Fruitful Decade for Antileishmanial Compounds ... - ACS Publications

Review pubs.acs.org/CR

Fruitful Decade for Antileishmanial Compounds from 2002 to Late 2011 Hidayat Hussain,*,† Ahmed Al-Harrasi,*,† Ahmed Al-Rawahi,† Ivan R. Green,‡ and Simon Gibbons*,§ †

UoN Chair of Oman’s Medicinal Plants and Marine Natural Products, University of Nizwa, P.O. Box 33, Birkat Al Mauz, Nizwa 616, Sultanate of Oman ‡ Department of Chemistry and Polymer Science, University of Stellenbosch, Private Bag X1, Matieland, Stellenbosch 7600, South Africa § Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London WC1N 1AX, United Kingdom

4.

CONTENTS 1. Introduction 2. Leishmaniasis 2.1. Epidemiology 2.2. Life Cycle 2.2.1. Targets for Chemotherapy 2.3. Taxonomy of Leishmania 2.4. Current Treatment of Leishmania 2.4.1. Pentavalent Antimonials 2.4.2. Amphotericin B 2.4.3. Miltefosine 2.4.4. Paromomycin 2.4.5. Pentamidine 2.4.6. Sitamaquine 2.5. Pathways and Potential Drug Targets in Leishmania 2.5.1. Sterol Biosynthetic Pathway 2.5.2. Purine Salvage Pathway 2.5.3. Protein Kinases 2.5.4. Proteinases 2.5.5. Folate Biosynthesis 2.5.6. Topoisomerases as Drug Targets 3. Natural Products with Leishmanicidal Activities 3.1. Alkaloids 3.1.1. Isoquinoline Alkaloids 3.1.2. Naphthylisoquinoline Alkaloids 3.1.3. Benzoquinolizidine Alkaloids 3.1.4. Diterpene Alkaloids 3.1.5. Pyrrolidinium Alkaloids 3.1.6. Acridone Alkaloids 3.1.7. β-Carboline Alkaloids 3.1.8. Manzamine-Type Alkaloids 3.1.9. Indole Alkaloids © 2014 American Chemical Society

5.

10370 10370 10370 10370 10371 10372 10372 10372 10372 10373 10373 10373 10373

6.

7. 8.

10374 10374 10374 10374 10374 10374 10374 10374 10374 10374 10375 10376 10376 10376 10376 10377 10377 10377

3.1.10. Pyridoacridone Alkaloids 3.1.11. Batzelladine Alkaloids 3.1.12. Steroidal Alkaloids 3.1.13. Bromopyrrole Alkaloids 3.1.14. Furoquinoline Alkaloids 3.1.15. Indolizidine Alkaloids 3.1.16. From Marine Invertebrates Phenolic Derivatives 4.1. Chalcones 4.2. Flavonoids 4.3. Isoflavones 4.4. Coumarins 4.5. Xanthones and Benzophenones 4.6. Other Phenolic Compounds Terpenes 5.1. Iridoids 5.2. Sesquiterpenes 5.3. Diterpenes 5.4. Triterpenes and Saponins Other Metabolites 6.1. Acetogenins 6.2. Peptides 6.3. Palmarumycin 6.4. Quinones Miscellaneous Synthetic Antileishmanial Compounds 8.1. Chalcone Derivatives 8.2. Quinoline Derivatives 8.3. Indole Derivatives 8.4. Curcumin Derivatives 8.5. Acridine Derivatives 8.6. Quinoxaline Derivatives 8.7. Imidazole and Imidazolidine Derivatives 8.8. Pyrimidines 8.9. Phospholipids 8.10. Buparvaquone Derivatives 8.11. N,C-Linked Arylisoquinolinium Salts 8.12. Amidoxime Derivatives 8.13. Paullone Derivatives 8.14. Piperine Derivatives 8.15. Pterocarpanquinones 8.16. Tetrahydronaphthyl Azoles 8.17. Quinazoline Derivatives

10377 10377 10377 10379 10379 10379 10379 10380 10380 10380 10381 10381 10382 10383 10384 10384 10385 10385 10386 10388 10388 10388 10388 10389 10390 10391 10391 10394 10396 10399 10399 10400 10402 10405 10406 10408 10408 10409 10409 10410 10410 10411 10411

Received: October 7, 2013 Published: September 25, 2014 10369

dx.doi.org/10.1021/cr400552x | Chem. Rev. 2014, 114, 10369−10428

Chemical Reviews 8.18. Azaterphenyl Diamidines 8.19. Pyridinones 8.20. Triazines 8.21. Triazole Derivatives 8.22. Aryl Azomethines 8.23. Pentamidine Congeners 8.24. Glycosyl Ureides 8.25. Pyrazolopyridine Derivatives 8.26. Thiadiazoles 8.27. Miscellaneous Compounds 9. Activity against Essential Leishmanial Enzymes 10. Conclusions and Future Prospects Author Information Corresponding Authors Notes Biographies References

Review

the antileishmanial activities of plant natural products and extracts only without describing any natural product structures. In 2008 Fotie17 and Polonio and Efferth18 described the antileishmanial activity of less than 50 compounds. In 2011, Rodriguez et al.19 reviewed 14 natural products’ activity against Trypanosomatid enzymes, which also included Leishmania spp. This review describes the antileishmanial activities of 340 natural products discovered from different natural sources during the past decade (from 2002 to the end of 2011). Importantly, this review also describes the synthesis and SAR studies of 476 synthetic compounds that showed strong antileishmanial activities. Interestingly, most of the synthetic compounds showed antileishmanial activities equal to or better than those of the standard drugs. Altogether, 816 antileishmanial compounds are included, belonging to more than 40 structural classes and supported by 465 references.

10412 10412 10413 10413 10414 10414 10415 10415 10415 10416 10418 10419 10420 10420 10420 10420 10421

2. LEISHMANIASIS 2.1. Epidemiology

1. INTRODUCTION Leishmaniasis, usually caused by the genus Leishmania, has not received the attention it deserves and in recent times has developed into a major health problem worldwide. 1,2 Leishmaniasis is prevalent in no fewer than 88 countries, and the disease affects approximately 12 million people. Unfortunately, more than 90% of visceral Leishmaniasis (VL) patients are present in just four countries alone, viz., India, The Sudan, Brazil, and Bangladesh.3 The annual cases of VL number is approximately 500 000.4 It has been reported that around 100 000 people are infected from VL annually in India alone. Of the more than 2000 European cases reported by the World Health Organization (WHO), 90% occur in four countries, viz., France, Spain, Italy, and Portugal. Some authors have suggested that data on HIV coinfection is an additional risk factor in Southern Europe associated with VL.5 In the past 20 years American Tegumentary Leishmaniasis (ATL) has increased in the South East, Middle West, and North East of Brazil.6−8 Farmers, the military, and people living in rural locations have all been affected by ATL, and transmission of this disease depends upon the extent of interface between urban and rural areas.9−12 Currently, a number of drugs are used in the treatment of Leishmaniasis. These drugs include pentavalent antimonials, viz., antimonate (glucantime), sodium stibogluconate (pentostam), meglumine pentamidine, amphotericin B, miltefosine, paromomycin, and sitamaquine. Unfortunately, most of these drugs cause side effects, and an inevitable resistance has developed in recent times in Leishmania parasites toward these drugs.5 The evolution of drug resistance in Leishmania parasites represents a major barrier to their control in all classes of administered agents to date and is a cause of serious concern. Approximately 5−70% of patients in endemic areas do not respond to the above-mentioned standard antiparasitic drugs. Consequently, novel, effective, and safe drugs having reduced side effects in their treatment regimens against Leishmania is a major priority for health researchers.5 The objectives of this review are to highlight the significant and ongoing body of research on antileishmanial compounds from 2002 to late 2011. A detailed review of antileishmanial natural products was published in 2001 covering the years 1980−2000,13 and a minireview has also appeared by Rocha et al.14 which covered the literature up to 2001. Tempone et al.15 reviewed mainly marine antileishmanial natural products, including 90 compounds, with 108 references. Sen and Chatterjee16 reported on

In the majority of cases, the clinical outcome of Leishmaniasis is divided into three forms, viz., visceral Leishmaniasis (VL), cutaneous Leishmaniasis (CL), and mucocutaneous Leishmaniasis (MCL).20 CL is primarily caused by L. major, L. tropica, and L. aethiopica in the Old World and L. mexicana, L. amazonensis, L. braziliensis, L. panamanesis, and L. guyanensis in the New World. Visceral Leishmaniasis (VL) is responsible for thousands of deaths each year and caused by L. infantum and L. donovanii in the Old World and L. chagasi in the New World.20,21 MCL is mainly caused by L. braziliensis and occasionally by L. panamensis or L. guyanensis.20 It is estimated that 12 million people are presently suffering with the disease worldwide, with approximately 350 million having a potential risk of contracting the disease. Furthermore, the annual mortality due to the disease is approximately 60 000. The number of new cases of VL each year in the world is thought to be approximately 500 000, and the number of new CL cases is thought to be approximately 1.5 million.22 VL represents the severest form of the disease since it affects mainly the internal organs, viz., bone marrow, liver, and spleen. Mucocutaneous Leishmaniasis (MCL), on the other hand, often results in facial disfiguration due to erosion of the mucocutaneous sites of the mouth and nose. Diffuse or disseminated CL is characterized by formation of nodules, plates, or multiple lumps, especially around the face and on the external surfaces of the arms and legs. Cutaneous Leishmaniasis is generally considered an auto limited infection.23 It has been reported that more than 90% of VL cases of infection are to be found in India and Sudan,24,25 and both CL and VL are present in Europe and account for 700 cases per annum.26 There are extraneous factors reported which suggest that CL and VL may expand their range to Northern Europe27 because the two visceral Leishmaniasis vectors, viz., Phlebotomus perniciosus and P. neglectus, have been detected in the Italian Alpine regions28,29 and some cases of human VL have been detected in southern Germany.30−33 In the WHO Eastern Mediterranean Region, both CL and VL are present in 14 of the 22 countries33 and Afghanistan, Iran, and Syria have the highest incidence of CL.34 In Latin America, Brazil has over 3000 cases of visceral leishmaniasis per year.35 2.2. Life Cycle

Leishmania species show two main developmental stages throughout their life cycle which are the amastigote, which 10370


Chemical Reviews

Review

research on Leishmania is that pure amastigotes are difficult to obtain in sufficient numbers. However, one possible solution that has emerged is to take advantage of the physiological equivalence between axenic amastigotes and lesion-derived amastigotes.40 Interestingly, it has been reported that axenic amastigotes can be obtained in reasonable numbers by exposing promastigotes in vitro to high temperature and pH.41 Their transformation into amastigote-like parasites can be brought about with cellular changes, and these changes include expression of specific stage proteins on their surface.37,40,42,43 2.2.1. Targets for Chemotherapy. Current chemotherapeutic interventions for treatment of Leishmaniasis suffer from several drawbacks, which necessitates continuous development of new effective compounds. Rapid, inexpensive, and reproducible assays are vital and essential factors to guide the discovery and development of new and original leads.44,45 Leishmania pathogens display an array of several life stages which in a sense directs investigators to determining the best parasite stage to target for the best results. There are three major options for targeting Leishmania, viz., (a) the intracellular amastigote stage, (b) the extracellular living promastigote stage, and (c) the axenic amastigote stage. Some authors have reported that as a consequence of the ease in purposefully utilizing promastigotes or axenic amastigotes in vitro both the promastigote and the axenic amastigote stage essentially fulfill the requirements of reproducibility, speed, and conservative cost requirements for high-throughput screens.46,47 The axenic amastigotes are excellent for testing the potency of compounds under mildly acidic conditions and thus afford the desired ability to easily screen for relevant-like stages of the parasite’s life cycle. Interestingly and noteworthy is that the absence of the host cell in these assays is a considerable disadvantage plaguing these two approaches, viz., promastigotes or the axenic amastigotes stages.44 The intracellular amastigote may therefore be the more appropriate target for primary screening since it survives and divides at the level of the tissue macrophages, thereby causing the actual disease (Figure 2).44,48 Amastigotes, which are situated within a parasitophorous vacuole and exposed to an acidic environment of a pH of between 4.5 and 5.0, thus have to develop certain and definite strategies for their nutrient acquisition and ion homeostasis in order to survive.48

reside inside the reticuloendothelial cells, and the promastigote, which replicate in the gut of a phlebotomine sandfly.36,37 The life cycle of Leishmania is initiated when the vertebrate host is bitten or stung by an infected insect (Figure 1).19,37 As a result,

Figure 1. Life cycle of Leishmania.19 (1) Sandfly takes a blood meal and injects metacyclic promastigotes into the mammalian host; (2) metacyclic promastigotes are phagocytozed by macrophages; (3) promastigotes differentiate to amastigotes inside the macrophages; (4−5) amastigotes multiply; (6) promastigotes disrupt the macrophage membrane and then infect other cells; (7) sandfly takes a blood meal ingesting infected macrophages; (8) during digestion, free amastigotes differentiate to promastigotes; (9) promastigotes multiply in the midgut and migrate to the proboscis; (10) promastigotes differentiate to metacyclic promastigotes.

the cardial valve becomes blocked at the digestive tract of the sandfly by the high densities of infectant parasites. The insect then swallows the blood from the host and expels the valve’s content. The saliva of the insects contains chemical factors which are responsible for the enhancement of the parasite’s infective power and exert a chemotactic effect upon the reticuloendothelial cells which then phagocytose the parasites, and this in turn fosters their reproduction and survival.37 The resulting lesion exists in the skin with dermotropic Leishmania species, but the parasite can expand from the initial skin lesion into the liver, spleen, and bone marrow as seen with viscerotropic Leishmania. The spread of this disease within the mammalian host starts when the parasite replicates within the reticuloendothelial cells and eventually bursts free from the infected macrophages. It is still however doubtful whether the host cells are actively involved in this event or undergo apoptosis.38,39 The parasites may then further differentiate into promastigotes when the insect bites an infected vertebrate host. The promastigotes migrate into the midgut and during the next 4−7 days develop into the metacyclic stage (infective parasites). Finally, the metacyclics shift to the cardial valve ready to be reinoculated into a vertebrate host, and during development of the promastigote stage the parasite is continually activating physiological responses.37 It is still not clear at this stage exactly how development of drug resistance to the interventions applied relates to the physiological events which trigger and regulate the parasite’s differentiation through its life cycle. It has been reported that the amastigote represents the cellular form for human disease. A major problem encountered in the

Figure 2. Membrane barriers that antileishmanial drugs have to penetrate.44,48 (a) Drugs in plasma (pl) gain access to Leishmania donovanii amastigotes (am) in liver macrophage (Kupffer cells) (lm), between hepatocytes (hc), by first entering the low-pH parasitophorous vacuole (probably by passive diffusion) and then entering the parasite itself via membrane transporters, endocytosis, or diffusion. Scale bar = 2 μm. (b) Amastigote (am) within a phagolysosomal vacuole, showing vacuole membrane (vm) and parasite membrane (pm) barriers that have to be crossed by drugs. Alternative route via fusion of an endosome containing nanoparticles (np) is also illustrated. Scale bar = 0.2 μm. 10371


Chemical Reviews

Review

Table 1. Newly Proposed Nomenclature for Leishmania Species Based on the Heat Shock Protein 70 (hsp70) Gene Sequence51,54 genus

complex

L. (Leishmania)

L. donovanii

species L. donovani

China, Indian subcontinent, Ethiopia, Sudan, Kenya, Iran, Saudi Arabia, Yemen

L. donovani

L. infantum

Albania, Algeria, France, Greece, Italy, Morocco, Portugal, Spain, Syria, Tunisia, Turkey, Yemen Argentina, Bolivia, Brazil, Colombia, Ecuador, El Salvador, Guadalupe, Guatemala, Honduras, Martinique, Mexico, Nicaragua, Paraguay, Suriname, Venezuela India, Sudan, Ethiopia, Lebanon, Israel Afghanistan, Algeria, Azerbaijan, Greece, Iran, Iraq, Israel, Morocco, Tunisia, Turkey, Yemen Ethiopia, Kenya Afghanistan, Algeria, Chad, Iran, Iraq, Israel, Libya, Mauritania, Morocco, Syria, Sudan Belize, Colombia, Costa Rica, Dominican Republic, Ecuador, Guatemala, Honduras, Mexico, Panama, Venezuela Bolivia, Brazil, Colombia, Costa Rica, Ecuador, French Guyana, Panama, Peru, Venezuela

L. tropica

L. chagasi

L. tropica

L. mexicana

L. (Viannia)

L. guyanensis

L. braziliensis

species according to hsp70 analysis

geographic distribution

L. L. L. L. L.

archibaldi tropica aethiopica major mexicana

L. amazonensis L. garnhami L. guyanensis L. panamensis L. naif f i L. braziliensis L. peruviana L. lainsoni

Venezuela Brazil, Colombia, Ecuador, French Guyana, Peru, Suriname, Venezuela Belize, Colombia, Costa Rica, Ecuador, Honduras, Nicaragua, Panama, Venezuela Brazil, French Guyana, Ecuador, Peru Argentina, Belize, Bolivia, Brazil, Colombia, Costa Rica, Ecuador, Guatemala, Honduras, Nicaragua Peru Brazil, Bolivia, Peru

