguez-Diéguez, A.; Salas, J. M.; SánchezMoreno, M.; Marín, C.; Ramírez-Macías, I.; Santamaría-Díaz, N.; Gutiérrez-Sánchez, R. Lanthanide Complexes Containing 5-Methyl1,2,4-Triazolo[1,5-α] Pyrimidin-7(4H)-One and Their Therapeutic Potential to Fight Leishmaniasis and Chagas Disease. J. Inorg. Biochem. 2014, 138, 39−46. (251) Caballero, A. B.; Marín, C.; Ramírez-Macías, I.; RodríguezDiéguez, A.; Quirós, M.; Salas, J. M.; Sánchez-Moreno, M. Structural Consequences of the Introduction of 2,2′-Bipyrimidine as Auxiliary Ligand in Triazolopyrimidine-Based Transition Metal Complexes. In Vitro Antiparasitic Activity. Polyhedron 2012, 33, 137−144. (252) Caballero, A. B.; Rodríguez-Diéguez, A.; Quirós, M.; Salas, J. M.; Huertas, Ó .; Ramírez-Macías, I.; Olmo, F.; Marín, C.; ChavesLemaur, G.; Gutierrez-Sánchez, R.; et al. Triazolopyrimidine Compounds Containing First-Row Transition Metals and Their Activity against the Neglected Infectious Chagas Disease and Leishmaniasis. Eur. J. Med. Chem. 2014, 85, 526−534. BK


Chemical Reviews

Review

(253) Ramírez-Macías, I.; Maldonado, C. R.; Marín, C.; Olmo, F.; Gutiérrez-Sánchez, R.; Rosales, M. J.; Quirós, M.; Salas, J. M.; SánchezMoreno, M. In Vitro Anti-Leishmania Evaluation of Nickel Complexes with a Triazolopyrimidine Derivative against Leishmania Infantum and Leishmania Braziliensis. J. Inorg. Biochem. 2012, 112, 1−9. (254) Waseem, D.; Butt, A. F.; Haq, I.; Bhatti, M. H.; Khan, G. M. Carboxylate Derivatives of Tributyltin (IV) Complexes as Anticancer and Antileishmanial Agents. Daru, J. Pharm. Sci. 2017, 25, 8. (255) Gfeller, D.; Grosdidier, A.; Wirth, M.; Daina, A.; Michielin, O.; Zoete, V. SwissTargetPrediction: A Web Server for Target Prediction of Bioactive Small Molecules. Nucleic Acids Res. 2014, 42, W32−W38. (256) Khan, M. I.; Baloch, M. K.; Ashfaq, M. Spectral Analysis and in Vitro Cytotoxicity Profiles of Novel Organotin(IV) Esters of 2Maleimidopropanoic Acid. J. Enzyme Inhib. Med. Chem. 2007, 22, 343− 350. (257) Shujha, S.; Shah, A.; Zia-Ur-Rehman; Muhammad, N.; Ali, S.; Qureshi, R.; Khalid, N.; Meetsma, A. Diorganotin(IV) Derivatives of ONO Tridentate Schiff Base: Synthesis, Crystal Structure, in Vitro Antimicrobial, Anti-Leishmanial and DNA Binding Studies. Eur. J. Med. Chem. 2010, 45, 2902−2911. (258) Rocha, M. N.; Nogueira, P. M.; Demicheli, C.; De Oliveira, L. G.; Da Silva, M. M.; Frézard, F.; Melo, M. N.; Soares, R. P. Cytotoxicity and in Vitro Antileishmanial Activity of Antimony (V), Bismuth (V), and Tin (IV) Complexes of Lapachol. Bioinorg. Chem. Appl. 2013, 2013, 1−7. (259) Barbosa, M. I. F.; Corrêa, R. S.; De Oliveira, K. M.; Rodrigues, C.; Ellena, J.; Nascimento, O. R.; Rocha, V. P. C.; Nonato, F. R.; Macedo, T. S.; Barbosa-Filho, J. M.; et al. Antiparasitic Activities of Novel Ruthenium/Lapachol Complexes. J. Inorg. Biochem. 