L. major L. mexicana

L. guyanensis

L. naif f i L. braziliensis

L. lainsoni

a species, while a previous study33 suggested that L. major was also an independent species. Of quite important note in this regard is that only L. (L) mexicana, L. (V) lainsoni, L. (V) braziliensis, and L. guyanensis were identified as separate species in the New World Leishmania and Viannia.54

It has furthermore been reported that a wide variety of transporters exist that could mediate in the drug uptake or drug efflux process and would therefore additionally play a determining role in the susceptibility of the parasite to modern chemotherapy. On the basis of current evidence, it may be safely suggested that over time Leishmania spp. have evolved a coexistence in different macrophage types having evolved and developed those survival adaptations in order to ensure their intracellular survival.48 Such species of Leishmania who evolved these adaptations could therefore be responsible for the different behavior toward drug susceptibility, and these changes would of necessity make it imperative that new and more appropriate laboratory models would need to be developed for assessing all new drugs and their current efficacy.48

2.4. Current Treatment of Leishmania

2.4.1. Pentavalent Antimonials. Pentavalent antimonials have been used in the treatment regimes for VL and CL for more than 60 years. However, an increasing incidence of resistance to pentavalent antimony (Sbv) has been reported in some parts of India.55−57 Other issues related to treatment regimes include side effects of low-cost generic drugs58 and cardiotoxicity.59,60 Pharmacokinetic studies on pentavalent antimonials have been accomplished by means of a twocompartment and three-term pharmacokinetic model.61 Structural studies on meglumine antimoniate (MA) and sodium stibogluconate (SSG) confirmed that in aqueous solutions MA and SSG were comprised of mixtures of 2:2, 2:3, and 2:1 Sbv− ligand complexes.62 Pentavalent antimonials can act as prodrugs with one of the requirements being its easy reduction to the trivalent form. Studies on the mechanism of action of sodium stibogluconate demonstrated that inhibition of energy metabolism and macromolecular biosynthesis via inhibition of glycolysis and fatty acid beta-oxidation may be the possible mechanisms of action.55,63,64 It has been reported that trivalent antimony directly interferes with the thiol metabolism in L. donovani (drug sensitive).65 2.4.2. Amphotericin B. Amphotericin B was originally isolated from Streptomyces nodosus, and in the crystalline form amphotericin B is insoluble in water. Different formulations are currently available, and amphotericin B deoxycholate (Fungizone) is the most highly effective.55,58 Amphotericin B as AmBisome represents the lipid-based formulations of amphotericin B which has been used for treatment of VL.66 Some treatment regimes of liposomal amphotericin B have been investigated in India,67−69 where it was found that single-dose

2.3. Taxonomy of Leishmania

Microscopic examination of the parasite culture illustrated that various species of Leishmania present identical morphologies, and in order to address this dilemma the early classification of Leishmania was actually based upon their geographical distribution, vector, tropism, and clinical manifestation.49−52 In this regard, Lainson and Shaw classified the Leishmania spp. into two subgenera, viz., Viannia and Leishmania.50,53 In the case of Viannia and its subgenus, which includes L. (Viannia) braziliensis and related parasites, these are known to grow and develop in the hindgut after which they migrate to the midgut and finally end up in the foregut (Peripylaria). In the case of the species belonging to the subgenus Leshmania, viz., L. (Leishmania) donovani, these are differentiated by the fact that they only occupy the midgut and foregut (Suprapylaria).50,53 Fraga et al. recently reported that only eight monophyletic groups have been detected (Table 1).54 This study furthermore suggested that only L. donovanii should be considered as a species and that only L. donovanii and L. infantum should be recognized as a subspecies. The study additionally confirmed that only L. tropica and not L. aethiopica has been recognized as 10372


Chemical Reviews

Review

Figure 3. Treatments used for cutaneous (CL) and visceral leishmaniasis (VL).8 Green arrows indicate drugs used in both CL and VL treatment, blue arrows indicate drugs used only for VL, and red arrows indicate drugs used only for CL.

methylbenzethonium chloride ointment.86 Possible adverse effects include injection-site pain,48 ototoxicity, and nephrotoxicity.86 Pharmacokinetic studies of paromomycin showed that it is quickly absorbed through intramuscular injection with peak plasma levels being reached within 1 h. Plasma levels on days 1, 8, 15, 21, and 22 two were found to be similar.46,55 Early studies in Leishmania spp. indicated that with the ribosomes, respiratory dysfunction and mitochondrial membrane depolarization are among the possible modes of action.87−89 It has also been reported that any paromomycin resistance in L. donovani was related to decreased drug uptake.90,91 2.4.5. Pentamidine. Pentamidine is still currently being used as a first-line drug for CL and as a second-line drug for VL because of toxicity and efficacy issues,55,58 and its use for VL treatment has been abandoned in India.59 It has been reported that the induction of insulin-dependent diabetes mellitus is one of the most serious concerns in the use of this agent.59 While the mode of action of pentamidine is not clear, some authors suggested that the mitochondrion appears to be a possible target. Collapse of mitochondrial membrane potential as well as alkalization of acidocalcisomes have been reported in L. donovani promastigotes to substantiate this.92,93 Unfortunately, it has also been reported that drug resistance is associated with mitochondrial alterations.94 Additional studies have shown that pentamidine enters both promastigotes and amastigotes of Leishmania via a carrier-mediated process which recognizes diamidines with high affinity.95 2.4.6. Sitamaquine. Sitamaquine (WR6026), a synthetic compound, is used in an oral treatment regime of VL.55,96,97 Some studies demonstrated that the cure rate in the intentionto-treat-population was 83% and 87% in Kenyan98 and Indian patients, respectively.99 Like pentamidine, sitamaquine unfortunately also has some side effects, viz., abdominal pain, headache, vomiting, dyspepsia, and cyanosis.55,98,99 Side chain oxidation and hydroxylation in the 5 position are the most important steps in the metabolic pathway of these 8-aminoquinolines.96,100 Previous studies illustrated that morphological changes in intracellular L. tropica amastigotes are induced by sitamaquine.55 However, collapse of the mitochondrial membrane potential in L. donovani92 has been reported as unrelated to sitamaquine accumulation in this organelle.101 Figure 3 illustrates the different drugs used for leishmaniasis treatment.8,102

liposomal amphotericin B was not inferior to and was less expensive than amphotericin B deoxycholate.70 Two other lipid-based formulations, viz., amphotericin B lipid complex and amphotericin B colloidal dispersion, are used for treatment of VL.71 Amphotericin B deoxycholate has some unfortunate side effects and some infusion-related side effects such as fever, chills, and thrombophlebitis.59 Furthermore, liposomal amphotericin B is far safer and more effective than amphotericin B deoxycholate.59,59 Effective tissue penetration (in liver and spleen) with sustained levels and stability in blood, macrophages, and tissues are the main features that increase efficacy and minimize toxicity of liposomal amphotericin B.72 The terminal elimination half-life of liposomal amphotericin B is around 7 h in humans,73 and longer half-lives have been reported with increased sampling times.74 In another study it has been reported that interaction with membranes leads to formation of transmembrane amphotericin B channels, aqueous pores, and leakage of cations.75−77 2.4.3. Miltefosine. Miltefosine was the first oral antileishmanial drug that reached the market and has been used for treatment of VL and CL.55,58 However, side effects include disturbance of the gastrointestinal tract77 and an elevation of hepatic enzymes.78 Furthermore, miltefosine has a teratogenic effect and is contraindicated for use during pregnancy.55,77 Similarly, mandatory contraception is also suggested for women of child-bearing age.77 Resistance to miltefosine at concentrations of 40 μM to Leishmania promastigotes has been reported, and resistance was conferred to the intracellular amastigote stage.79,80 Glycosylphosphatidylinositol (GPI) anchor biosynthesis, perturbation of ether−lipid metabolism, and signal transduction are possible targets of miltefosine in Leishmania.81,82 Recently, two other targets of miltefosine in L. donovani promastigotes have been reported, viz., mitochondria and the cytochrome c oxidase.83 Reports that miltefosine demonstrated an effect in L. donovani promastigotes that was related to their lipid metabolism, fatty acid, and sterol content have also emerged.55,84 2.4.4. Paromomycin. Paromomycin is one of the latest registered antileishmanial drugs used for VL in India, and in a clinical trial paromomycin was better when compared to amphotericin B.55,85 Paromomycin is formulated for topical treatment of CL58,86 and is also used for CL in Israel as a 10373


Chemical Reviews

Review

2.5. Pathways and Potential Drug Targets in Leishmania

2.5.4. Proteinases. Aspartate, cysteine, serine, and metalloenzymes are the four types of proteinases, while the cysteine proteinases (CPs) are the most well defined of these enzymes in parasitic protozoa. Cysteine proteinases have potential as drug targets because CPs play a most important role in host cell−parasite interactions,103 and in this regard 65 cysteine proteinases are currently known. Two cathepsin L-like proteinases (CPA and CPB) are currently known, and CPC is a cathepsin B-like proteinase. These three proteinases are strongly involved in host−parasite interactions.107 Some natural products have been reported that show inhibitory activity against CP (ICP) (L. mexicana) and CPB.103 2.5.5. Folate Biosynthesis. The folate pathway has a long history in anti-infective drug discovery and is of utility as a drug target for Leishmania and in development of anticancer and antimalarial agents. Since they are important for growth, enzymes such as thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are involved in their biosynthesis and have obvious relevance as drug targets.103 The two enzymes are also involved in the synthesis of thymine and dTMP. Inhibitors of dihydrofolate reductase are also active against Leishmania.108 It has been reported that only some compounds showed activity toward both DHFR-TS and PTR1 (in L. major).109 2.5.6. Topoisomerases as Drug Targets. DNA topoisomerases I and II are crucially important in DNA transcription, replication, repair, and recombination and therefore represent highly valuable drug targets for antiparasitic and bactericidal diseases. DNA topoisomerase I has been characterized from both T. cruzi and L. donovani and is independent of ATP.103,110 Similarly, L. donovani topoisomerase I was present in the nucleus and kinetoplast. 111 Camptothecin, sodium stibogluconate, and urea stibamine have all been shown to be type I topoisomerase inhibitors in these species. It has been reported that camptothecin displays activity toward the nuclear and mitochondrial topoisomerase I of T. b. brucei with an IC50 = 1.6 μM.112 Interestingly, camptothecin derivatives such as 9-chloro-10,11-methylenedioxycamptothecin were 40 times more trypanocidal than camptothecin with an IC50 = 0.041 μM.112 Topoisomerase II has been characterized from T. brucei,113 T. cruzi,114 and L. donovani,115 and interestingly, dihydrobetulinic acid (IC50 = 4.1 μM)116 has activity toward topoisomerase II.

In drug discovery, one of the most important features is the identification of highly relevant drug targets in a biological pathway, which allow development of inexpensive and specific assay systems for screening of compounds.103,104 2.5.1. Sterol Biosynthetic Pathway. Sterols are important constituents of cell membranes which are crucial to cellular function and cell structure maintenance. Trypanosomatids prepare ergosterol, which is needed for their viability and growth, but sterols are not however present in mammalian cells. This is the main reason why the sterol biosynthetic pathway for Leishmania has been suggested to be an important druggable target (Figure 4).103

Figure 4. Sterol biosynthetic pathway in Leishmania.103 Pathway shows the important steps and enzymes involved in sterol biosynthesis. Final product in trypanosomatids is ergosterol as opposed to cholesterol in mammalian cells.

2.5.2. Purine Salvage Pathway. Leishmania is contingent on the purine salvage system to use purine bases from the mammalian host because there is no enzyme in Leishmania for synthesis of the purine nucleotide (Figure 5). Nucleoside transporters transport these metabolites through the parasite cell surface.103

3. NATURAL PRODUCTS WITH LEISHMANICIDAL ACTIVITIES 3.1. Alkaloids Figure 5. Purine salvage pathway of Leishmania species.103 Enzymes involved in salvage of purines are (1) phosphoribosyltransferase, (2) adenine deaminase, (3) guanine deaminase, (4) adenosine deaminase, (5) nucleoside kinase, (6) nucleotidase, (7) AMP deaminase, (8) AMP kinase, (9) GMP kinase, (10) IMP dehydrogenase, (11) GMP synthetase, (12) GMP reductase: AMP, adenosine monophosphate; ADP, adenosine diphosphate; IMP, inosine monophosphate; XMP, xanthine monophosphate; GMP, guanosine monophosphate; GDP, guanosine diphosphate.

3.1.1. Isoquinoline Alkaloids. The antiparasitic activities of the isoquinoline alkaloids (1−2) (Figure 6), isolated and purified from the plant Annona fetida (Annonaceae), were investigated on Leishmania sp.117 Annomontine (2) showed significant antileishmanial activity with IC50 values less than 6 μM for L. braziliensis. Among the pyrimidine-β-carboline alkaloids, annomontine (2) was six times more active against L. braziliensis than N-hydroxyannomontine (1). However, alkaloid 1 was active against L. guyanensis, whereas alkaloid 2 proved to be inactive. This selectivity between species is intriguing. Two further alkaloids (+)-neolitsine (3) and cryptodorine (4), from Guatteria dumetorum, showed leishmanicidal activities against the promastigotes of L. mexicana with IC50 values of 15 and 3 μM, respectively.118 These compounds were also evaluated for their toxicities toward murine macrophages and VERO cells. Alkaloids 3 and 4 both showed

2.5.3. Protein Kinases. Among drug targets cyclindependent kinases (CDKs) are very important for cell division in Leishmania. It has been reported that two CDKs in L. mexicana, LmexCRK1 and LmexCRK3,103,105 are considered to be crucial to the promastigote form. It has also been reported that CRK3 is active all over in L. mexicana life cycle.106 10374


Chemical Reviews

Review

of 100, 50, and 25 μg/mL and 86.6%, 81.3%, and 49.7% for promastigotes (Pms) and amastigotes (Ams),121 respectively. 3.1.2. Naphthylisoquinoline Alkaloids. Among the naphthylisoquinoline alkaloids, ancistrocladiniums A (14) and B (15) (Figure 8), reported from species of the Ancistrocla-

Figure 6. Structures of isoquinoline alkaloids 1−9.

lower toxicities (>300 μM) in both of these two cell types. Moreover, alkaloids 3 and 4 demonstrated a high selectivity index (SI) (3, SI 25.1; 4, SI 21.3) toward L. mexicana over the murine macrophages.118,119 Five further alkaloids, duguetine (5), duguetine-β-N-oxide (6), dicentrinona (7), N-methyltetrahydropalmatine (8), and N-methylglaucine (9) (Figure 6), reported from Duguetia f urf uracea (Annonaceae), were also tested for their leishmanicidal activities with duguetine-β-Noxide (9) (IC50 0.11 μM) and dicentrinona (7) (IC50 0.01 μM) proving to be the most active in this series.120 Xylopine (10) and nornuciferine (11) were isolated from Guatteria amplifolia, and cryptodorine (4) and nornantenine (12) (Figure 7) were isolated from G. dumetorum.119

Figure 8. Structures of naphthylisoquinoline alkaloids 14−18.

daceae family, demonstrated antileishmanial activities against L. major, with IC50 values of 2.61 and 1.52 μg/mL, respectively.2,122 Since both metabolites share some structural features with miltefosine (see section 2.4.3), a possible mode of action could possibly be the apoptosis-like death pathway. Both natural products have also been isolated from a Congolese Ancistrocladus species collected in the habitat of Yeteto.123 The most significant activities were detected against Old World Leishmania species, and ancistrocladiniums A (14) and B (15) proved to be highly active against L. donovani, the pathogen responsible for visceral leishmaniasis, with IC50 values of 0.7 and 1.1 μg/mL, respectively. Against L. major, a pathogen that causes cutaneous Leishmaniasis, 14 (IC50 3.08 μg/mL) and 15 (IC50 2.69 μg/mL) displayed noteworthy activities. Compound 15 also showed a 15-fold higher activity than miltefosine (reference compound). However, both 14 and 15 were highly toxic against L-6 myoblast cells and J774.1 macrophages. However, the indices describing the cytotoxicities of these compounds against the cell lines in relation to their activities against the parasites (IC50 cytotoxicity/IC50 activity), for ancistrocladinium A (14) against L. donovani and for ancistrocladinium B (15) against L. major, suggest pharmacological profiles which are better than that of miltefosine in experiments performed in parallel.123 The naphthylisoquinoline alkaloid ancistrocladidine (16), reported from Ancistrocladus tanzaniensis (Ancistrocladaceae), demonstrated promising activity (IC50 = 2.9 μg/mL) against L. donovani. However, its activity was twice as weak compared with the highly active ancistrotanzanine B (17) (IC50 = 1.6 μg/ mL) and weaker by a factor of 10 compared with miltefosine (the positive control). Another alkaloid belonging to the same group, ancistrotanazanine A (18) (Figure 8), showed a similarly promising activity against L. donovani (IC50 = 1.6 μg/ mL).124,125

Figure 7. Structures of isoquinoline alkaloids 10−13.