2014, 136, 33−39. (260) Sirajuddin, M.; Ali, S.; McKee, V.; Sohail, M.; Pasha, H. Potentially Bioactive Organotin(IV) Compounds: Synthesis, Characterization, in Vitro Bioactivities and Interaction with SS-DNA. Eur. J. Med. Chem. 2014, 84, 343−363. (261) Qureshi, Q. U. A. H.; Nadhman, A.; Sirajuddin, M.; Shahnaz, G.; Ali, S.; Shah, A.; Yasinzai, M. M. Organotin(IV) Complexes of Carboxylate Derivative as Potential Chemotherapeutic Agents against Leishmania. Inorg. Chim. Acta 2014, 423, 220−228. (262) Sirajuddin, M.; Ali, S.; McKee, V.; Zaib, S.; Iqbal, J. Organotin(Iv) Carboxylate Derivatives as a New Addition to Anticancer and Antileishmanial Agents: Design, Physicochemical Characterization and Interaction with Salmon Sperm DNA. RSC Adv. 2014, 4, 57505−57521. (263) Shaukat, A.; Mirza, H. M.; Ansari, A. H.; Yasinzai, M.; Zaidi, S. Z.; Dilshad, S.; Ansari, F. L. Benzimidazole Derivatives: Synthesis, Leishmanicidal Effectiveness, and Molecular Docking Studies. Med. Chem. Res. 2013, 22, 3606−3620. (264) Uddin, N.; Sirajuddin, M.; Uddin, N.; Tariq, M.; Ullah, H.; Ali, S.; Tirmizi, S. A.; Khan, A. R. Synthesis, Spectroscopic Characterization, Biological Screenings, DNA Binding Study and POM Analyses of Transition Metal Carboxylates. Spectrochim. Acta, Part A 2015, 140, 563−574. (265) Paladi, C. d. S.; Pimentel, I. A. S.; Katz, S.; Cunha, R. L.; Judice, W. A. d. S.; Caires, A. C.; Barbieri, C. L. In Vitro and in Vivo Activity of a Palladacycle Complex on Leishmania Amazonesis. PLoS Neglected Trop. Dis. 2012, 6, e1626. (266) Cantalupo Lima, C. B.; Arrais-Silva, W. W.; Rodrigues Cunha, R. L. O.; Giorgio, S. A Novel Organotellurium Compound (RT-01) as a New Antileishmanial Agent. Korean J. Parasitol. 2009, 47, 213−218. (267) Pimentel, I. A. S.; Paladi, C. de S.; Katz, S.; Júdice, W. A. de S.; Cunha, R. L. O. R.; Barbiéri, C. L. In Vitro and In Vivo Activity of an Organic Tellurium Compound on Leishmania (Leishmania) Chagasi. PLoS One 2012, 7, e48780. (268) Cunha, R. L. O. R.; Urano, M. E.; Chagas, J. R.; Almeida, P. C.; Bincoletto, C.; Tersariol, I. L. S.; Comasseto, J. V. Tellurium-Based Cysteine Protease Inhibitors: Evaluation of Novel Organotellurium(IV) Compounds as Inhibitors of Human Cathepsin B. Bioorg. Med. Chem. Lett. 2005, 15, 755−760.

(269) Abondanza, T. S.; Oliveira, C. R.; Barbosa, C. M. V.; Pereira, F. E. G.; Cunha, R. L. O. R.; Caires, A. C. F.; Comasseto, J. V.; Queiroz, M. L. S.; Valadares, M. C.; Bincoletto, C. Bcl-2 Expression and Apoptosis Induction in Human HL60 Leukaemic Cells Treated with a Novel Organotellurium(IV) Compound RT-04. Food Chem. Toxicol. 2008, 46, 2540−2545. (270) Lima-Junior, D. S.; Costa, D. L.; Carregaro, V.; Cunha, L. D.; Silva, A. L. N.; Mineo, T. W. P.; Gutierrez, F. R. S.; Bellio, M.; Bortoluci, K. R.; Flavell, R. a.; et al. Inflammasome-Derived IL-1β Production Induces Nitric Oxide-Mediated Resistance to Leishmania. Nat. Med. 2013, 19, 909−915. (271) Fernández-Figueroa, E. A.; Rangel-Escareno, C.; EspinosaMateos, V.; Carrillo-Sánchez, K.; Salaiza-Suazo, N.; Carrada-Figueroa, G.; March-Mifsut, S.; Becker, I. Disease Severity in Patients Infected with Leishmania Mexicana Relates to IL-1β. PLoS Neglected Trop. Dis. 2012, 6, e1533. (272) Moravej, A.; Rasouli, M.; Kalani, M.; Asaei, S.; Kiany, S.; Najafipour, S.; Koohpayeh, A.; Abdollahi, A. IL-1β(−511T/C) Gene Polymorphism Not IL-1B (+3953T/C) and LT-a (+252A/G) Gene Variants Confers Susceptibility to Visceral Leishmaniasis. Mol. Biol. Rep. 2012, 39, 6907−6914. (273) Adriazola, I. O.; Amaral, A. E. Do; Amorim, J. C.; Correia, B. L.; Petkowicz, C. L. O.; Mercê, A. L. R.; Noleto, G. R. Macrophage Activation and Leishmanicidal Activity by Galactomannan and Its Oxovanadium (IV/V) Complex in Vitro. J. Inorg. Biochem. 2014, 132, 45−51. (274) Amaral, A. E. Do; Petkowicz, C. L. O.; Mercê, A. L. R.; Iacomini, M.; Martinez, G. R.; Merlin Rocha, M. E.; Cadena, S. M. S. C.; Noleto, G. R. Leishmanicidal Activity of Polysaccharides and Their Oxovanadium(IV/V) Complexes. Eur. J. Med. Chem. 2015, 90, 732− 741. (275) Andrews, P. C.; Frank, R.; Junk, P. C.; Kedzierski, L.; Kumar, I.; MacLellan, J. G. Anti-Leishmanial Activity of Homo- and Heteroleptic Bismuth(III) Carboxylates. J. Inorg. Biochem. 2011, 105, 454−461. (276) Andrews, P. C.; Junk, P.; Kedzierski, L.; Peiris, R. M. AntiLeishmanial Activity of Novel Homo- and Heteroleptic Bismuth (III) Thiocarboxylates. Aust. J. Chem. 2013, 66, 1297−1305. (277) Andrews, P. C.; Blair, V. L.; Ferrero, R. L.; Junk, P. C.; Kedzierski, L.; Peiris, R. M. Bismuth(III) β-Thioxoketonates as Antibiotics against Helicobacter Pylori and as Anti-Leishmanial Agents. Dalton Trans 2014, 43, 1279−1291. (278) Luqman, A.; Blair, V. L.; Brammananth, R.; Crellin, P. K.; Coppel, R. L.; Kedzierski, L.; Andrews, P. C. Homoleptic and Heteroleptic Bismuth(III) Thiazole-Thiolates and the Influence of Ring Substitution on Their Antibacterial and Antileishmanial Activity. Eur. J. Inorg. Chem. 2015, 2015, 725−733. (279) Loh, A.; Ong, Y. C.; Blair, V. L.; Kedzierski, L.; Andrews, P. C. Bismuth(III) α-Hydroxy Carboxylates: Highly Selective Toxicity of Glycolates towards Leishmania Major. JBIC, J. Biol. Inorg. Chem. 2015, 20, 1193−1203. (280) Islam, A.; Da Silva, J. G.; Berbet, F. M.; Da Silva, S. M.; Rodrigues, B. L.; Beraldo, H.; Melo, M. N.; Frézard, F.; Demicheli, C. Novel Triphenylantimony(V) and Triphenylbismuth(V) Complexes with Benzoic Acid Derivatives: Structural Characterization, in Vitro Antileishmanial and Antibacterial Activities and Cytotoxicity against Macrophages. Molecules 2014, 19, 6009−6030. (281) Aulton, M. E.; Taylor, K. M. G. Aulton’s Pharmaceutics E-Book: The Design and Manufacture of Medicines; Elsevier, 2017. (282) Hamill, R. J. Amphotericin B Formulations: A Comparative Review of Efficacy and Toxicity. Drugs 2013, 73, 919−934. (283) Antimisiaris, S. G.; Ioannou, P. V.; Loiseau, P. M. In Vitro Antileishmanial and Trypanocidal Activities of Arsonoliposomes and Preliminary In-Vivo Distribution in BALB/c Mice. J. Pharm. Pharmacol. 2003, 55, 647−652. (284) Franco, A. M. R.; Grafova, I.; Soares, F. V.; Gentile, G.; Wyrepkowski, C. D. C.; Bolson, M. A.; Sargentini, E., Jr.; Carfagna, C.; Leskelä, M.; Grafov, A. Nanoscaled Hydrated Antimony (V) Oxide as a New Approach to First-Line Antileishmanial Drugs. Int. J. Nanomed. 2016, 11, 6771−6780. BL