Compounds 4 and 10−12 showed promising activities against L. mexicana and L. panamensis. Xylopine (10) and cryptodorine (4) were among the most active with values of LD50 = 3 and 3 μM, respectively. However, xylopine (10) demonstrated a higher toxicity (37-fold) toward L. mexicana than toward macrophages (the regular host cells of Leishmania sp.).119 Recently,3-hydroxy-2,9,11-trimethoxy-5,6-dihydroisoquino[3,2-a]isoquinolinylium (13) was reported from stem bark of Tinospora sinensis and demonstrated significant in vitro antileishmanial potential toward L. donovani promastigotes and intracellular amastigotes. Interestingly, this compound showed 96.6%, 93.7%, and 81.0% inhibition at concentrations 10375


Chemical Reviews

Review

Figure 9. Structures of benzoquinolizidine alkaloids 19−25.

3.1.3. Benzoquinolizidine Alkaloids. Two benzoquinolizidine alkaloids, viz., klugine (19) and cephaeline (20) (Figure 9), isolated from Psychotria klugii, showed reasonable leishmanicidal activity against L. donovani.126,127 Of these, cephaeline (20) was quite exceptional and the most potent (IC50 0.03 μg/mL), while its activity was 20-fold higher than pentamidine and 5-fold higher than amphotericin B (IC50 0.7 and 0.17 μg/mL, respectively). In addition, klugine (19) demonstrated strong activity (IC50 0.40 μg/mL) against L. donovanii and advantageously had no significant toxicity against VERO cells. Antiprotozoal compounds from the crude extracts of the plant, Triclisia patens, showed inhibitory activity toward L. donovani promastigotes (IC 50 = 1.5 μg/mL), and phytochemical investigation of T. patens yielded five benzoquinolizidine alkaloids named funiferine (21), tiliageine (22), oxyacanthine (23), fangchinoline (24), and isotriboline (25) (Figure 9). It is interesting to note that these alkaloids showed significant activity with IC50 values less than 1 μM. Among these alkaloids fangchinoline (24) (IC50 = 0.39 μM) displayed stronger activity than pentamidine (IC50 = 0.40 μM).128 3.1.4. Diterpene Alkaloids. Three diterpene alkaloids 15,22-O-diacetyl-19-oxo-dihydroatisine (26), azitine (27), and isoazitine (28) (Figure 10), reported from Aconitum sp., exhibited activities toward L. infantum promastigotes.129 Interestingly, alkaloid 28, the structural isomer of the imine alkaloid 27, showed higher activity toward L. infantum promastigotes (IC50 24.6 μM after 72 h of culture). However, these IC50 values were lower than that of the reference drug pentamidine isethionate. Metabolites 26 (IC50 33.7 μM) and 27 (IC 50 27.9 μM) also showed fair activity against promastigotes of L. infantum after 72 h of culture. As a group, these alkaloids did not show toxicity against the host cell, and 26 had an IC50 of 162.3 μM.129

Figure 10. Structures of diterpene alkaloids 26−28.

3.1.5. Pyrrolidinium Alkaloids. The pyrrolidinium derivative (2S,4R)-2-carboxy-4-(E)-p-coumaroyloxy-1,1-dimethylpyrrolidinium inner salt (29) (Figure 11), reported from Phlomis brunneogaleata of the family Lamiaceae, demonstrated antileishmanial potential toward L. donovani axenic amastigotes with an IC50 value of 9.1 μg/mL.130 3.1.6. Acridone Alkaloids. The two acridone alkaloids, viz., rhodesiacridone (30) and gravacridonediol (31) (Figure 12), were reported from Thamnosma rhodesica. The anti-

Figure 11. Structure of pyrrolidinium alkaloid 29. 10376


Chemical Reviews

Review

with an IC50 against the amastigote form of 1.2 μM and displayed significant selectivity for Leishmania parasites (SI > 200).134 3.1.8. Manzamine-Type Alkaloids. Among the manzamine alkaloids, activities of manzamine A (39), (+)-8hydroxymanzamine A (40), manzamine A N-oxide (41), manzamine E (42), 6-hydroxymanzamine E (43), manzamine F (44), manzamine J (45), ircinol A (46), ircinal A (47), manzamine X (48), 6-deoxymanzamine X (49), and manzamine Y (50) (Figure 14) were reported from the Indonesian sponge Acanthostrongylophora sp.135−137 Manzamines are unique β-carboline alkaloids isolated from Indo-Pacific sponges and contain a characteristic intricate nitrogen-containing polycyclic scaffold system. These metabolites (39−50) exhibited good activities against L. donovani promastigote in the IC50 range of 0.9−6.2 μg/mL. These activities are comparable to those of the standard drugs amphotericin B (IC50 = 0.6 μM) and pentamidine (IC50 = 2.1 μg/mL) used as positive controls. Interestingly, manzamine A (39), ircinol A (46), manzamine A N-oxide (41), and manzamine Y (50) displayed strong activity with IC50 values of 0.9, 0.9, 1.1, and 1.6 μg/mL, respectively. The significant leishmanicidal activity of ircinol A (46; IC50 = 0.9 μg/mL) suggested that the β-carboline group is not important for in vitro activity. Additionally, most of the tested alkaloids demonstrated low or no toxicity toward VERO cells.135−137 3.1.9. Indole Alkaloids. Two indole alkaloids, viz., ramiflorine A (51) and ramiflorine B (52) (Figure 15), demonstrated significant antipromastigote activities (LD50: 51 16.3 ± 1.6 μg/mL and 52 4.9 ± 0.9 μg/mL), and interestingly, the activity of ramiflorine B (52) was higher than the clinically used drug pentamidine (LD50 = 10.0 μg/mL).138 Due to their similarity to the Corynanthe dimeric indole, the mode of action of these alkaloids could be as inhibitors of protein synthesis, as DNA intercalators, or as topoisomerase inhibitors.138 3.1.10. Pyridoacridone Alkaloids. A series of pyridoacridinone alkaloids (53−60) (Figure 16) was tested in vitro for their antileishmanial activity against L. donovani.139 Compounds 53−60 were shown to exhibit promising activity toward L. donovani promastigote, with IC50 values ranging from 0.78 to 8.7 μg/mL. However, compounds 53−60 showed high toxicity toward RAW 264.7 host cells, which is why these compounds were not tested against intracellular amastigotes.139 3.1.11. Batzelladine Alkaloids. Among the batzelladine alkaloids, six polycyclic guanidine alkaloids, viz., batzelladines L and M (61 and 62), ptilomycalin A (63), crambescidine (64), batzelladine C (65), and dehydrobatzelladine C (66) (Figure 17), were isolated from the Jamaican sponge Monanchora unguifera, and their in vitro and in vivo antileishmanial actions were reported.140 All of these metabolites showed antileishmanial activities against L. donovani, with IC50 values in the range of 1.9−8.5 μg/mL. Among the metabolites investigated in this series, batzelladine L (61) displayed strong activity toward L. donovani (IC50 = 1.9 μg/mL).140 3.1.12. Steroidal Alkaloids. Phytochemical investigation of a Nepalese species Sarcococca hookeriana yielded 17 steroidal alkaloids, and antileishmanial activities of all of these compounds have been tested against L. major. The most active included 67a, 68−75, 76a−c, 77, and 80−83 (Figure 18), having IC50 values ranging from 0.20 to 6.67 μg/mL.5,141 An SAR study of these alkaloids showed that 68, having a senecioylamino moiety at the C-3 position, demonstrated strong antileishmanial potential (IC50 = 0.20 μg/mL), and its

Figure 12. Structures of acridone alkaloids 30−33.

leishmanial potential of these alkaloids was evaluated toward L. major promastigotes (at 10 μM) and displayed promising activity: 30, 69%; 31, 46%.130 However, 30 and 31 showed the highest activities against the amastigote form of the parasites, viz., 90% at 10 μM and 50% at 1 μM, respectively, and gratifyingly, no toxicity was observed with murine macrophages at these concentrations.131 Recently, two acridone alkaloids, normelicopicine (32) and arborinine (33), isolated from Teclea trichocarpa, showed activities against L. donovani with IC50 values of 1.08 and 5.20 μg/mL, respectively.132 3.1.7. β-Carboline Alkaloids. Among the β-carboline alkaloids, canthin-6-one (34) and 5-methoxycanthin-6-one (35) displayed both in vitro and in vivo antileishmanial activity.133 The in vivo antileishmanial potential of 34 and 35 (Figure 13) was performed against L. amazonensis infected BALB/c mice and displayed a moderate reduction of the parasite loads in the lesion.

Figure 13. Structures of β-carboline alkaloids 34−38.

Moreover, N-hydro-xyannomontine (36) and annomontine (37), reported from Annona fetida, showed significant antileishmanial potential. It was found that metabolite 37, with an IC50 of 34.8 μM, displayed a 6-fold higher activity against L. braziliensis promastigotes than alkaloid 36. Conversely, 36 displayed good activity against L. guyanensis promastigotes, while quite surprisingly, 37 was inactive.117 Phytochemical investigation of Nauclea diderrichii yielded an indole alkaloid named cadambine acid (38) which showed promising in vitro antileishmanial potential toward L. infantum 10377


Chemical Reviews

Review

Figure 14. Structures of manzamine alkaloids 39−50.

Figure 15. Structures of indole alkaloids 51 and 52.

Figure 16. Structures of pyridoacridone alkaloids 53−60.

activity was similar to amphotericin B (IC50 = 0.12 μg/mL). Similarly, alkaloid 69 and 71 showed activity with IC50 = 3.78 and 3.36 μg/mL, respectively. The acetylated derivative of 67, viz., 67a, displayed slightly higher activity (IC50 = 6.67 μg/mL) than the acetylated analogue 68a (IC50 = 12.74 g/mL), which had a β-acetoxy group at C-3. This finding indicated that a βacetoxy, an α-hydroxyl, and a double bond in ring D are important chemical and structural features for antileishmanial activity. In addition, alkaloid 82 demonstrated stronger activity (IC50 = 1.28 μg/mL) than compounds having a mono-

Figure 17. Structures of batzelladine alkaloids 61−66.

methylamino group which include 72, 74, and 81. Alkaloids possessing a 3′,4′-dimethyl-2′-pentenamido group, viz., 80, showed promising activity (IC50 = 0.46 μg/mL), whereas compounds without this group, viz., 70, showed only a mild activity (IC50 = 6.49 μg/mL).5,141 10378


Chemical Reviews

Review

Figure 18. Structures of steroidal alkaloids 67−83.

Phytochemical investigation of Sarcococca hookeriana yielded eight 5R-pregnane-type steroidal alkaloids such as hookerianamides J (84) and K (85), hookerianamides H (86) and I (87), chonemorphine (88), vagenine A (89), 2,3-dehydrosarsalignone (90), and sarcovagine C (91) (Figure 19). All of these compounds displayed moderate to potent leishmanicidal potential toward L. major, with IC50 values ranging from 0.7 to 9.3 μg/mL.142 Two of the compounds, viz., 89 (IC50 0.7 μM) and 91 (IC50 0.7 μM), exhibited the highest potencies and were comparable to the positive controls: amphotericin B (IC50 0.5 μM) and pentamidine (IC50 7.5 μM). Recently, three steroidal alkaloids, hookerianamide L (92), hookerianamide O (93), and N-formylchonemorphine (94), were isolated from S. hookeriana, and all three displayed antileishmanial activities with IC50 values of 8.8, 9.3, and 7.2 μg/mL, respectively. Interestingly, the activity values of these compounds were higher than that of the standard drug pentamidine (IC50 9.5 μg/mL).143 3.1.13. Bromopyrrole Alkaloids. Among the bromopyrrole alkaloids, dibromopalauamine (95) was reported from Axinella verrucosa (marine sponge) and longamide (96) (Figure 20) from Agelas dispar.144 Dibromopalauamine (95) and longamide (96) demonstrated activity against L. donovani (IC50 95 1.09 μg/mL; 96 3.85 μg/mL), and their activities compared well with standard drug miltefosine (IC50 0.21 μg/ mL).144 3.1.14. Furoquinoline Alkaloids. Among the furoquinoline alkaloids, γ-fagarine (97) (Figure 21), isolated from Helietta apiculata, showed antileishmanial activity with 97% inhibition, and its activity was the same as that of the reference drug.145 This compound additionally demonstrated promising activity against L. amazonensis-infected mice.145 3.1.15. Indolizidine Alkaloids. Δ1,6-Juliprosopine (98), together with the previously known indolizidine analogues 99− 104 (Figure 22), were reported from Prosopis glandulosa, and

Figure 19. Structures of steroidal alkaloids 84−94.

Figure 20. Structures of bromopyrrole alkaloids 95 and 96.

Figure 21. Structure of furoquinoline alkaloid 97.

interestingly, alkaloids 100 and 103 showed the most promising activity toward the promastigote/amastigote form of L. donovani (IC50 100 0.18/1 μg/mL; 103 0.3/2 μg/mL).146 It is interesting to note that activities of alkaloids 100 and 103 were similar to the pentamidine (0.8/2.1 μg/mL). The quaternary salts 99, 102, and 104 were less toxic against VERO cells compared to the tertiary bases 100 and 103. Interestingly, compound 98 displayed potent activity toward L. donovani promastigotes and axenic amastigotes (IC50 = 0.8 and 1.8 μg/mL, respectively).146 3.1.16. From Marine Invertebrates. There seems to be a perception that the numbers of antileishmanial marine natural 10379


Chemical Reviews

Review

tropica (IC50 3.82 μg/mL) and L. infantum (IC50 6.35 μg/mL) with a bonus of low toxicity (8% viability at 20 μg/mL). Flavokavin B (125) from a related species (Piper rusbyi) in its evaluation displayed antileishmanial activity against all three of the Leishmania species (L. braziliensis, L. amazonensis, and L. donovani promastigotes) with IC50 values of 11.2 μg/mL, which meant it was even more potent than the reference drug, pentamidine (IC50 16.8 μg/mL).151 Chalcone 125 was also evaluated in mice infected with L. amazonensis and showed a significant reduction (P < 0.05) of the average lesion size (32.1%). These results in particular highlight the leishmanicidal activity of the Piper species, particularly Piper rusbyi as a traditional herbal remedy for fevers, since chalcone 125 also demonstrates potent leishmanicidal activity in vivo.152 P. arborescens extracts exhibited significant activities against L. donovani, and a phytochemical investigation of the extracts led to isolation of a chalcone named isoliquiritigenin 108,153 which proved to be a most effective and significant antiamastigote against L. donovani, displaying IC50 values below 21 nM. However, 108 displayed a low selectivity of approximately 3fold for the parasites over the mammalian Vero cells. Two further naturally occurring chalcones, viz., 2′,4′-dihydroxy-6′methoxy-3′,5′-dimethylchalcone (126) and 2,2′,4′-trihydroxy6′-methoxy-3′,5′-dimethylchalcone (127), exhibited promising leishmanicidal activities (IC50 126 5.0 μg/mL; 127 7.5 μg/mL). Additionally, these chalcones were also tested against L. mexicana-preinfected macrophages and showed 96% reduction of infected macrophages while displaying no toxicity to the host cells.154

Figure 22. Structures of indolizidine alkaloids 98−104.

compounds are somewhat limited due to the rather low numbers of isolated molecules exhibiting this activity.147 Investigation of the marine sponge Neopetrosia sp. provided an alkaloid named renieramycin A (105) (Figure 23), which displays an antileishmanial effect (IC50 = 0.2 μg/mL) in L. amazonensis by means of a green fluorescent protein (La/egfp) bioassay.148

4.2. Flavonoids

Tasdemir and co-workers evaluated different flavonoids against L. donovani, and the majority of metabolites tested (128−162, Figure 25) possessed remarkable leishmanicidal potential, with IC50 values in the range from 0.6 to 10.9 μg/mL.155 Among these, 3-hydroxyflavone (149) and fisetin (155) were suggested to be the most potent with IC50 = 0.6 and 0.8 μg/mL, respectively. These IC50 values were compatible to the standard miltefosine (IC50 0.34 μg/mL). Among the remaining compounds, 15 had IC50 values within the range from 1.1 to 3.0 μg/mL, and luteolin-7-O-glucoside (147), 3-hydroxyflavone (149), fisetin (155), quercetin (156), and myricetin (161) were evaluated in vivo against L. donovani (BALB/c mice infected). In this regard, only quercetin (156) displayed some in vivo effect (15.3%), while the remaining flavonoids did not show any in vivo activity.155 Quercitrin (163) and its 3-O-α-L-rhamnopyranoside analogue (164) (Figure 26) from Kalanchoe pinnata were screened for leishmanicidal activity toward intracellular L. amazonensis amastigotes.156 The commercial drug Pentostam was used as the positive control for this evaluation. Interestingly, quercitrin (163) and its 3-O-α-L-rhamnopyranoside analogue (164) exhibited leishmanicidal activity with IC50 values of 8 and 45 μg/mL, respectively, compared with Pentostam (standard drug) (IC50 20 μg/mL). These results suggested that the quercitrin moiety is an important structural feature for eliciting antileishmanial activity.156 The difference in their activity may be related to the presence of the arabinosyl unit attached at the inner rhamnosyl unit in flavonoid 164, which may be as a result of the membrane solubility and bioavailability of this compound.157 Cannflavin A (165), from Cannabis sativa, exhibited strong antileishmanial activity (IC50 4.5 μg/mL),158 and similarly, luteolin-7-O-ß-D-glucopyranoside (166) and

Figure 23. Structure of alkaloid 105.