Chemical Reviews

Review

(285) Fernandes, F. R.; Ferreira, W. A.; Campos, M. A.; Ramos, G. S.; Kato, K. C.; Almeida, G. G.; Corrêa, J. D.; Melo, M. N.; Demicheli, C.; Frézard, F. Amphiphilic Antimony(V) Complexes for Oral Treatment of Visceral Leishmaniasis. Antimicrob. Agents Chemother. 2013, 57, 4229−4236. (286) Lanza, J. S.; Fernandes, F. R.; Corrêa-Júnior, J. D.; Vilela, J. M.; Magalhães-Paniago, R.; Ferreira, L. A.; Andrade, M. S.; Demicheli, C.; Melo, M. N.; Frezard, F. Polarity-Sensitive Nanocarrier for Oral Delivery of Sb (V) and Treatment of Cutaneous Leishmaniasis. Int. J. Nanomed. 2016, 2305−2318. (287) Frézard, F.; Martins, P. S.; Bahia, A. P. C. O.; Le Moyec, L.; de Melo, A. L.; Pimenta, A. M. C.; Salerno, M.; Silva, J. B. B. da; Demicheli, C. Enhanced Oral Delivery of Antimony from Meglumine Antimoniate/β-Cyclodextrin Nanoassemblies. Int. J. Pharm. 2008, 347, 102−108. (288) Singh, P. K.; Ajay, A.; Kushwaha, S.; Tripathi, R. P.; MisraBhattacharya, S. Towards Novel Antifilarial Drugs: Challenges and Recent Developments. Future Med. Chem. 2010, 2, 251−283. (289) World Health Organization (WHO). Lymphatic Filariasis. http://www.who.int/en/news-room/fact-sheets/detail/lymphaticfilariasis (accessed Apr 26, 2018). (290) Chandra, M.; Sahay, A. N.; Pandey, D. S.; Tripathi, R. P.; Saxena, J. K.; Reddy, V. J. M.; Carmen Puerta, M.; Valerga, P. Potential Inhibitors of DNA Topoisomerase II: Ruthenium(II) Poly-Pyridyl and Pyridyl-Azine Complexes. J. Organomet. Chem. 2004, 689, 2256−2267. (291) Loiseau, P. M.; Jaffe, J. J.; Craciunescu, D. G. In Vitro Antifilarial Activity of Organometallic Complexes against Infective Larvae of Molinema Dessetae and Adult Females of Brugia Pahangi. Int. J. Parasitol. 1998, 28, 1279−1282. (292) Dikti Vildina, J.; Kalmobe, J.; Djafsia, B.; Schmidt, T. J.; Liebau, E.; Ndjonka, D. Anti-Onchocerca and Anti-Caenorhabditis Activity of a Hydro-Alcoholic Extract from the Fruits of Acacia Nilotica and Some Proanthocyanidin Derivatives. Molecules 2017, 22, 748. (293) World Health Organization (WHO). Lymphatic Filariasis. http://www.who.int/en/news-room/fact-sheets/detail/lymphaticfilariasis (accessed May 25, 2018). (294) Lustigman, S.; McCarter, J. P. Ivermectin Resistance in Onchocerca Volvulus: Toward a Genetic Basis. PLoS Neglected Trop. Dis. 2007, 1, e76 : 1−3. . (295) Mainsah, E. N.; Ntum, S.-J. E.; Samje, M.; Cho-ngwa, F.; Ndifon, P. T.; Yong, J. N. Synthesis and Anti-Onchocercal Activity of Isonicotinoylhydrazones and Their Copper (II) and Zinc (II) Complexes. Anti-Infect. Agents 2016, 14, 47−52. (296) Biot, C.; Castro, W.; Botté, C. Y.; Navarro, M. The Therapeutic Potential of Metal-Based Antimalarial Agents: Implications for the Mechanism of Action. Dalton Trans 2012, 41, 6335−6450. (297) Ferreira, Mô. S.; de Oliveira, R. N.; de Oliveira, D. N.; Esteves, C. Z.; Allegretti, S. M.; Catharino, R. R. Revealing Praziquantel Molecular Targets Using Mass Spectrometry Imaging: An Expeditious Approach Applied to Schistosoma Mansoni. Int. J. Parasitol. 2015, 45, 385−391. (298) World Health Organization (WHO). Schistosomiasis Fact Sheet. http://www.who.int/mediacentre/factsheets/fs115/en/ (accessed Nov 17, 2017). (299) Gryseels, B.; Polman, K.; Clerinx, J.; Kestens, L. Human Schistosomiasis. Lancet 2006, 368, 1106−1118. (300) Challenger, F.; Pritchard, F. The Action of Inorganic Halides on Organometallic Compounds. J. Chem. Soc., Trans. 1924, 125, 864−875. (301) Adenowo, A. F.; Oyinloye, B. E.; Ogunyinka, B. I.; Kappo, A. P. Impact of Human Schistosomiasis in Sub-Saharan Africa. Braz. J. Infect. Dis. 2015, 19, 196−205. (302) Stauffer, J. R., Jr; Arnegard, M. E.; Cetron, M.; Sullivan, J. J.; Chitsulo, L. A.; Turner, G. F.; Chiotha, S.; McKaye, K. R. Controlling Vectors and Hosts of Parasitic Diseases Using Fishes. BioScience 1997, 47, 41−49. (303) Vale, N.; Gouveia, M. J.; Rinaldi, G.; Brindley, P. J.; Gärtner, F.; Correia da Costa, J. M. Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action and Resistance. Antimicrob. Agents Chemother. 2017, 61, e02582-16.

(304) Cioli, D.; Pica-Mattoccia, L.; Basso, A.; Guidi, A. Schistosomiasis Control: Praziquantel Forever? Mol. Biochem. Parasitol. 2014, 195, 23−29. (305) Hess, J.; Keiser, J.; Gasser, G. Toward Organometallic Antischistosomal Drug Candidates. Future Med. Chem. 2015, 7, 821− 830. (306) Kuntz, A. N.; Davioud-Charvet, E.; Sayed, A. A.; Califf, L. L.; Dessolin, J.; Arnér, E. S. J.; Williams, D. L. Thioredoxin Glutathione Reductase from Schistosoma Mansoni: An Essential Parasite Enzyme and a Key Drug Target. PLoS Med. 2007, 4, e206. (307) Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Keiser, J.; Gasser, G. Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis, and Biological Evaluation. J. Med. Chem. 2012, 55, 8790−8798. (308) Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Gasser, R. B.; Keiser, J.; Gasser, G. [(η6-Praziquantel)Cr(CO)3] Derivatives with Remarkable in Vitro Anti-Schistosomal Activity. Chem. - Eur. J. 2013, 19, 2232−2235. (309) Patra, M.; Gasser, G. The Medicinal Chemistry of Ferrocene and Its Derivatives. Nat. Rev. Chem. 2017, 1, 0066. (310) Patra, M.; Merz, K.; Metzler-Nolte, N. Planar Chiral (η 6 -Arene)Cr(CO) 3 Containing Carboxylic Acid Derivatives: Synthesis and Use in the Preparation of Organometallic Analogues of the Antibiotic Platensimycin. Dalton Trans 2012, 41, 112−117. (311) Jaouen, G.; Vessieres, A.; Top, S.; Ismail, A. A.; Butler, I. S. Metal Carbonyl Fragments as a New Class of Markers in Molecular Biology. J. Am. Chem. Soc. 1985, 107, 4778−4780. (312) Patra, M.; Gasser, G.; Pinto, A.; Merz, K.; Ott, I.; Bandow, J. E.; Metzler-Nolte, N. Synthesis and Biological Evaluation of Chromium Bioorganometallics Based on the Antibiotic Platensimycin Lead Structure. ChemMedChem 2009, 4, 1930−1938. (313) Top, S.; Vessieres, A.; Jaouen, G. Synthesis of Tritium-labeled (3)-O-(3-hydroxypropyl)-17α-estradiol Chromium Tricarbonyl: The First Radioactive Transition Metal Carbonyl Steroid Hormone. J. Labelled Compd. Radiopharm. 1987, 24, 1257−1263. (314) Vessieres, A.; Top, S.; Ismail, A. A.; Butler, I. S.; Louer, M.; Jaouen, G. Organometallic Estrogens: Synthesis, Interaction with Lamb Uterine Estrogen Receptor, and Detection by Infrared Spectroscopy. Biochemistry 1988, 27, 6659−6666. (315) Bielig, H.; Velder, J.; Saiai, A.; Menning, M.; Meemboor, S.; Kalka-Moll, W.; Krönke, M.; Schmalz, H. G.; Kufer, T. A. AntiInflammatory Arene-Chromium Complexes Acting as Specific Inhibitors of NOD2 Signalling. ChemMedChem 2010, 5, 2065−2071. (316) Patra, M.; Ingram, K.; Leonidova, A.; Pierroz, V.; Ferrari, S.; Robertson, M. N.; Todd, M. H.; Keiser, J.; Gasser, G. In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η6Praziquantel)Cr(CO)3 Derivatives. J. Med. Chem. 2013, 56, 9192− 9198. (317) Clède, S.; Cowan, N.; Lambert, F.; Bertrand, H. C.; Rubbiani, R.; Patra, M.; Hess, J.; Sandt, C.; Trcera, N.; Gasser, G.; et al. Bimodal X-Ray and Infrared Imaging of an Organometallic Derivative of Praziquantel in Schistosoma Mansoni. ChemBioChem 2016, 17, 1004− 1007. (318) Meister, I.; Ingram-Sieber, K.; Cowan, N.; Todd, M.; Robertson, M. N.; Meli, C.; Patra, M.; Gasser, G.; Keiser, J. Activity of Praziquantel Enantiomers and Main Metabolites against Schistosoma Mansoni. Antimicrob. Agents Chemother. 2014, 58, 5466−5472. (319) da Silva, V. B. R.; Campos, B. R. K. L.; de Oliveira, J. F.; Decout, J. L.; do Carmo Alves de Lima, M. Medicinal Chemistry of Antischistosomal Drugs: Praziquantel and Oxamniquine. Bioorg. Med. Chem. 2017, 25, 3259−3277. (320) Foster, R.; Cheetham, B. L. Studies with the Schistosomicide Oxamniquine (UK-4271) I. Activity in Rodents and in Vitro. Trans. R. Soc. Trop. Med. Hyg. 1973, 67, 674−684. (321) Pica-Mattoccia, L.; Novi, A.; Cioli, D. Enzymatic Basis for the Lack of Oxamniquine Activity in Schistosoma Haematobium Infections. Parasitol. Res. 1997, 83, 687−689. (322) Pica-Mattoccia, L.; Carlini, D.; Guidi, A.; Cimica, V.; Vigorosi, F.; Cioli, D. The Schistosome Enzyme That Activates Oxamniquine BM