4. PHENOLIC DERIVATIVES 4.1. Chalcones

In one study, 20 naturally occurring chalcones (106−123) (Figure 24) were evaluated for their activity toward promastigotes of L. infantum, L. donovani, L. major, and L. enriettii as well as against intracellular amastigotes of L. donovani.149 These natural products exhibited antileishmanial activities against Leishmania species, with EC50 values of less than 10.0 μg/mL. Although chalcone 112 proved to be the most active compound toward L. donovani amastigotes (EC50 = 0.39 μg/mL), it also demonstrated toxicity toward murine macrophages (EC50 0.62 μg/mL). It is interesting to note that in comparison with amphotericin B, compounds 108, 109, 115, 119, and 122 also revealed better activities against the amastigote form. Chalcones 108, 109, 115, 119, and 122 also displayed relatively high toxicities for bone marrow-derived macrophages (BMMΦ) and were therefore considered to be only moderately selective (SI > 1.0). It was found that chalcones 113, 115, 116, 121, and 123 showed moderate intracellular activity against L. donovani [EC50 > 4.4 μg/mL], and the remaining chalcones in this series showed moderate antileishamnial activity against L. donovani (EC50 less than 4.0 μg/mL; SI 1.11−0.45).149 Dihydrochalcone 124 from Piper elongatum was evaluated for antileishmanial activity against L. braziliensis, L. tropica, and L. infantum in vitro150 and displayed promising activity against L. 10380


Chemical Reviews

Review

Figure 24. Structures of chalcones 106−127.

dimethylallyl)isoflavone (177), the new 2-(2′-hydroxy-4′,5′methylenedioxyphenyl)-6-methoxybenzofuran-3-carbaldehyde (178), and 4-hydroxymaackiain (179) (Figure 28). These isoflavones displayed leishmanicidal activities against L. donovani amastigotes, with IC50 values of 13.0, 38.4, and 37.3 μM, respectively.153 A novel isoflavan-4-ol, pumilanol (180), was reported from Tephrosia pumila and exhibited significant activity toward L. donovani (IC50 = 17.2 μg/mL). However, this natural product exhibited toxicity toward L-6 rat skeletal myoblasts (IC50 17.12 μg/mL).162 The isoflavonoid, 6,7-dimethoxy-3′,4′-methylenedioxyisoflavone (181), was reported from Millettia puguensis and displayed moderate antileishmanial activity against L. infantum, with an IC50 of 32 μM.163

chrysoeriol-7-O-ß-D-glucopyranoside (167) also showed potent leishmanicidal activity toward L. donovani with IC50 values of 1.1 and 4.1 μg/mL, respectively.159 Recently, Tasdemir et al.155 reported that the flavanones naringenin (168) and 5,7-dimethoxy-8-methylflavanone (169) showed antileishmanial activities against L. donovani (IC50 168 5.0 μg/mL; 169 2.5 μg/mL). Similarly, the same research group155 reported that (−)-gallocatechingallate (170) (Figure 27) displayed significant leishmanicial activity against L. donovani (IC50 = 8.9 μg/mL). Phytochemical investigation of Mimulus bigelovii provided four most interesting C6-geranyl flavanones, viz., diplacone (171), 3′-O-methyldiplacone (172), 4′-O-methyldiplacone (173), and 3′-O-methyldiplacol (174)160 (Figure 27). Compounds 172 and 173 were reported as a 1:1 mixture. All of these compounds demonstrated significant antileishmanial activities toward axenic L. donovani amastigotes, and the IC50 values were within the range from 4.8 to 7.5 μg/ mL. However, diplacone (171) was the most potent (IC50 = 4.8 μg/mL).

4.4. Coumarins

Aurapten (182) (Figure 29), a 7-geranyloxycoumarin, isolated from the rutaceous species Esenbeckia febrif uga, showed significant growth inhibition, with an LD50 of 30 μM against the tropical parasite L. major. Recently, Iranshahi et al.164 isolated aurapten (182) from Ferula szowitsiana and reported on its activity against L. major as having an IC50 of 4.9 μg/ mL.125 Another coumarin, umbelliprenin (183), also isolated from Ferula szowitsiana, showed potent leishmanicial activity toward L. major (IC50 of 5.1 μg/mL). Similarly, bergaptol (184) showed significant activity toward L. donovani (IC50 = 2.5 μM).98 The coumarin (−) mammea A/BB (185) reported from Calophyllum brasiliense displayed promising antileishmanial activities toward L. amazonensis (promastigote IC50 = 3.0 μg/mL) and amastigote (IC50 = 0.88 μg/mL).165 Compound 185 was also evaluated for its cytotoxicity against J774G8 macrophages and showed no toxicity. Recently, 3-(1′-

4.3. Isoflavones

Among the isoflavone class, biochanin A (175) from Cassia f istula161 showed leishmanicial activity toward L. chagasi promastigotes (IC50 175 18.96 μg/mL; Pentamidine 0.09 μg/ mL). Interestingly, biochanin A (175) was approximately 10fold less toxic than pentamidine against peritoneal macrophages. In a further test, biochanin A (175) also demonstrated potent activity toward L. donovani (IC50 2.5 μg/mL), while the isoflavone genistein (176) showed activity, with an IC50 of 8.0 μg/mL.155 Phytochemical investigation of Psorothamnus arborescens afforded three isoflavones, viz., 5,7,3′,4′-tetrahydroxy-2′-(3,310381


Chemical Reviews

Review

Figure 25. Structures of flavones 128−162.


dimethylallyl)-decursinol (186) and (−)-hellietin (187), isolated from Helietta opiculata, reduced the parasite loads by 95.6% and 98.6%, respectively, and their activities were equal to the reference drug.145 The 3-(1′-dimethylallyl)-decursinol (186) and (−)-hellietin (187) were also tested against L. amazonensis-infected mice and showed promising activity. These results indicated that coumarins 186 and 187 may be of potential use for development in the treatment of cutaneous Leishmaniasis.145


μg/mL).166 Phytochemical investigations of the fungus Chaetomium sp. afforded three new xanthones named chaetoxanthones A−C (190−192) (Figure 30). All three demonstrated significant activities against L. donovani with IC50 values of 5.3, 3.4, and 3.1 μg/mL, respectively.167 Two further xanthones, viz., pancixanthones A (193) and 1,6-dihydroxyxanthone (195) and the benzophenone deriva-

4.5. Xanthones and Benzophenones

Two xanthones, allanxanthone D (188) and 1,3,6,7-tetrahydroxy-2-(3-methylbut-2-enyl)xanthone (189), from Allanblackia gabonensis, displayed leishmanicidal activity toward axenic amastigotes of L. amazonensis (IC50 188 13.9 μg/mL; 189 13.3 10382


Chemical Reviews

Review

Figure 31. Structures of xanthones 193 and 195 and benzophenone 194.

4.6. Other Phenolic Compounds

A tetrahydrofuran lignan, viz., machilin-G (196), reported to be isolated from Nectandra megapotamica, has been screened for in vitro antileishmanial activity toward L. donovani with moderate activity and having an IC50 value of 18 μg/mL.169 Machaerium multif lorum yielded three new (+)-trans-hexahydrodibenzopyrans (HHDBPs), viz., machaeriol C (197), machaeridiol B (198), and machaeridiol C (199) (Figure 32). Machaeridiol B

Figure 28. Structures of isoflavones 175−181.

Figure 29. Structures of coumarins 182−187.

Figure 30. Structures of xanthones 188−192.

tive, 3-geranyl-2,4,6-trihydroxybenzophenone (194) (Figure 31), isolated from Garcinia vieillardii, showed significant antileishmanial activities toward promastigote forms of L. mexicana and L. infantum and against L. infantum amastigote.168 It is interesting to note that compounds 193−195 showed promising activity toward the amastigote forms of L. infantum with IC50 values 2.5, 3.1, and 0.7 μg/mL, respectively. Even more noteworthy is the fact that benzophenone derivative 194 displayed activities as high as amphotericin B (0.2 μg/mL).

Figure 32. Structures of compounds 196−203.

(198) demonstrated strong inhibition against L. donavani (IC50 0.64 μg/mL), whereas 197 and 199 displayed slightly lower but nevertheless significant antileishmanial activities, with IC50 values of 3.0 and 3.3 μg/mL, respectively.170 Grandiuvarone A (200) was reported from Uvaria grandif lora and exhibited leishmanicidal activity with an IC50 10383


Chemical Reviews

Review

value of 0.7 μg/mL. In these studies and under the same conditions the positive controls pentamidine and amphotericin B had IC50 values of 1.6 and 0.17 μg/mL, respectively.171 The resorcinol derivative, 5-heptadeca-8′Z,11′Z,16-trienylresorcinol (201), isolated from Merulius incarnatus, demonstrated promising activity (IC50 3.6 μg/mL), and interestingly, it was not cytotoxic in the Vero cell test.172 Two further 5alkylresorcinols, viz., 5-(11′(S)-hydroxy-8′-heptadecenyl)resorcinol (202) and 5-(12′(S)-hydroxy-8′,14′-heptadecadienyl)-resorcinol (203), reported from Stylogyne turbacensis, showed the strongest activities in the Leishmania assay with IC50 values of 7 and 3 μM, respectively.173 The benzoic acid ester, methyl 3,4-dihydroxy-5-(3′-methyl2′-butenyl)benzoate (204), isolated from Piper sp., exhibited an antileishmanial potential (IC50 13.8−18.5 μg/mL) toward three Leishmania strains employed in that investigation (L. braziliensis, L. amazonensis, and L. donovani).174 A cannabigerol derivative, 5-acetyl-4-hydroxycannabigerol (205), showed strong antileishmanial activity (IC50 10.7 μM) against L. donovani.175 The natural products pseudopyronines A (206) and B (207) (Figure 33), containing a 2-pyrone moiety,


parasites. Additionally, compound 212 reduced the number of L. mexicana-preinfected macrophages (96%) with no detectable toxicity to the host cell.154 Two new caffeic acid esters, viz., (S)-1′-methylbutyl caffeate (213) and (S)-1′-methyloctyl caffeate (214) reported to be present in Piper sanguineispicum, exhibited appreciable antileishmanial activities (IC50 2.0 and 1.8 μM, respectively) against L. amazonensis, with only moderate cytotoxicities toward murine macrophages.179 Momordicatin (215) purified from Momordica charantia was screened in vitro against kala azar caused by L. donovani and displayed leishmanicidal activity toward Leishmania promastigotes with a really excellent IC50 value of 0.02 mg/L.180 Momordicatin (215) also showed 100% parasite clearance in the hamster model of visceral leishmaniasis (10 mg/kg).180

5. TERPENES 5.1. Iridoids

Two spirolactone iridoids, plumericin (216) and isoplumericin (217) (Figure 35), from Himatanthus sucuuba, both displayed


were found to exhibit good potencies displaying IC50 values of 2.63 and 1.38 μg/mL, respectively, as well as some selectivities toward L. donovani.176 Three stilbenes, viz., 2-hydroxystilbene (208), 2-hydroxy-2′-methyl-4′,5′-methylenedioxystilbene (209), and 2-hydroxy-2′-methoxy-4′,5′-methylenedioxystilbene (210), isolated from Cicer bijugum, exhibited leishmanicidal effects with IC50 values falling in the range of 2.5−6.1, 3.35− 13.3, and 2.28−12.2 μg/mL, respectively, against the three Leishmania strains investigated, namely, L. aethiopica promastigotes, L. major promastigotes, L. tropica promastigotes, and L. aethiopica amastigotes.177 Another stilbene, piceatannol (211) (Figure 34), was tested for its activity against the promastigote form of L. infantum and L. major and toward L. donovani (promastigote/amastigote forms). Piceatannol (211) showed moderate activity toward the extracellular forms of Leishmania species but a higher activity than the standard drug (Pentostan) toward the intracellular form of L. donovani.178 Dalrubone (212), isolated from Psorothamnus polydenius, exhibited fair leishmanicidal (IC50 = 7.5 μg/mL) properties and displayed an encouraging 6-fold selectivity against L. donovani

Figure 35. Structures of iridoids 216−218.

strong activities toward L. amazonensis axenic amastigotes with IC50 values of 0.21 and 0.28 μg/mL, respectively, and notably, their activities were higher than the standard drug amphotericin B (IC50 0.52 μg/mL).181 The iridoids 216 and 217 were further tested for their cytotoxicities on mouse peritoneal macrophages, and both compounds displayed the same activity with an IC50 of 1.86 μM. These results indicated that compounds 216 and 217 exhibited less toxicity compared with their activities on Leishmania amastigotes.181 In antitumoral assays, isoplumericin (217) was found to be more toxic than plumericin (216), which also exhibited a 10384


Chemical Reviews

Review

reduction of L. amazonensis-infected macrophages with the same efficacy as amphotericin B, while isoplumericin (217) demonstrated toxicity toward infected macrophages. The IC50 value for plumericin (216) was 0.9 μM compared to 1 μM for amphotericin B. Finally, Phlomis brunneogaleata (Lamiaceae) yielded the iridoid glycoside brunneogaleatoside (218). This compound showed promising leishmanicidal activity toward L. donovani with an IC50 value of 4.7 μg/mL.158 5.2. Sesquiterpenes

The asteraceous plant Elephantopus mollis showed potent antileishmanial activity, and following a rigorous chemical investigation it yielded six sesquiterpene lactones, viz., (4β-H)8α-(2-methylpropenoyloxy)-2-oxo-1(5),10(14),11(13)-guaiatriene-12,6α-olide (219), (4β-H)-5α-hydroxy-8α-(2-methylpropenoyloxy)-1(10),11(13)-guaiadiene-12,6α-olide (220), molephantin (221), elephantopin (222), isoelephantopin (223), and 2-deethoxy-2β-methoxyphantomolin (224) (Figure 36). Interestingly, all six sesquiterpenes demonstrated significant leishmanicidal properties against L. major with IC50 values ranging from 0.1 to 1.0 μg/mL.182

Figure 37. Structures of sesquiterpenes 225−230.

chagasi (IC50 75 μM) promastigotes and L. amazonensis amastigotes (IC50 67 μM) in vitro.185 Nerolidol (227) also showed a 95% reduction against L. amazonensis-infected macrophages at 100 μM, and promising reductions in the sizes of lesions were observed in L. amazonensis-infected BALB/c mice.185 The sesquiterpene elatol (228), isolated from Laurencia dendroidea, was investigated for its antileishmanial activity toward L. amazonensis and additionally showed activity toward promastigote (IC50 4.0 μM) and amastigote forms (IC50 0.45 μM) of L. amazonensis and with no toxicity to macrophages.186 Odonne et al.187 isolated two sesquiterpene lactones, viz., (+)-8,13-diacetyl-piptocarphol (229) and (+)-8-acetyl-13-Oethyl-piptocarphol (230) from Pseudelephantopus spicatus. Interestingly, when the in vitro antileishmanial activities of compounds 229 and 230 were measured with L. amazonensis axenic amastigotes, compounds 229 (IC50 0.20 μM) and 230 (IC50 0.37 μM) displayed a greater activity compared to amphotericin B (IC50 0.41 μM). Six germacranolides, viz., calealactone D (231), calealactone C (232), calein D (233), calein A (234), calealactone E (235), and 8β-angeloxy-9α-acetyloxycalyculatolide (236) (Figure 38), were isolated from Calea zacatechichi.188 All compounds demonstrated significant activities, and their IC50 values were within the rang from 1.9 to 8.5 μM. Interestingly, compounds 231 and 232 (1.9 and 2.2 μM) were, in this instance, more active than the standard drug (pentamidine, IC50 2.9 μM). Phytochemical investigations of the Brazilian red alga, Laurencia dendroidea, afforded two sesquiterpenes, viz., elatol (228) and obtusol (237) (Figures 37 and 39).189 These two triquinane derivatives showed significant antileishmanial activities toward both the promastigote (IC50 6.2 and 9.7 μg/ mL, respectively) and the amastigote forms (IC50 3.9 and 4.5 μg/mL, respectively). Compounds 228 and 237 did not promote nitric oxide production by macrophages and showed no toxicity against the peritoneal macrophages or lymph node cells.189


The sesquiterpene 1R,2S,3S,4S,5S,6R,7R,9S,10R)1,2,3,6,9,12,15-heptaacetoxy-4-hydroxy-8-oxodihydro-β-agarofuran (225), isolated from Maytenus chiapensis, showed weak activity (growth inhibition 28% at 60 μM) toward a multidrugresistant L. tropica line. The compound is presumably too bulky to bind effectively at the active site. This finding is in agreement with previous observations that the steric properties of sesquiterpenes in the same class can modulate their activities.183 Parthenolide (226) (Figure 37), which was purified from Tanacetum parthenium, demonstrated promising activity toward L. amazonensis promastigotes with 50% inhibition of cell growth at 0.37 μg/mL. Similarly, this compound also showed 50% inhibition of the amastigote form at a concentration of 0.81 μg/mL and did not show cytotoxicity toward J774G8 macrophages.184 Nerolidol (227) showed leishmanicidal activity toward L. braziliensis (IC50 74 μM), L. amazonensis (IC50 85 μM), and L.