Chemical Reviews

Review

Has the Characteristics of a Sulfotransferase. Mem. Inst. Oswaldo Cruz 2006, 101, 307−312. (323) Valentim, C. L. L.; Cioli, D.; Chevalier, F. D.; Cao, X.; Taylor, A. B.; Holloway, S. P.; Pica-Mattoccia, L.; Guidi, A.; Basso, A.; Tsai, I. J.; et al. Genetic and Molecular Basis of Drug Resistance and SpeciesSpecific Drug Action in Schistosome Parasites. Science 2013, 342, 1385−1389. (324) Hess, J.; Panic, G.; Patra, M.; Mastrobuoni, L.; Spingler, B.; Roy, S.; Keiser, J.; Gasser, G. Ferrocenyl, Ruthenocenyl, and Benzyl Oxamniquine Derivatives with Cross-Species Activity against Schistosoma Mansoni and Schistosoma Haematobium. ACS Infect. Dis. 2017, 3, 645−652. (325) Hess, J.; Patra, M.; Jabbar, A.; Pierroz, V.; Konatschnig, S.; Spingler, B.; Ferrari, S.; Gasser, R. B.; Gasser, G. Assessment of the Nematocidal Activity of Metallocenyl Analogues of Monepantel. Dalton Trans 2016, 45, 17662−17671. (326) Hess, J.; Patra, M.; Rangasamy, L.; Konatschnig, S.; Blacque, O.; Jabbar, A.; Mac, P.; Jorgensen, E. M.; Gasser, R. B.; Gasser, G. Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates. Chem. - Eur. J. 2016, 22, 16602−16612. (327) Hess, J.; Patra, M.; Pierroz, V.; Spingler, B.; Jabbar, A.; Ferrari, S.; Gasser, R. B.; Gasser, G. Synthesis, Characterization, and Biological Activity of Ferrocenyl Analogues of the Anthelmintic Drug Monepantel. Organometallics 2016, 35, 3369−3377. (328) Biot, C.; Glorian, G.; Maciejewski, L. A.; Brocard, J. S.; Domarle, O.; Blampain, G.; Millet, P.; Georges, A. J.; Abessolo, H.; Dive, D.; et al. Synthesis and Antimalarial Activity in Vitro and in Vivo of a New Ferrocene-Chloroquine Analogue. J. Med. Chem. 1997, 40, 3715−3718. (329) Biot, C.; Dubar, F.; Khalife, J.; Slomianny, C. Opening up the Advantages of the Ruthenocenic Bioprobes of Ferroquine: Distribution and Localization in Plasmodium Falciparum-Infected Erythrocytes. Metallomics 2012, 4, 780−783. (330) Dubar, F.; Egan, T. J.; Pradines, B.; Kuter, D.; Ncokazi, K. K.; Forge, D.; Paul, J. F.; Pierrot, C.; Kalamou, H.; Khalife, J.; et al. The Antimalarial Ferroquine: Role of the Metal and Intramolecular Hydrogen Bond in Activity and Resistance. ACS Chem. Biol. 2011, 6, 275−287. (331) Keiser, J.; Vargas, M.; Rubbiani, R.; Gasser, G.; Biot, C. In Vitro and in Vivo Antischistosomal Activity of Ferroquine Derivatives. Parasites Vectors 2014, 7, 424. (332) Biot, C.; Taramelli, D.; Forfar-Bares, I.; Maciejewski, L. A.; Boyce, M.; Nowogrocki, G.; Brocard, J. S.; Basilico, N.; Olliaro, P.; Egan, T. J. Insights into the Mechanism of Action of Ferroquine. Relationship between Physicochemical Properties and Antiplasmodial Activity. Mol. Pharmaceutics 2005, 2, 185−193. (333) Portes, M. C.; De Moraes, J.; Véras, L. M. C.; Leite, J. R.; MaFud, A. C.; Mascarenhas, Y. P.; Luz, A. E. V.; De Lima, F. C. D. A.; Do Nascimento, R. R.; Petrilli, H. M.; et al. Structural and Spectroscopic Characterization of Epiisopiloturine-Metal Complexes, and Anthelmintic Activity vs. S. Mansoni. J. Coord. Chem. 2016, 69, 1663−1683. (334) Kljun, J.; Scott, A. J.; Lanišnik Rižner, T.; Keiser, J.; Turel, I. Synthesis and Biological Evaluation of Organoruthenium Complexes with Azole Antifungal Agents. First Crystal Structure of a Tioconazole Metal Complex. Organometallics 2014, 33, 1594−1601. (335) Patra, M.; Joshi, T.; Pierroz, V.; Ingram, K.; Kaiser, M.; Ferrari, S.; Spingler, B.; Keiser, J.; Gasser, G. DMSO-Mediated Ligand Dissociation: Renaissance for Biological Activity of N-Heterocyclic[Ru(η6-Arene)Cl2] Drug Candidates. Chem. - Eur. J. 2013, 19, 14768− 14772. (336) Nii, T.; Takamura, A.; Mohri, K.; Ishii, F. Factors Affecting Physicochemical Properties of Liposomes Prepared with Hydrogenated Purified Egg Yolk Lecithins by the Microencapsulation Vesicle Method. Colloids Surf., B 2003, 27, 323−332. (337) Baker, W. C.; Choi, M. J.; Hill, D. C.; Thompson, J. L.; Petillo, P. A. Synthesis of Lipophilic Paramagnetic Contrast Agents. J. Org. Chem. 1999, 64, 2683−2689.