5.3. Diterpenes

Three clerodane diterpenes, viz., (5R,8R,9S,10R)-12-oxo-ent3,13(16)-clerodien-15-oic acid (238), 16-hydroxy-clerod3,13(14)-diene-15,16-olide (239), and ent-12-oxolabda10385


Chemical Reviews

Review

strong antileishmanial activities against axenically cultured amastigotes, whereas 240 exhibited a weaker activity (LD50 19.2 μg/mL).190 Recently, Misra et al.191 reported the in vivo potential of compound 239 via oral administration at four dose levels toward L. donovani infection in hamsters. Interestingly, one compound, in particular, i.e., 239, at a dose level of 250 mg kg−1, displayed strong activity in bone marrow (89.1%), spleen (91%) and liver (87.5%). Moreover at a dose of 100 mg kg−1, compound 239 demonstrated 84.2%, 86.8%, and 83.7% and at 50 mg kg−1 80.2%, 85.5%, and 77.9% inhibition in bone marrow, spleen, and liver, respectively. On the other hand, compound 239 did not show any activity at 25 mg kg−1. Further studies showed that compound 239 showed no cytotoxicity to the macrophages, and the animal survived for 6 months after treatment, which indicated that 239 upon further development could lead to a potent antileishmanial drug.191 Phytochemical investigations of Cistus monspeliensis extracts afforded seven clerodane-type diterpenes, viz., cistadiol (241), 18-acetoxy-cis-clerod-3-en-15-ol (242), 15,18-diacetoxy-cis-clerod-3-ene (243), 15-acetoxy-cis-clerod-3-en-18-ol (244), 18acetoxy-cis-clerod-3-en-15-oic acid (245), 15-acetoxy-cis-clerod3-en-18-al (246), and 15-hydroxy-cis-clerod-3-en-18-al (247). Similarly, an investigation of the extracts of Cistus creticus yielded three labdane-type diterpenes, viz., ent-3β-acetoxy-13epi-manoyl oxide (248), 13(E)-labda-7,13-diene-15-ol (249), and 13(E)-labd-13-en-8α,15-diol (250). Compounds 241−250 displayed potent activity toward L. donovani promastigotes with IC50 values below 20 μg/mL.192 Among these natural products, the most potent were the cis-clerodane diterpenes 242, 243, and 246 having IC50 values of 3.3, 3.4, and 5.0 μg/mL, respectively. All compounds were additionally evaluated for their cytotoxicities against VERO cells (monkey kidney fibroblasts). None of these compounds exhibited cytotoxicity toward the mammalian cells.192 Phytochemical investigations of Juniperus procera afforded numerous diterpenes, including totarol (251), ferruginol (252), and 7β-hydroxyabieta-8,13-diene-11,12-dione (253) (Figure 41). These compounds demonstrated good antileishmanial activities against L. donovani promastigotes with IC50 values ranging from 3.5 to 4.6 μg/mL.193 Phytochemical investigations of Zhumeria majdae afforded 12,16-dideoxy aegyptinone B (254), which demonstrated significant leishmanicidal activity (IC50 = 0.75 μg/mL, SI 16). Interestingly, the activity of 254 was stronger than the standard pentamidine but less potent than amphotericin B. 194 Phytochemical investigations of Baccharis dracunculifolia afforded hautriwaic acid lactone (255) with significant leishmanicidal activity toward L. donovani (IC50 = 7.0 μg/ mL).195 Two novel diterpenoid 1,2-quinones, viz., cryptotanshinone (256) and 1-oxomiltirone (257), isolated from Perovskia abrotanoides, showed leishmanicidal activities in vitro against L. major with IC50 values of 18.4 and 17.9 μg/ mL, respectively.196


Figure 39. Structure of sesquiterpene 237.

8,13(16)-dien-15-oic acid (240) (Figure 40), were reported from Premna schimperi and P. oligotricha.190 Diterpenes 238 (LD50 = 1.08 μg/mL) and 239 (LD50 = 4.12 μg/mL) showed

5.4. Triterpenes and Saponins

The quinone methide triterpene pristimerin (258), from Maytenus senegalensis, exhibited promising leishmanicidal activity toward L. major promastigote with an IC50 value of 6.8 μg/mL. The cytotoxicity of triterpene 258 was evaluated and demonstrated an IC50 value of 6.8 μg/mL in the lymphocyte proliferation model.197 Antileishmanial activity assays were performed on the two bisnortriterpenes:

Figure 40. Structures of diterpenes 238−250. 10386


Chemical Reviews

Review

(IC50 15.0 μg/mL). However, this compound displayed significant toxicity toward both promastigotes and intracellular amastigotes which limits its potential as an antileishmanial agent.200 Six new pentacyclic triterpene saponins, maesabalides I−VI (263−268) (Figure 43), exhibiting significant antileishmanial

Figure 41. Structures of diterpenes 251−257.

isoiguesterin (259) and 20-epi-isoiguesterinol (260) (Figure 42) purified from Salacia madagascariensis. Both compounds were strongly active against L. donovani (IC50 0.032 and 0.027 μg/mL), respectively.198

Figure 43. Structures of saponins 263−268.

activities [L. infantum amastigotes (in vitro)], were isolated from Maesa balansae. Compounds 265 and 266 showed the strongest activities, both having an IC50 value of 20 ng/mL (0.013 nM). Compounds 263, 264, 267, and 268 also demonstrated promising activities with IC50 values of 70 (0.046 nM), 50 (0.033 nM), 3400 (2.16 nM), and 700 ng/mL (0.45 nM), respectively. It is interesting to note that pentostam (IC50 = 8.1 nM for the standard drug) was 300 fold less active than 265 and 266.201 Both compounds 265 and 266 displayed no toxicity toward the human fibroblast (MRC-5) cell line (CC50 > 32 μg/mL), and both compounds showed in vivo activity in a BALB/C mouse model with >90% reduction of the liver amastigote.202 Neothyoside C (269) (Figure 44), a lanostane-type triterpene saponin, was isolated from the body walls of the sea cucumber Neothyone gibbosa and shown to be a most active antileishmanial compound, inhibiting 100% of the promastigotes of both L. mexicana strains at 5 and 10 μg/mL.203

Figure 42. Structures of triterpenes 258−261 and saponin 262.

The pentacyclic triterpenoid taraxerone (261), isolated from the fruits of Dregea volubilis Benth (Asclepiadaceae), exhibited a decrease in the growth of Leishmania promastigotes in a dosedependent manner under the specific conditions of the study and had an IC50 value of 3.8 μg/mL.199 Triterpenoid saponin arborenin (262), isolated from Careya arborea, displayed an in vitro leishmanicidal activity toward L. donovani (strain AG 83) 10387


Chemical Reviews

Review

this compound also showed potent activity toward drugresistant strains (IC50 from 5.1 to 9.8 μM). In addition, a preliminary in vivo experiment on an L. donovani LV9/Balb/C mice model compound 270 demonstrated reduction up to 48% of the liver parasite.204 6.2. Peptides

The peptide viridamide A (277) (Figure 46) from Oscillatoria nigrowiridis demonstrated antileishmanial activity toward L.

Figure 44. Structure of saponin 269.

6. OTHER METABOLITES 6.1. Acetogenins

The acetogenins, isoannonacin (270), 2,33-dihydroannonacin (271), isorolliniastatin-1 (272), panalicin (273), narumicin-1, (274), narumicin-2 (275), and cherimolin (276), were reported from the Annonaceae plant family.204 The IC50 values of these acetogenins toward L. donovani (promastigote forms) were found to be between 4.7 and 23.3 μM. However, only four compounds (270 and 274−276, Figure 45) exhibited in vitro activity on the intramacrophage amastigote model, and the IC50 values were within the range from 2.5 to 29.7 μM. Isoannonacin (270) displayed significant activity toward intramacrophagic amastigotes (IC50 6.2 μM; SI 2.05), and

Figure 46. Structures of peptides 277 and 278.

mexicana with an IC50 of 1.5 μM.205 Similarly, another marine cyanobacterium, Symploca sp., yielded symplocamide A (278), which exhibited antileishmanial activity toward L. donovani with an IC50 of 9.5 μM.206 Ciliatamides A and B (279 and 280) (Figure 47) were reported from Aaptos ciliate and subsequently evaluated for their antileishmanial activity in a fluorometric microplate assay using L. major/egfp promastigotes. The results indicated that ciliatamides A (279) and B (280) inhibited growth at 50% and 45.5%, respectively, when dosed at 10 μg/mL.207 Recently, Lyngbya majuscula was found to produce dragonamides A (281) and E (282) and herbamide B (283). These were shown to exhibit antileishmanial activity toward L. donovani with IC50 values of 6.5, 5.1, and 5.9 μM, respectively.208 The Indonesian tunicate Didemnum molle yielded the cyclic hexapeptide mollamide B (284) (Figure 48), which has been evaluated for its antileishmanial activity and proved to be active toward L. donovani with an IC50 of 18 μg/mL.209 An investigation of Schizothrix sp. provided gallinamide A (285), which demonstrated activity toward L. donovani with an IC50 of 9.3 μM.210 6.3. Palmarumycin

Various palmarumycins, including preussomerin EG1 (286), palmarumycin CP2 (287), palmarumycin CP17 (288), palmarumycin CP18 (289), CJ-12,371 (290), and palmarumycin CP19 (291), were reported from the fungus Edenia sp. Compounds 286−291 (Figure 49) were screened against L. donovani and showed strong activity (IC50 from 0.12 to 8.40 μM). Interestingly, compound 286 (IC50 = 0.12 μM) showed the same level of activity toward amastigotes as amphotericin B (IC50 0.09 μM) and, moreover, displayed moderate cytotoxicity against mammalian Vero cells (IC50 9 μM). Interestingly,

Figure 45. Structures of acetogenins 270−276. 10388


Chemical Reviews

Review

palmarumycin 286 was more active than palmarumycins 288 (IC50 = 1.34 μM) and 289 (IC50 = 0.62 μM), but compounds 288 (174 μM) and 289 (152 μM) displayed less cytotoxicity to mammalian Vero cells.211,212 6.4. Quinones

The quinone emodin (292) and vismione D (293) were isolated from Vismia orientalis Engl. (Clusiasceae) (Figure 50).

Figure 50. Structures of quinones 292−295 and vismione D (293).

It is interesting to note that compound 293 (IC50 0.37 μg/mL) displayed a similar level of activity as miltefosine (IC50 0.23 μg/ mL) toward amastigote form of L. donovani. Compound 292 also demonstrated pronounced activity (IC50 2.05 μg/mL) toward amastigote form of L. donovani but proved to be less active than 293.213 The naphthoquinone compounds dioncoquinones A (294) and B (295), from Ancistrocladus abbreviatus, showed significant antileishmanial activity against L. major, displaying growth inhibition percentages of 49.6 and 79.2, respectively. In comparison, the reference drug miltefosine showed 53% growth inhibition.214 Ali et al.215 tested 18 natural products that were isolated from plants of the family Boraginaceae. These compounds included simple naphthoquinones, viz., 1,4-naphthoquinone (296), menadione (297), juglone (298), naphthazarin (299), plumbagin (300), 301, 302, the alkannin/shikonin derivatives (303−308), dimers (309−311), and the furanonaphthoquinones (312 and 313) (Figure 51). Naphthoquinone 296 showed significant activity toward promastigotes (IC50 = 2.0 μM), which in most respects is similar to amphotericin B (IC50 = 2.0 μM). Unfortunately, 296 displayed only a moderate antilieshmanial activity toward the amastigote form (IC50 = 8.5 μM). Naphthoquinone 297, having a C-2 methyl group, displayed a slight increase in the antileishmanial activity toward amastigotes (IC50 = 6.2 μM). Among the tested oxygenated derivatives, compounds 298−300 showed the most promising antileishmanial properties toward both amastigotes and promastigotes and with weaker toxic effects toward the host cell controls (SI 2.3−3.2). Within the alkannin/shikonin series, compounds 303 and 304 showed the highest activities toward L. major GFP parasites, displaying IC50 values of 1.3 and 1.9 μM, respectively. Furthermore, metabolites 305−307 showed antileishmanial activity with IC50 values of 2.7, 3, and 5 μM, respectively.215 Naphthoquinone 308 showed antileishmanial activity with an IC50 value of 4.1 μM, and a mixture of 309 and 310 displayed an interesting and pronounced antileishmanial activity (IC50 = 1.1 μM), while compound 311 acted only as a weak antileishmanial agent. Finally, a mixture of the furanonaphthoquinone isomers 312 and 313 showed significant effects toward both amastigotes and promastigotes (IC50 = 4

Figure 47. Structures of peptides 279−283.

Figure 48. Structures of peptides 284 and 285.

Figure 49. Structures of palmarumycins 286−291.

10389


Chemical Reviews

Review

Figure 51. Structures of naphthoquinones 296−313.

μM). Toxic effects could be detected on the macrophage host cells when the concentration of the sample was increased by at least 2-fold (SI = 2).215

L. major assay, compounds 317−321 displayed pronounced activity, displaying IC50 values of 1.4−7.0 μg/mL.218

7. MISCELLANEOUS The steroid clerosterol (314) (Figure 52) obtained from Cassia f istula was analyzed using various models. Growth of


Five physalins (322−326) (Figure 54) have been isolated from the whole plant of Physalis minima and were screened in an in vitro assay. They were found to have significant antileishmanial activities (IC50 0.92−7.0 μg/mL). Compound Figure 52. Structures of compounds 314−316.

promastigotes (L. chagasi) was inhibited by up to 50%, and it was found that the intracellular amastigotes were highly susceptible to treatment with clerosterol, exhibiting an IC50 value of 18 μg/mL. In a mammalian cytotoxicity test, compound 314 was 3.6-fold less toxic than the standard drug pentamidine.216 Two γ-pyrones (315 and 316) isolated from Podolepsis hieracioides displayed antileishmanial activity toward the promastigote forms of L. donovani, L. infantum, L. major, and L. enriettii (IC50 = 3.76−5.43 μg/mL). Moreover γ-pyrones 315 and 316 also displayed activity toward L. donovani amastigote with IC50 values ranging from 8.29 to 8.59 μg/mL.217 Cordia f ragrantissima, collected in Burma (Myanmar), was found to exhibit significant activity against L. major. Bioassayguided purification of the extract afforded five compounds, viz., cordiaquinol J (317), cordiachromes A (318) and B (319), cordiaquinol C (320), and alliodorin (321) (Figure 53). In the

Figure 54. Structures of physalins 322−326. 10390


Chemical Reviews

Review

322 exhibited an IC50 value of 0.92 μg/mL, and for comparison, the reference drug amphotericin B had an IC50 of 0.12 μg/mL. It was apparent that the absence of OH groups on the molecular scaffold significantly decreased the activity of these types of molecules as shown by the IC50 value of compound 324 (IC50 5.00 μg/mL).219 Four acnistins, viz., acnistin A (327), acnistin C (328), acnistin E (329), and acnistin G (330), and one withajardin, withajardin B (331) (Figure 55), were studied in terms of their

(−)-α-bisabolol (334) and pentamidine (control) showed 100% inhibition toward the promastigote form of L. infantum at concentrations of 500 and 1000 μg/mL.223 On the other hand, the antileishmanial potential of the control pentamidine was slightly higher than compound 334 at lower concentrations (15.6, 12.5, 7.8, and 6.25 μg/mL) with comparable IC50 values for pentamidine and 334 of 7.57 μg/mL and 10. 99 μg/mL respectively.223

8. SYNTHETIC ANTILEISHMANIAL COMPOUNDS 8.1. Chalcone Derivatives

The antileishmanial activities of several chalcones have been reported in the literature.149,152,153,224−227 Nazarian et al.228 synthesized various chalcones (Scheme 1) with the view of Scheme 1. Synthesis of Chalcone Derivativesa


a

Reagents and conditions: (i) acrolein, 1,4-dioxane, K2CO3, reflux; (ii) appropriate acetophenone, NaOH, EtOH; (iii) methyl vinyl ketone, 1,4-dioxane, K2CO3, reflux; (iv) appropriate aldehyde, NaOH, EtOH.

interactions with L. panamensis amastigotes. These compounds were found to have significant antileishmanial activities (EC50 1−7.9 μg/mL). Among these compounds, acnistin E (329) and withajardin B (331) proved to be the most active toward L. panamensis amastigotes (EC50 1.0 and 1.1 μg/mL, respectively).220 The crude extract of Tridax procumbens showed effective antileishmanial activity, and a bioguided isolation of active agents yielded an oxylipin (polyacetylene) (332) (Figure 56)

designing new antileishmanial agents. Reaction between 5chloro-2-hydroxybenzaldehyde (335) and acrolein provided chromene-3-carbaldehyde (336). Subsequently, this compound was reacted with different cetophenones via a classical Claisen− Schmidt condensation to furnish a small library of 3-(6-chloro2H-chromen-3-yl)propen-1-ones, viz., 337−340. A further series of similar compounds was prepared by a different route (Scheme 1). Thus, compound 335 was treated with methyl vinyl ketone in the presence of base (K2CO3) to afford 1-(6chloro-2H-chromen-3-yl)ethanone (341). A subsequent Claisen−Schmidt condensation of compound 341 with various aldehydes provided a second small library of 1-(6-chloro-2Hchromen-3-yl)propen-1-ones, viz., 342−345.228 The new chalcones, viz., 337−340 and 342−345, were evaluated for leishmanicidal activity toward L. major, and quite gratifyingly, the IC50 values indicated that all tested compounds exhibited high activities against this species (IC50 ≤ 3.0 μM). The structure−activity relationship study was not comprehensive enough to make any substantive conclusions. However, it was notable that compounds 338 and 342 (which contained the 2-chlorophenyl and 2-bromophenyl groups, respectively) exhibited IC50 values of 1.22 ± 0.31 and 1.33 ± 0.52 μM being the most potent of the tested compounds. A comparison of the IC50 values revealed that certain substituents on the phenyl ring, such as methyl, dimethoxy, and trimethoxy, are well tolerated but did not enhance the inhibitory activity against


which was active against promastigotes of L. mexicana (IC50 0.478 μg/mL) but did not show significant cytotoxicity. However, 332 proved to be more active toward the parasites than mammalian cells, resulting in significant SI values of 1001 and 380, respectively.221 The interesting anhydride, cantharidin (333), showed leishmanicidal activity toward the amastigote form of L. major with an IC50 value of 1.2 μg/mL.222 Similarly, 10391


Chemical Reviews

Review

Scheme 3. Synthesis of Heterocyclic Chalcone Derivativesa

Leishmania promastigotes compared to compounds with halogen-substituted rings.228 Various trimethoxychalcone derivatives (350−354) have been synthesized by Bello et al.229 via an aldol condensation between different acetophenones and aldehydes using KOH in methanol230 (Scheme 2). Scheme 2. Synthesis of Trimethoxychalcone Derivativesa

a

Reagents and conditions: (i) (a) CH3CN, ZnCl2, ether, HCl, 0−5 °C; (b) H2O, reflux; (ii) Me2SO4, K2CO3, acetone; (iii) Me2SO4, NaOH/acetone, reflux, 24 h; (iv) appropriate aldehyde, KOH 50% w/ v, MeOH, rt, 24 h. a Reagents and conditions: (i) H3PO4, AcOH; (ii) POCl3, DMF; (iii) NaOH.

The trimethoxychalcone derivatives 350−354 were evaluated against L. braziliensis promastigotes and exhibited the best antileishmanial profile, yielding IC50 values of less than 10 μM. Among them, 351 (IC50 = 2.70 μM), 352 (IC50 = 3.94 μM), and 353 (IC50 = 4.62 μM) were more active than the reference antileishmanial agent pentamidine (IC50 = 6.0 μM). Of these three antileishmanial analogues, compound 351 showed the lowest activity toward the L. braziliensis promastigote. Interestingly, 352 inhibited iNOS and displayed no toxicity toward macrophages. The significant activity of 352 (IC50 = 3.9 μM and CC50 = 216 μM) suggested that this chalcone derivative should be further developed as the basis for the synthesis of new analogues as potential antileishmanial drugs.229 Rizvi et al. synthesized 38 heterocyclic chalcones (359−396) by condensing formyl quinolines with various methyl aryl ketones.231 The syntheses of these were based on the Claisen− Schmidt condensation,232,233 in which the previously prepared formyl quinolines (357a,b) were condensed with commercially available methyl aryl ketones (358a−s) in the presence of NaOH (Scheme 3). Compounds 359−396 were tested for antileishmanial activity toward L. major promastigotes, and all demonstrated strong antileishmanial activity, exhibiting IC50 values of 0.16−0.93 μg/mL, which were equally potent to the positive control amphotericin B (IC50 = 0.56 μg/mL). Furthermore, of all the tested compounds, 21, viz., 361−363, 365, 368−371, 374, 376, 377, 384, 387−393, 395, 396, showed stronger antileishmanial activity than amphotericin B. These results further illustrated that the unsubstituted thiophenyl derivatives 359 and 378 had IC50 values of 0.58 and 0.59 μg/mL, respectively, which were comparable to amphotericin B. In addition, their activity was enhanced by

introduction of methyl or halogen moieties at C-5 of the thiophenyl ring.231 Among the 5-substituted derivatives, the chloro analogues (IC50 = 0.23 μg/mL for 365 and 384) were the most active. Incorporation of a methyl group at the 4 position (361) increased the activity with respect to the 3methyl analogue 360 (IC50 = 0.75 μg/mL for 360 and IC50 = 0.27 μg/mL for 361). Although replacing the two methyl moieties at C-2 and C-5 of the thiophenyl ring (363, 382) by two chloro groups (366, 385) significantly decreased the activity (by approximately 5-fold) for compounds in the series 359−377 (R = H), the reverse is observed for compounds in the series 378−396 (R = Me). Considering the furanyl analogues, inclusion of a second methyl moiety at position 2 decreased the activity (372, IC50 = 0.84 μg/mL) with respect to the monosubstituted derivative (371, IC50 = 0.37 μg/mL).231 Boeck et al.234 previously demonstrated that 2′,6′-dihydroxy4′-methoxychalcone (DMC) showed promising antleishmanial activities.235,236 In another study Boeck et al. prepared a synthetic derivative, viz., 2′-hydroxy-4′,6′-dimethoxychalcone, of xanthoxyline previously reported to be isolated from Sebastiana chottiana237 which had demonstrated antifungal,234 antibacterial,234 and antioedematogenic238 activities. Following on from the inspiring results of Boeck et al., 11 other chalcone analogues were synthesized by base-catalyzed condensation of the appropriate aldehydes with xanthoxyline or modified xanthoxylines (Scheme 4). The synthesized chalcones were screened for antileishmanial activity toward L. amazonensis promastigotes. Interestingly, chalcones 400−403, 405−407, and 409 showed stronger activity against promastigotes compared to the reference drug 10392


Chemical Reviews

Review

Scheme 5. Synthesis of Chromeno Dihydrochalconesa

Scheme 4. Synthesis of 2′-Hydroxy-4′,6′-dimethoxychalcone Derivativesa

a

Reagents and conditions: (i) CHO-Ph-X, NaOH/EtOH; (ii) 2naphthaldehyde, NaOH/EtOH; (iii) 2-furaldehyde, NaOH/EtOH; (iv) 3,4-(methylenedioxy)benzaldehyde; (v) Br2/AcOH.

Reagents and conditions: (i) Py, 150 °C, 7 h; (ii) aq. KOH/EtOH; (iii) Pd/C, H2, MeOH, 6 h. a

and most significantly 86% inhibition at 0.25 μg/mL toward promastigotes. Compound 416, in which the nitro group is at position 3, also demonstrated pronounced inhibition (99%) at 10 μg/mL and 95% inhibition at 1 μg/mL against promastigotes. Finally, this compound also exhibited 84% inhibition at 10 μg/mL against amastigotes.227 Two dihydrochalcones were reported from Piper elongatum and showed promising antileishmanial activity.78 Synthetic derivatives (418−423) of these two natural chalcones were prepared (Figure 57) and assayed to establish what structural requirements were essential to elicit antileishmanial activity.239

pentamidine (IC50 = 6.0 μM).234 The most active compounds against promastigotes were 402, 403, 406, 407, and 409, all of which showed antileishmanial activity of less than 1 μM. Similarly, compounds 400, 403, 404, 406, and 408 showed stronger activity against amastigotes than the standard pentostan (IC50 = 4.4 μM). Chalcones 400, 403, 405, and 406 were more potent than the standard drugs against both promastigotes and the amastigotes form of L. amazonensis. Additionally, compound 402 significantly controlled the growth of the lesions after treatment of L. amazonensis-infected mice,234 and the activity of compound 402 was higher than Pentostan. Introduction of a bromine atom into ring A (409) further enhanced the activity of compound 402.234 Chromeno dihydrochalcones containing a 2′,2′-dimethyl benzopyran system are frequently present in many natural products, and some members of this class of compound have demonstrated significant biological properties.152,226,227 Narender et al.227 synthesized several chromeno dihydrochalcones by performing Claisen−Schmidt condensations between acetophenone and various aldehydes, followed by Pd/C-catalyzed reduction of the chalcone linker double bond (Scheme 5). The synthetic chromeno dihydrochalcones 411−417 were screened toward extracellular promastigotes and intracellular amastigotes of L. donavani, and all tested compounds showed strong antileishmanial activity. Chalcone 414 demonstrated high activity with 99% inhibition at 10 μg/mL and 82% inhibition at 0.25 μg/mL against promastigotes. It further exhibited 96% inhibition against amastigotes at 10 μg/mL. In addition, compound 411, having the OH group at the 4 position of ring A, demonstrated 97% inhibition toward promastigotes at 10 μg/mL and an acceptable 89% toward amastigotes at 5 μg/mL.227 However, its dihydro derivative (417) exhibited diminished activity, with inhibition percentages of 95% at 10 μg/mL in promastigotes and 47% at 25 μg/mL in amastigotes. These results indicated that conjugation of the ketone functionality within the chromene unit plays an important role in its activity. Compound 412, which has a nitro group at position 4, exhibited 99% inhibition at 10 μg/mL

Figure 57. Structures of synthetic dihydrochalcones 418−423.

An analysis of the measured activities of the series of dihydrochalcones, viz., 418−423, indicated that the B ring was not important for antileishmanial activity. Interestingly, insertion of an acetate group increased the leishmanicidal activity as well as decreased the cytotoxicity toward macrophages, and activities of the acetylated derivatives, 419 and 420, were approximately 7- and 8-fold higher, respectively, than that of the parent chalcone.150 Compounds 420−422 proved to be most potent (IC50 < 1 μg/mL) but were also found to be highly toxic toward macrophages. In contrast, compound 423 equally as potent (IC50 = 3.65 μg/mL) displayed no toxic effects toward macrophages.239 To compare the susceptibility of different parasite species to these molecules, compounds 418− 423 were assayed against L. infantum, L. braziliensis, and L. 10393


Chemical Reviews

Review

Scheme 7. Synthesis of Quinoline Derivativesa

tropica. Compound 419 showed significant activity toward L. braziliensis, and compounds 418 and 419 displayed significant activity toward L. infantum (IC50 = 9.11 μg/mL). Interestingly, compounds 418 (94% viability at 5.0 μg/mL) and 419 (90% viability at 2.4 μg/mL) displayed low toxicities. Ultimately, 419 (IC50 = 2.98 μg/mL) and 423 (IC50 = 3.65 μg/mL) displayed the best antilieshmanial activity, without producing any toxic effects on macrophages at a concentration near to their respective IC50 values.150 Foroumadi et al.240 synthesized a series of chromene-based chalcones 427−430 starting from the phenolic derivative 424. Compound 424 was first converted into the salicylaldehyde derivative 425,241,242 which was then transformed to chromene 426 after reaction with methyl vinyl ketone and K2CO3. Claisen−Schmidt condensations of 426 with various aldehydes provided chalcones 427−430 (Scheme 6). Scheme 6. Synthesis of Chromene-Based Chalconesa

Reagents and conditions: (i) glycerol, H2SO4, As2O5, 110 °C, 21 h; (ii) (CH3)3CCO2H, AgNO3, (NH4)2S2O8, 10% H2SO4, CH3CN, 70 °C, 15 min; (iii) concentrated HCl, 95% EtOH, 100 °C, 2 h; (iv) POCl3, 80 °C, 2 h; (v) 3-(trifluoromethyl)phenol, KOH, p-xylene, 12 h, 150 °C; (vi) Raney nickel, H2, EtOH, 45 psi, 45 min; (vii) 2-(4bromopentyl)-1,3-isoindolinedione, Et3N, 120 °C, 24 h; (viii) NH2NH2·H2O, EtOH, reflux, 8 h. a

a

Reagents and conditions: (i) NaOH, CHCl3, H2O, reflux; (ii) methyl vinyl ketone, 1,4-dioxane, K2CO3, reflux; (iii) appropriate aldehyde, NaOH, EtOH.

The activity results indicated that at a 10 μM concentration, chromene-based chalcones 427−430 showed pronounced activity toward Leishmania (100% inhibition). The chlorosubstituted chalcones 428−430 displayed activity against L. major (promastigote) with IC50 values of less than 1.0 μM. The influence of chlorine substitutions at different positions on the phenyl ring was also investigated by synthesizing all three monochlorinated compounds (2-Cl, 3-Cl, and 4-Cl) in addition to the 2,4-dichloro derivatives. Best results were obtained with the 3-chloro and 4-chloro derivatives. Cytotoxicities of the target compounds 427−430 were then assessed, the results of which indicated that these compounds displayed antileishmanial activity without any toxicity. Previous studies on antileishmanial chalcones suggested that the substitution pattern on ring A was of less importance for antileishmanial activity than that of the B ring.149,243,244

quinolinamines (439−441) in three steps using previously reported procedures.248 It is interesting to note that all three 8-quinolinamines 439− 441 displayed pronounced antileishmanial activities, with IC50 values of 3.0, 3.4, and 2.9 μg/mL, respectively and these compounds showed activity with the same efficacy as the reference drug pentamidine (IC50 = 3.4 μg/mL).245 Kaur et al.249 synthesized two series of 8-quinolinamines with in vitro antileishmanial activities, namely, N1-{4-[2-(tert-butyl)6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-amino-substituted amides 448−452 and N1-[4-(4-ethyl-6-methoxy-5pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-amino-substituted amides 459−462. These compounds were prepared in six steps starting from either 6-methoxy-8-nitroquinoline or 4methoxy-2-nitro-5-pentyloxyaniline. Initially 6-methoxy-8-nitroquinoline (442) produced 443 (Scheme 8) upon direct alkylation of the ring via an Ag-catalyzed oxidative decarboxylation of pivalic acid using (NH4)2S2O8.248 Catalytic hydrogenation of 443 in 95% EtOH using Raney nickel as the catalyst afforded the highly hygroscopic and light-sensitive compound 444, which was treated with 2-(4-bromopentyl)-1,3-isoindolinedione250 and Et3N to produce quinoline 445. This in turn yielded compound 446 upon treatment with hydrazine hydrate in 95% EtOH.248 Treatment of 453 with O-phosphoric acid and As2O5 afforded compound 454, which was converted to 457 in three steps (Scheme 8). Alkaloids 446 and 457 were reacted with Cbz- or Boc-protected L/D-amino acids to give 447a−e and 458a−e, respectively. Finally, 447a−e and 458a−e

8.2. Quinoline Derivatives

Jain et al.245 synthesized a number of 8-quinolinamines 439− 441 (Scheme 7) and evaluated them for antileishmanial activity against L. donovani promastigotes. 4-Alkyl-5,6-dimethoxy-8nitroquinolines (432a−c) were first synthesized using previously reported procedures.246,247 These were then converted into compounds 433a−c by direct alkylation of the ring using an Ag-catalyzed oxidative decarboxylation of pivalic acid using (NH4)2S2O8.248 Subsequently, the 5-methoxy moiety was demethylated with HCl to afford compounds 434a−c, and further reaction with POCl3 produced 435a−c. These chloro derivatives (435a−c) were then reacted with 3(trifluoromethyl)phenol in the presence of KOH to afford 436a−c, which were efficiently converted into the desired 810394


Chemical Reviews

Review

golden hamsters were infected with L. donovani,252 and compound 464 decreased the parasite burden by 93.2% in the spleen and liver. As a comparison, sodium antimony gluconate (SAG) caused reductions of 82.5% (spleen) and 72.6% (liver).251 Tempone et al.253 synthesized 3-substituted quinolines and evaluated them for their antileishmanial activity. The synthetic amino esters, 466a,b, were obtained by condensing the ethyl 3oxobutanoates 465a,b with aniline. The corresponding quinoline derivatives 467a,b were then formed via an intramolecular cyclization upon heating, followed by aromatization. Furthermore, 467b was further reacted with POCl3 to replace the 4OH group by a Cl to produce 468b (Scheme 10).