(338) Khan, A.; Nicholson, G.; Greenman, J.; Madden, L.; Mcrobbie, G.; Pannecouque, C.; De Clercq, E.; Ullom, R.; Maples, D. L.; Maples, R. D.; et al. Binding Optimization through Coordination Chemistry: CXCR4 Chemokine Receptor Antagonists from Ultrarigid Metal Complexes Binding Optimization through Coordination Chemistry: CXCR4 Chemokine Receptor Antagonists from Ultrarigid Metal Complexes. J. Am. Chem. Soc. 2009, 131, 3416−3417. (339) Hubin, T. J.; Amoyaw, P. N.-A.; Roewe, K. D.; Simpson, N. C.; Maples, R. D.; Carder Freeman, T. N.; Cain, A. N.; Le, J. G.; Archibald, S. J.; Khan, S. I.; et al. Synthesis and Antimalarial Activity of Metal Complexes of Cross-Bridged Tetraazamacrocyclic Ligands. Bioorg. Med. Chem. 2014, 22, 3239−3244. (340) Shircliff, A. D.; Wilson, K. R.; Cannon-Smith, D. J.; Jones, D. G.; Zhang, Z.; Chen, Z.; Yin, G.; Prior, T. J.; Hubin, T. J. Synthesis, Structural Studies, and Oxidation Catalysis of the Manganese(II), Iron(II), and Copper(II) Complexes of a 2-Pyridylmethyl Pendant Armed Side-Bridged Cyclam. Inorg. Chem. Commun. 2015, 59, 71−75. (341) Khan, M. O. F.; Levi, M. S.; Tekwani, B. L.; Khan, S. I.; Kimura, E.; Borne, R. F. Synthesis and Antimalarial Activities of Cyclen 4Aminoquinoline Analogs. Antimicrob. Agents Chemother. 2009, 53, 1320−1324. (342) Khan, M. O. F.; Keiser, J.; Amoyaw, P. N. A.; Hossain, M. F.; Vargas, M.; Le, J. G.; Simpson, N. C.; Roewe, K. D.; Freeman, T. N. C.; Hasley, T. R.; et al. Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes. Antimicrob. Agents Chemother. 2016, 60, 5331−5336. (343) Vincendeau, P.; Bouteille, B. Immunology and Immunopathology of African Trypanosomiasis. An. Acad. Bras. Cienc. 2006, 78, 645− 665. (344) Ponte-Sucre, A. An Overview of Trypanosoma Brucei Infections: An Intense Host-Parasite Interaction. Front. Microbiol. 2016, 7, 2126. (345) Kennedy, P. G. E. Clinical Features, Diagnosis, and Treatment of Human African Trypanosomiasis (Sleeping Sickness). Lancet Neurol. 2013, 12, 186−194. (346) Sternberg, J. M. Human African Trypanosomiasis: Clinical Presentation and Immune Response. Parasite Immunol. 2004, 26, 469− 476. (347) Pays, E.; Vanhollebeke, B.; Vanhamme, L.; Paturiaux-Hanocq, F.; Nolan, D. P.; Pérez-Morga, D. The Trypanolytic Factor of Human Serum. Nat. Rev. Microbiol. 2006, 4, 477−486. (348) Simarro, P. P.; Jannin, J.; Cattand, P. Eliminating Human African Trypanosomiasis: Where Do We Stand and What Comes Next? PLoS Med. 2008, 5, e55. (349) Sutherland, C. S.; Stone, C. M.; Steinmann, P.; Tanner, M.; Tediosi, F. Seeing beyond 2020: An Economic Evaluation of Contemporary and Emerging Strategies for Elimination of Trypanosoma Brucei Gambiense. Lancet Glob. Heal. 2017, 5, e69−e79. (350) Stich, A.; Ponte-Sucre, A.; Holzgrabe, U. Do We Need New Drugs against Human African Trypanosomiasis? Lancet Infect. Dis. 2013, 13, 733−734. (351) Vansterkenburg, E. L. M.; Coppens, I.; Wilting, J.; Bos, O. J. M.; Fischer, M. J. E.; Janssen, L. H. M.; Opperdoes, F. R. The Uptake of the Trypanocidal Drug Suramin in Combination with Low-Density Lipoproteins by Trypanosoma Brucei and Its Possible Mode of Action. Acta Trop. 1993, 54, 237−250. (352) Denise, H.; Barrett, M. P. Uptake and Mode of Action of Drugs Used against Sleeping Sickness. Biochem. Pharmacol. 2001, 61, 1−5. (353) Yun, O.; Priotto, G.; Tong, J.; Flevaud, L.; Chappuis, F. NECT Is next: Implementing the New Drug Combination Therapy for Trypanosoma Brucei Gambiense Sleeping Sickness. PLoS Neglected Trop. Dis. 2010, 4, e720. (354) de Koning, H. P.; Jarvis, S. M. Adenosine Transporters in Bloodstream Forms of Trypanosoma Brucei Brucei: Substrate Recognition Motifs and Affinity for Trypanocidal Drugs. Mol. Pharmacol. 1999, 56, 1162−1170. (355) Kansiime, F.; Adibaku, S.; Wamboga, C.; Idi, F.; Kato, C. D.; Yamuah, L.; Vaillant, M.; Kioy, D.; Olliaro, P.; Matovu, E. A Multicentre, Randomised, Non-Inferiority Clinical Trial Comparing a BN