Scheme 8. Synthesis of 8-Quinolinaminesa

Scheme 10. Synthesis of 3-Substituted Quinolinesa

Reagents and conditions: (i) aniline, 60 °C; (ii) Ph2O, 250 °C; (iii) POCl3, Δ. a

The antileishmanial efficacies for three of these novel quinoline derivatives (467a,b and 468b) were determined in vitro toward L. chagasi and displayed significant antileishmanial activities against L. chagasi, with IC50 values of 0.79, 0.091, and 1.79 μg/mL, respectively. Interestingly, only compound 467b displayed significant activity toward L. chagasi-infected macrophages (IC50 = 3.55 μg/mL), and this compound was 8.3 times more potent than the reference pentavalent antimony (IC50 = 29.55 μg/mL).253 The 2-substituted quinolines have been reported for their activity toward L. donovani,254,255 leishmanial GDP-mannosepyrophosphorylase,254 and antiviral activity in HIV-infected cells.256,257 Loiseau et al.254 prepared 2-substituted quinolines 475 and 476 to test against L. donovani. Synthesis of these compounds began with the bromination of 469 under Pearson conditions (Br2, t-BuNH2, −78 °C)258 to produce the desired 7-bromo derivative 470 (Scheme 11). A Perkin-type condensation between 470 and aldehyde 471 then furnished styrylquinoline 472 (66%), which in turn was converted into the trimethoxy derivative 473. Installation of aroyl/acyl moiety at C-7 was achieved using the Queguiner procedure,259 in which the initial lithiated compound was condensed with 3nitrobenzaldehyde or 2-nitrobenzaldehyde to furnish compounds 474a,b. Finally, treatment of 474a,b with BBr3 afforded the target compounds 475 and 476.260 Compounds 475 and 476 were screened in vitro for leishmanicidal activity toward L. donovani. Interestingly, compound 476 displayed pronounced leishmanicidal activity with an IC50 value of 1.2 μM, which proved to be 10- and 8-fold more active than the reference compounds miltefosine and sitamaquine, respectively, that were employed in this evaluation. Additionally, compound 476 displayed a selectivity index of 121.5, which was 607- and 60-fold higher, respectively,

a

Reagents and conditions: (i) (CH3)3CCO2H, AgNO3, (NH4)2S2O8, 10% H2SO4, CH3CN, 70 °C; (ii) Raney Ni, EtOH, H2, 45 psi, 45 min; (iii) 2-(4-bromopentyl)-1,3-isoindolinedione, Et3N, 120 °C, 24 h; (iv) NH2NH2·H2O, EtOH, reflux, 8 h; (v) suitably N- and side-chainprotected L/D-amino acid, DCC, DCM, rt, 6 h; (vi) H2, Pd/C, MeOH, 1 h, rt or 4 N HCl/MeOH, 1 h, rt or 30% HBr/AcOH, 45 min, rt; (vii) 1-chloro-3-pentanone, 85% o-H3PO4, As2O5, 80 °C, 3 h.

were deprotected, producing compounds 448−452 and 459− 462.249 The two 8-quinolinamine analogue series, viz., 448−452 and 459−462, exhibited strong antileishmanial activities against L. donovani, and the IC50 values were within a reasonable range of 2.7 and 4.6 μg/mL. These compounds showed higher activity than primaquine (IC50 = 19.9 μg/mL). However, 8-quinolinamine analogues 448−452 and 459−462 were less active than amphotericin B (IC50 = 0.19 μg/mL).249 Sahu et al.251 synthesized the new quinoline analogue, 2-(2methylquinolin-4-ylamino)-N-phenylacetamide (464), by reaction with 2-chloro-N-phenylacetamide, 4-aminoquinaldine (463), NaH, and DMSO (Scheme 9). Compound 464 (concentration 5.0 μg/mL) displays a 95% inhibition (L. donovani promastigotes) on the seventh day of culture. A set of Scheme 9. Synthesis of Quinoline Analogue

10395


Chemical Reviews

Review

Scheme 11. Synthesis of 2-Substituted Quinolinesa

8.3. Indole Derivatives

A series of indolylglyoxylamide derivatives was synthesized by Chauhan et al.262 and evaluated in vitro toward the amastigote form of L. donovani. Ester 484 was prepared by reacting D/Ltryptophan with thionyl chloride in methanol, and this compound was cyclized with various aromatic aldehydes using a Pictet−Spengler cyclization to produce both the cis and the trans isomers of several tetrahydro-β-carboline derivatives. A series of indolylglyoxylamide derivatives (487− 502) was then synthesized in high yields by reacting these βcarbolines with indole oxalyl chloride 486 in refluxing THF in the presence of K2CO3263−265 (Scheme 13). Scheme 13. Synthesis of Indolylglyoxylamide Derivativesa

Reagents and conditions: (i) Br2, t-BuNH2, toluene, −78 to 20 °C, 74%; (ii) 2 equiv of 471, Ac2O, 140 °C, 18 h; (iii) H2O, py, 100 °C, 2 h, 66%; (iv) K2CO3, 10 equiv of CH3I, acetone, DMF, 70 °C, 12 h, 62%; (v) (a) 2.5 equiv of PhLi, cyclohexane, Et2O, −78 °C, (b) 1.25 equiv of 3-nitrobenzaldehyde or 2-nitrobenzaldehyde, THF, HMPA, −78 to 20 °C; (vi) BBr3, CH2Cl2, −78 to 20 °C, 8 h. a

than those of the reference compounds.254 Compound 475 had an IC50 of 2.1 μM and a selectivity index of 27.3. Khan et al.261 synthesized various isoquinuclidine analogues of chloroquine. The one target compound 480 was prepared as follows. Methylation of bicyclic amine 477 (with HCHO and HCO2H) provided 478 (90%), which was subsequently reduced with LiAlH4 to produce amine 479 (80%), and this was followed by conversion to compound 480. Similarly, compound 483 was prepared by a similar procedure as described for compound 480 with some obvious changes (Scheme 12). Compounds 480 and 483 were subsequently Scheme 12. Synthesis of Isoquinuclidine Analogues of Chloroquinea

a

Reagents and conditions: (i) aromatic aldehyde, MeOH, reflux; (ii) THF, K2CO3, reflux, 5 h.

These indolylglyoxylamide derivatives (487−502) demonstrated encouraging in vitro biological activities. Their IC50 values were within the range of 3.79−8.04 μM, and their SI values were in the range of 2.60−31.48. Both of these results compared favorably with reference drugs such as pentamidine (IC50 = 20.43, SI = 2.58) and SSG (IC50 = 71.90, SI = 5.53). Compound 489, which has an ethyl group at the para position on its phenyl ring, emerged as the most promising of all the candidates in this series because it possessed the strongest leishmanicidal activity (IC50 = 5.17 μM), coupled with a high selectivity index of 31.48. This lead molecule is 12- and 5-fold more potent than the reference compounds pentamidine and sodium stibogluconate (SSG), respectively. To study the influence of structural parameters on their antileishmanial

a Reagents and conditions: (i) K2CO3, DMF, 140 °C, 48 h; (ii) LiAlH4, rt, 18 h; (iii) 4,7-dichloroquinoline, HCO2H, HCHO, 60 °C, 8 h.

evaluated for antileishmanial activity against L. donovani and turned out to be quite potent, with IC50 values of 3.0 and 1.9 μg/mL, respectively. Interestingly, compound 483 was more potent and compound 480 was less active than the reference compound pentamidine (IC50 2.8 μg/mL).261 10396


Chemical Reviews

Review

activities, Chauhan et al.292 made several modifications to these molecules. A comparison of different tetrahydro-β-carboline isomers showed that these stereochemical modulations did not have a significant effect on the antileishmanial activities of these indolylglyoxylamide derivatives. However, variations on the phenyl rings of the tetrahydro-β-carboline units exhibited a remarkable influence on their antileishmanial activity. It was observed that incorporating an electron-withdrawing group onto the phenyl ring resulted in a decrease in IC50 values by a factor of almost 2. For example, compound 493, which has a chlorine atom at the para position on its phenyl ring, displayed an IC50 value of 4.36 μM, and alkaloid 494, which has a bromine atom at the ortho position on its phenyl ring, displayed an IC50 value of 3.79 μM. These values were lower than that of the corresponding analogue 488, which has a methyl group at the para position on its phenyl ring and an IC50 of 6.79 μM.262 To investigate the SAR effects of electron-withdrawing substituents on the indole nucleus, another small library of indolylglyoxylamides (495−502) was synthesized by combining 5-bromoindole oxalyl chloride with the tetrahydro-βcarbolines described above. These compounds all displayed IC50 values in the range of 3.91−5.86 μM and, additionally, displayed a better inhibitory activity compared to their nonbrominated analogues (487−494). Moreover, methylsubstituted compound 496 had an IC50 of 4.79 μM, whereas the corresponding chloro- and bromo-substituted analogues 501 and 502 showed slightly lower IC50 values of 4.02 and 4.09 μM, respectively. This demonstrated that an electron-withdrawing group attached to the phenyl ring of the tetrahydro-βcarboline unit exhibited a direct effect on the IC50 values that was similar to the one observed for the series of nonbrominated indole compounds.262 A series of [1,2,4]triazino[5,6-b]indol-3-ylthio-1,3,5-triazines was prepared by Gupta et al.266 and subsequently tested for their in vitro antileishmanial activity toward L. donovani. Synthesis of these compounds began with methylation of isatin (503) using (Me)2SO4267 to give N-methylisatin (504). Subsequent cyclization was achieved using thiosemicarbazide268 to afford 5-methyl-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (505). Compounds 3-(4,6-dichloro-1,3,5-triazin-2-ylthio)-5methyl-5H-[1,2,4]triazino[5,6-b]indole (506) and 3-(2-chloro6-methylpyrimidin-4-ylthio)-5-methyl-5H-[1,2,4]triazino[5,6b]indole (510) were then prepared by reaction of compound 505 with 2,4,6-trichloro-1,3,5-triazine and 6-methyl-2,4-dichloropyrimidine, respectively. Subjection of compound 506 to chlorine substitution with various amines afforded compounds 507−509, and similar substitutions at the 2 position of pyrimidine intermediate 510 using K2CO3 in DMF269 produced the final compounds 511−513 (Scheme 14). Compound 507 was found to be the most active of these synthetic compounds having an IC50 value of 4.01 μM (MIC = 20.54 μM), and also this compound displayed the lowest toxicity (CC50 = 227.04 μM). Interestingly, based on its SI of 56.57, compound 507 was shown to be 20- and 10-fold more active compared to the reference drugs pentamidine and sodium stibogluconate (SSG), respectively. In contrast, the 1,2,4-triazinoindole-pyrimidine derivative 511 displayed an IC50 value of 25.70 μM and a CC50 value of 173.29 μM.266 This constitutes a decrease in selectivity compared to compound 507. Furthermore, the 1,2,4-triazinoindole-triazine hybrid 508 showed an IC50 of 15.51 μM, an MIC of 26.55 μM, and a CC50 of 93.17 μM, resulting in an SI value of 6.74, which is similar to

Scheme 14. Synthesis of Triazinesa

a

Reagents and conditions: (i) Dimethyl sulfate, MeOH, 10% methanolic KOH, rt; (ii) thiosemicarbazide, K2CO3, water, reflux; (iii) 2,4,6-trichloro-1,3,5-triazine, THF, rt; (iv) various amines, K2CO3, THF, reflux; (v) 6-methyl-2,4-dichloropyrimidine, DIPEA, DMF, reflux; (vi) various amines, K2CO3, DMF, reflux.

that of the reference compound SSG. However, the corresponding compound 512 exhibited decreased potency (IC50 = 26.31 μM) and poor selectivity. Compound 509 had a better IC50 value (17.38 μM), and replacement of R with nbutylamine in compound 513 resulted in an improved selectivity with the best IC50 value (18.33 μM) of all of the pyrimidine derivatives tested. On the basis of these results it is evident that molecules comprising a [1,2,4]triazinoindole[1,3,5]triazine moiety showed higher activity than the analogous [1,2,4]triazinoindole-pyrimidine hybrids.266 In 1998, the tetrahydro-β-carboline alkaloid, buchtienine (514)270,271 was isolated from Kopsia grif f ithii and evaluated. The results indicated that the alkaloid had good antileishmanial activity (IC50 > 0.30−1.56 μg/mL) toward L. donovani, which turned out to be better than the antileishmanial properties exhibited by harmine (515)272 reported from Peganum harmala. Pinheiro’s group isolated the pyrimidine-β-carboline alkaloid annomontine (516) (Scheme 15) from Annona fetida11 and after investigation discovered that it had antileishmanial properties against L. braziliensis, displaying an IC50 value of 34.8 ± 1.5 μg/mL. In addition, synthetic analogues of 2-aminopyrimidines containing a hydrophobic handle at the 4 position were reported to be good antileishmanial agents.273−275 Encouraged by this, Kumar et al.270 prepared small libraries of novel nitrogen heterocycles as potential antileishmanial agents. The strategy for preparation of 2-(pyrimidin-2-yl)-1phenyl-2,3,4,9-tetrahydro-1H-β-carbolines 520−530 is illustrated in Scheme 15. Initially, m-chloroperbenzoic acid oxidation of 2-thiomethyl-4,6-dichloropyrimidine (517) pro10397


Chemical Reviews

Review

Scheme 15. Synthesis of β-Carboline Derivativesa

Similarly, compound 530 showed potent activity toward amastigotes in the same range as compound 521 but had a lower selectivity index.270 Na et al.277 synthesized the 3-imidazolylalkylindole, 1-(2bromobenzyl)-3-(1H-imidazol-1-ylmethyl)-1H-indole (534). Reduction of 532 using LiAlH4 afforded the intermediate alcohol 533, which was then condensed with 1,1-carbonyldiimidazole (CDI) in THF, producing carbamates that underwent decarboxylation to finally provide 534 (Scheme 16). Scheme 16. Synthesis of 3-Imidazolylalkylindolea

a

Reagents and conditions: (i) NaH, DMSO, 2-bromobenzyl chloride, rt; (ii) LiAlH4, THF, rt; (iii) CDI, THF, reflux.

Compound 534 was screened for leishmanicidal activity toward L. mexicana promastigotes using ketoconazole and amphotericin B as standard drugs. Interestingly, 534 exhibited an encouragingly low IC50 value of 0.011 μg/mL and was 273 and 2.7 times more active than ketoconazole and amphotericin B, respectively. Compound 534 was consequently further evaluated against L. mexicana amastigotes and displayed strong activity (IC50 = 0.018 μg/mL) which translated into it being 72 and 26 times more active than ketoconazole and amphotericin B, respectively. Furthermore, compound 534 displayed cytotoxicity toward an MRC5 cell line with IC50 of 29.12 μg/ mL. In this evaluation, compound 534 showed a high selectivity and thus offers a potentially safer therapeutic option to be considered.277 Porwal et al.278 synthesized the pentamidine−aplysinopsin hybrid compounds (538a,b, 541) (Scheme 17) and tested them for their antileishmanial activity. Synthesis of 538a,b was achieved by formylation of indole (531) or 1H-pyrrolo[2,3b]pyridine (535b), followed by alkylation and finally condensation with 2-thiohydantoin. Compound 541 was synthesized following a similar procedure. Compounds 538a,b and 541 were screened for antileishmanial activity toward L. donovani (promastigote). The results of this investigation demonstrated that 538a inhibits amastigote growth by 62% in infected macrophages at a concentration of 12.5 μg/mL. Surprisingly, this compound was also found to be active in vivo. Thus, 538a displayed an average of 62.1 ± 9.8% (SE) parasite reduction in hamsters (dosage 4 × 50 mg/kg) administered intraperitoneally. Additionally, compound 538a showed no toxicity.278 Interestingly, the E-configured structure of the molecule 541 proved to be the most potent of the indole derivatives in this series (IC50 = 2.0 μM and SI = 53.35), even reducing parasites in infected macrophages. Furthermore, compound 541 was 10 times more potent and 401-fold less toxic against human macrophages than the drug pentamidine in the intracellular amastigote assay. Rapamycin and mevastatin are good examples of drug molecules based on natural products that possess good bioavailability and selectivity profiles.279,280

a Reagents and conditions: (i) m-CPBA, CH2Cl2, 0 °C to rt, 4 h; (ii) tryptamine, EtOH, reflux, 2 h; (iii) PTSA, ethanol, reflux, 3 h; (iv) neat amine, reflux, 10 h.