Chemical Reviews

Review

Nifurtimox-Eflornithine Combination to Standard Eflornithine Monotherapy for Late Stage Trypanosoma Brucei Gambiense Human African Trypanosomiasis in Uganda. Parasites Vectors 2018, 11, 105. (356) Lutje, V.; Seixas, J.; Kennedy, A. Chemotherapy for SecondStage Human African Trypanosomiasis (Review). Cochrane Database Syst. Rev. 2010, CD006201. (357) Pyana, P. P.; Lukusa, I. N.; Ngoyi, D. M.; van Reet, N.; Kaiser, M.; Shamamba, S. K. B.; Büscher, P. Isolation of Trypanosoma Brucei Gambiense from Cured and Relapsed Sleeping Sickness Patients and Adaptation to Laboratory Mice. PLoS Neglected Trop. Dis. 2011, 5, e1025. (358) Robays, J.; Nyamowala, G.; Sese, C.; Kande, V. B. K. M.; Lutumba, P.; Van Der Veken, W.; Boelaert, M. High Failure Rates of Melarsoprol for Sleeping Sickness, Democratic Republic of Congo. Emerging Infect. Dis. 2008, 14, 966−967. (359) Mesu, V. K. B. K.; Kalonji, W. M.; Bardonneau, C.; Mordt, O. V.; Blesson, S.; Simon, F.; Delhomme, S.; Bernhard, S.; Kuziena, W.; Lubaki, J. P. F.; et al. Oral Fexinidazole for Late-Stage African Trypanosoma Brucei Gambiense Trypanosomiasis: A Pivotal Multicentre, Randomised, Non-Inferiority Trial. Lancet 2018, 391, 144−154. (360) Kondratskyi, A.; Kondratska, K.; Vanden Abeele, F.; Gordienko, D.; Dubois, C.; Toillon, R. A.; Slomianny, C.; Lemière, S.; Delcourt, P.; Dewailly, E.; et al. Ferroquine, the next Generation Antimalarial Drug, Has Antitumor Activity. Sci. Rep. 2017, 7, 15896. (361) Pomel, S.; Biot, C.; Bories, C.; Loiseau, P. M. Antiprotozoal Activity of Ferroquine. Parasitol. Res. 2013, 112, 665−669. (362) Chavain, N.; Vezin, H.; Dive, D.; Touati, N.; Paul, J. F.; Buisine, E.; Biot, C. Investigation of the Redox Behavior of Ferroquine, a New Antimalarial. Mol. Pharmaceutics 2008, 5, 710−716. (363) Pomel, S.; Dubar, F.; Forge, D.; Loiseau, P. M.; Biot, C. New Heterocyclic Compounds: Synthesis and Antitrypanosomal Properties. Bioorg. Med. Chem. 2015, 23, 5168−5174. (364) Velásquez, A. M. A.; Francisco, A. I.; Kohatsu, A. A. N.; Silva, F. A. D. J.; Rodrigues, D. F.; Teixeira, R. G. D. S.; Chiari, B. G.; De Almeida, M. G. J.; Isaac, V. L. B.; Vargas, M. D.; et al. Synthesis and Tripanocidal Activity of Ferrocenyl and Benzyl Diamines against Trypanosoma Brucei and Trypanosoma Cruzi. Bioorg. Med. Chem. Lett. 2014, 24, 1707−1710. (365) Simpson, P. V.; Schmidt, C.; Ott, I.; Bruhn, H.; Schatzschneider, U. Synthesis, Cellular Uptake and Biological Activity against Pathogenic Microorganisms and Cancer Cells of Rhodium and Iridium N-Heterocyclic Carbene Complexes Bearing Charged Substituents. Eur. J. Inorg. Chem. 2013, 2013, 5547−5554. (366) Demoro, B.; Sarniguet, C.; Sánchez-Delgado, R.; Rossi, M.; Liebowitz, D.; Caruso, F.; Olea-Azar, C.; Moreno, V.; Medeiros, A.; Comini, M. A.; et al. New Organoruthenium Complexes with Bioactive Thiosemicarbazones as Co-Ligands: Potential Anti-Trypanosomal Agents. Dalton Trans 2012, 41, 1534−1543. (367) Loiseau, P. M.; Jennings, F. W.; Lubert, P.; Wolf, J. G. The Effect of Spiroarsoranes on Trypanosoma Brucei Brucei and T. b. Rhodesiense. Parasitol. Res. 1996, 82, 477−480.

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