duced sulfone derivative 518, which was followed by nucleophilic substitution of the methanesulfonyl group with tryptamine to afford 519 in good yield. The Pictet−Spengler cyclization276 of 519 with various substituted benzaldehydes provided 2-(4,6-dichloropyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline derivatives 520−525 in high yields. Similarly, compounds 526−530 were prepared by reaction of the corresponding dichloro derivatives 519, 521, 522, and 525b with the corresponding amines. All of the tetrahydro-βcarboline derivatives 520−528 were obtained as racemic mixtures. Of all the synthesized compounds tested on L. donovani, nine, viz., 520−522, 524, 526−530, exhibited antileishmanial activity with IC50 values of less than 5 μg/mL, and three other compounds (519, 523, and 525a) showed activity within a slightly higher IC50 range of 5−10 μg/mL. In contrast, the standard drugs pentamidine and SSG had IC50 values of 12.11 and 53.6 μg/mL, respectively, measured under similar conditions. Gratifyingly, the 3,4-dimethoxyphenyl-substituted derivative 521 exhibited an IC50 value of 1.93 μg/mL toward amastigotes with a selectivity index (SI) of 15.43. It is interesting to note that both the activity of 521 and its SI were higher than the standard drugs, sodium stibogluconate (SSG) and pentamidine. The position of the substituents plays an important role for relative antileishmanial activity within a series. Compared to 521, the presence (520) or absence of a methoxy group (522) decreased activity 2-fold.270 Compound 528 exhibited less inhibitory potency against amastigotes, but the selectivity index in this case was comparable to that of compound 521. Compounds 526−528 were more active than their corresponding dichloro analogue 522 and displayed better selectivity indices. Compound 529 inhibited amastigotes, displaying an IC50 value of 3.05 μg/mL and with less selectivity. 10398


Chemical Reviews

Review

compound 552, respectively. Similarly, subjection of enone 551 to DDQ oxidative dehydrogenation provided dienone 553 and trienone 554293 in 23% and 32% yields, respectively. Large numbers of alkyl derivatives of enone 551 were additionally prepared. Pentylation of 551 with n-pentyl iodide provided the mono-O-n-pentyl analogues 555a and 555b (1:1 mixture) and the di-O-n-pentyl analogue 556 in 53% and 27% yields, respectively. Similarly, acetylation of enone 551 gave a 1:1 mixture of the monoacetates 557a and 557b and the diacetate 558. These curcuminoids were screened against L. major promastigotes. Five of these analogues, viz., 543, 544, 553, 555a and 555b, exhibited antileishmanial activity with EC50 values of less than 5 μM, and 10 other curcuminoid analogues, viz., 545−548, 551, 552, 554, 556, 557a, and 557b, showed activity within an EC50 range of 5−10 μM. The most active of these analogues were 544 (IC50 = 2.8 ± 0.4 μM) and 553 (IC50 = 2.7 ± 0.4 μM). All of the synthesized curcumin derivatives were evaluated toward axenic L. mexicana amastigotes and displayed pronounced antileishmanial activity, especially those of 543, 553, and 554. These compounds also demonstrated submicromolar activity against T. b. brucei, suggesting that they act on a target that is well conserved among the kinetoplastids.281 However, enone 551, which was the most active compound against T. b. brucei, performed relatively poorly toward L. mexicana amastigotes, with an EC50 value of 17 ± 2 μM. Five of the compounds, viz., 543−545, 553, and 554 displayed in vitro activities toward the amastigote stage, which were higher than the standard drug pentamidine (EC50 = 16 ± 2 μM; n = 6).281 An independent SAR study showed that the parent curcuminoid 542 exhibited activity toward promastigotes with an IC50 of 33 ± 4 μM, while its mono-Odemethylated analogue 543 was 8 times more potent. Additionally, the di-O-methylated derivative 544 displayed a 12 times increase in leishmanicidal activity compared to compound 542. Interestingly, mono-O-alkyl analogues 545 and 546 were 5.7 and 4.3 times more potent compared to the parent curcuminoid 542.281

Scheme 17. Synthesis of Pentamidine−Aplysinopsin Hybrid Compoundsa

Reagents and conditions: (i) DMF, POCl3, 0 °C to rt. (ii) pcyanophenoxypentyl bromide, toluene, NaOH, TBAB, rt. (iii) ethanolamine, EtOH, 60 °C; (iv) AcCN, K2CO3, 60 °C; (v) 1-Me2-thiohydantoin, ethanolamine, EtOH, 60 °C.

a

8.4. Curcumin Derivatives

Changtam et al. synthesized a large number of derivatives of curcumin (542) illustrated in Scheme 18 in order to evaluate them for antileishmanial activity.281 Curcuminoids have been reported from Curcuma longa L. and from other Curcuma species. These natural products have been used as food additives for many years, and the main curcuminoid isolated from C. longa is curcumin (542). Curcuminoids exhibit many interesting biological properties,282 including antioxidant,283,284 antiinflammatory,285,286 anticancer,283,287,288 antiprotozoal,289 and anti-HIV activities.290 Additionally, curcumin (542) is active against Trypanosoma brucei 291 and L. major. 292 Demethylation of compound 542 provided the mono-Odemethyl analogue 543 in 43% yield. Moreover, analogue 544 was obtained in 80% yield after methylation of compound 542 with MeI. Initially two corresponding alkyl ethers, viz., mono-O-allylcurcumin (545) (33%) and mono-O-(3,3dimethylallyl)curcumin (546) (43%), were prepared (Scheme 18), and later 4″-O-(2-hydroxyethyl)demethoxy-curcumin (547) was prepared from compound 542 by reaction with 2bromoethanol. Additionally, benzoylation of 542 with benzoic acid anhydride in pyridine furnished the monobenzoate 548 in 47% yield. Catalytic hydrogenation of compound 542 using palladium on charcoal as catalyst produced hexahydrocurcumin (549), and the tetrahydro analogue 550 was obtained in a similar fashion from bisdemethoxycurcumin. To prepare monoketo analogues of the curcuminoid 542, compounds 549 and 500 were reacted with catalytic amounts of ptoluenesulfonic acid, which afforded the enone 551 and

8.5. Acridine Derivatives

Giorgio et al.294 synthesized diaminoacridinic derivatives by benzoylating compound 559 using various benzoyl chlorides, as shown in Scheme 19. Acylation of proflavine was achieved with acetic anhydride using an Albert and Linnell295 protocol. This strategy produced chemoselectively the N-(6-amino-3-acridinyl) monoacetamide (566) as a single product in 84% yield after which this product was reacted at the free amine function with various benzoyl chlorides to give the corresponding amides 567 and 568 in good yields. Dibenzoylamino compound 561 demonstrated a strong affinity for both forms of the parasite, displaying average IC50 values of 1.1 and 4.3 μM toward promastigotes and amastigotes, respectively. Compounds 562 and 563 displayed the most potent activities against promastigotes, exhibiting IC50 values of 0.11 and 1.7 μM, respectively. Interestingly, compounds 561−565, 567, and 568 had strong activities against amastigotes, and IC50 values were within the range of 0.01−1.3 μM. Acridine 562 showed strong activity toward promastigotes with an IC50 of 0.11 μM, and the diamide 563 displayed potent activity toward amastigotes (IC50 0.03 μM).294 Carole et al.296 synthesized the acridine derivatives 572−575 and evaluated them for antileishmanial activity toward L. infantum (promastigote/amastigote forms). Compound 572 10399


Chemical Reviews

Review

Scheme 18. Synthesis of Curcumin Derivativesa

a Reagents and conditions: (i) BBr3, CH2Cl2, 0 °C, then ambient temp.; (ii) CH3I, K2CO3, acetone, reflux; (iii) allyl bromide, K2CO3, acetone, reflux; (iv) 3,3-dimethylallyl bromide, K2CO3, acetone, reflux; (v) 2-bromoethanol, K2CO3, acetone, reflux; (vi) (PhCO)2O, py; (vii) H2/Pd−C, EtOH; (viii) p-TsOH, C6H6, reflux; (ix) NaBH4, EtOH; (x) p-TsOH, C6H6, reflux; (xi) DDQ, THF; (xii) n-pentyl iodide, K2CO3, acetone, reflux; (xiii) Ac2O, py.

was synthesized using the Hess and Stewart procedure,297 and compounds 573 and 574 were synthesized by classical methods for amide formation by reacting the hydrochloride salt of 572 with various acyl chloride derivatives (Scheme 20). Evaluation of compounds 572−575 resulted in the discovery of interesting amastigote-specific activities, with IC50 values of less than 5 μM. Compound 575 showed pronounced activity toward the amastigote form of the parasite (IC50 = 0.6 μM) with a selectivity index of more than 200. Different experiments were conducted in order to elucidate the mode of action of 575, and results showed that it did not increase NO production by the macrophages. On the contrary, it prevented infection of the human macrophages by inhibiting internalization of promastigotes.296

quently, the 3-amino-1,4-di-N-oxide quinoxaline-2-carbonitrile analogues 577a−c were prepared by subjecting the benzofuroxane derivatives (576a−c) to the Beirut reaction using malononitrile and catalytic amounts of triethylamine in N,Ndimethylformamide (DMF).301 Finally, these compounds were condensed with sulfonyl chlorides to produce various sulfonamides (578−580). Compounds 578 and 579 inhibited 50% of the Leishmania parasite growth at approximately 3 μM. In infected macrophages, compound 580 displayed a strong selectivity index (>15), which was comparable to that of amphotericin B. Guillon et al.302 synthesized an interesting library of 4substituted pyrrolo[1,2-a]quinoxaline analogues 585−591 (Scheme 22) from 1-(2-aminophenyl)pyrroles 583a−c, which in turn were prepared via a Clauson−Kaas reaction between various 2-nitroanilines and 2,5-dimethoxytetrahydrofuran followed by reduction (with BiCl3−NaBH4) of the resulting 1-(2nitrophenyl)pyrroles 582a−c to afford the desired 1-(2aminophenyl)pyrroles 583a−c (Scheme 22). However, 5methoxy-2-nitroaniline was synthesized according to a

8.6. Quinoxaline Derivatives

Barea et al.298 prepared three 1,4-di-N-oxide quinoxaline analogues (578−580) (Scheme 21) and evaluated them for their antileishmanial activity against L. amazonensis. The benzofuroxane starting materials (576a−c) were synthesized according to previously published methods.299,300 Subse10400


Chemical Reviews

Review

Scheme 19. Synthesis of Diaminoacridinic Derivativesa

Scheme 22. Synthesis of 4-Substituted Pyrrolo[1,2a]quinoxaline analoguesa

Reagents and conditions: (i) Py, Et3N, 1 h, 80 °C; (ii) acetic anhydride, AcOH. a

Scheme 20. Synthesis of Acridine Derivativesa

Reagents and conditions: (i) DMTHF, AcOH, Δ; (ii) BiCl3, NaBH4, EtOH; (iii) RCOCl, py, dioxane, Δ; (iv) (a) POCl3, toluene, Δ; (b) NaHCO3, H2O, rt; (v) CO(OCCl3)2, toluene, Δ; (vi) (a) POCl3, Δ; (b) R−B(OH)2, Pd[P(C6H5)3]4, Na2CO3, C6H6, Δ; (vii) H2CCH− B(O-n-Bu)2, KOH; Pd[P(C6H5)3]4, C6H6, Δ; (viii) R−B(OH)2, PdCl2[P(C6H5)3]2, Na2CO3, C6H6, Δ; (ix) PdCl2[P(C6H5)3]2, HC CR, CuI, TEA, Δ. a

a Reagents and conditions: (i) BMME, H2SO4, 50 °C; (ii) NaN3, DMSO; (iii) Pd/C, H2; (iv) TEA, Me2CO; (v) CaCO3, H2O, dioxane.

Scheme 21. Synthesis of Quinoxaline Derivativesa

a

then prepared via the Bischler−Napieralski reaction.302 Reaction between 583d,e and triphosgene followed by chlorodehydroxylation with phosphorus oxychloride305 provided chlorides 583f,g. 4-Alkenyl-pyrrolo[1,2-a]quinoxaline 592 was then easily prepared via a Suzuki cross-coupling reaction between 4-chloroquinoxaline 583f and various alkenylboronic acids using Pd(PPh3)4 as the catalyst. Derivative 593 was prepared through a cross-coupling reaction (Pd catalyzed) between a vinylboronate and 583f. Additionally, subjection of compounds 583f,g to a Sonogashira coupling reaction with 1-hexyne using [PdCl2(PPh3)2]/CuI provided 594.306,307 The newly established library of compounds 585−594 was subsequently evaluated for their in vitro antileishmanial potential toward L. amazonensis and L. infantum. Interestingly, pyrroloquinoxalines 585−594 proved to be more potent toward the L. amazonensis (promastigote forms), and values

Reagents and conditions: (i) malononitrile, DMF, Et3N; (ii) py, 0 °C.

previously reported method.303,304 Treatment of different alkyl or aryl chlorides with 583a−c provided acetamides 584a−j. The 4-substituted pyrrolo[1,2-a]quinoxalines 585−591 were 10401


Chemical Reviews

Review

were measured in the range of 0.5−7 μM. It is interesting to note that compound 585 was 10-fold more potent than the standard alkaloid chimanine B (IC50 = 0.5 vs 5 μM). In addition, the 7-methoxy- and 8-methoxy-4-(E)-propenylpyrroloquinoxalines 586 (IC50 = 7 μM) and 587 (IC50 = 1 μM) also showed encouraging activity, while compounds 592 (IC50 = 4 μM) and 593 (IC50 = 3 μM), which had a (Z)-propenyl or a vinyl group on C-4 of the pyrroloquinoxaline, were slightly less active compared to compound 585.261 Compounds 585, 588− 590, and 594 all showed strong activity toward L. infantum promastigotes with IC50 values being evaluated in the range of 1−7 μM. It should also be noted that four of the tested compounds, viz., 585, 587, 592, and 593, all had an IC50 of 30). The monoimidazolylmethyl analogues 614−618, on the one hand, displayed strong activity toward intracellular amastigotes with IC50 values in the range of 0.71−4.57 μg/ mL, while on the other hand, the selectivity index for all of these compounds was below 10, except for 618, which had a high SI value (SI 140.84). Furthermore, bisimidazolyl derivatives 622 (IC50 = 3.00 μg/mL) and 624 (IC50 = 3.02 μg/mL) also expressed interesting antiamastigote activities with both having an SI > 30. Six compounds (607, 608, 611, 618, 622, and 624) were also evaluated for their in vivo antileishmanial property. Compound 611, which contains a

Scheme 23. Synthesis of 4-(E)-Alkenylpyrrolo[1,2a]quinoxaline Analoguesa

Reagents and conditions: (i) DMF, THF, AcOH, Δ; (ii) CuSO4, NaBH4, EtOH, rt; (iii) CO(OCCl3)2, toluene, Δ; (iv) POCl3, Δ; (v) CH3(CH2)3CHCH−B(O−C(CH3)2−)2, KOH, Pd[P(C6H5)3]4, C6H6, Δ; or CH3(CH2)4−6CHCH−B(OH)2, Pd[P(C6H5)3]4, Na 2 CO 3 , C 6 H 6 , EtOH, Δ; or CH 3 (CH 2 ) 7 CHCH−BF 3 K, PdCl2(dppf)·CH2Cl2, Cs2CO3, THF-H2O, Δ. a

reaction. Pyrroles 582a−c were subsequently reduced to the corresponding pyrrole amines 583a−c,305,309,310 which were subsequently reacted with triphosgene to provide lactams 583d−f. Further reaction with phosphorus oxychloride produced the chloro analogues 583g−i, and these were subjected to a direct Pd-catalyzed Suzuki−Miyaura coupling reaction with (E)-1-hexenylboronic acid pinacol ester to produce the target compounds 595−603.311,312 Compounds 595−603 were subsequently evaluated for their in vitro leishmanicidal properties toward L. amazonensis and L. infantum and found to be active against L. amazonensis promastigotes. Their IC50 values were evaluated to be in the range of 0.5−2 μM.308 The geometric isomers 595, 598, and 10402


Chemical Reviews

Review

Scheme 24. Synthesis of Imidazole and Imidazolidine Derivativesa

a Reagents and conditions: (i) (HCHO)3, pyrrolidine hydrochloride (2.0 equiv), isopropanol; (ii) imidazole, EtOH:H2O (2:3); (iii) NaBH4; (iv) K(t-OBu), DMSO, substituted Ar−X; (v) (HCHO)3, py (1.0 equiv), L-proline (0.3 equiv), DMSO; (vi) Br2, CCl4; (vii) imidazole, DMF; (viii) NaBH4; (ix) NaH, DMF, substituted Ar−X.

bismethylimidazolyl group and a 2-fluoro-4-nitroaryloxy group, showed pronounced in vivo activity, inhibiting 77.9% of the parasite growth. Compounds 618 and 624 displayed moderate activity, producing 55.3% and 56.6% inhibition, respectively.313 Bhandari et al.316 synthesized a series of aryloxyalkyl imidazoles (Scheme 25), which were subsequently evaluated in vitro as antileishmanial compounds toward L. donovani. Synthesis of these aryloxyalkyl imidazoles is summarized in Scheme 25. Ketones 625a−c were treated with paraformaldehyde and pyrrolidine via an asymmetric Mannich reaction to afford the corresponding Mannich products.317 Pyrrolidine unit replacement with imidazole subsequently afforded 626a and 626b, whereas 626c was synthesized by a recently reported procedure.318 Subsequent reduction with NaBH4 provided the hydroxyl intermediates 627a−c (cis-627c was produced with an 8.5:1.5 diastereoselectivity), and further reaction with various substituted aryl halides furnished the desired ethers 628−633. Several aryloxyalkyl imidazoles (637−640) and diaryloxyalkyl imidazoles (641 and 642) were synthesized by the same protocol. Ring opening of epoxides 634 and 635319 with imidazole provided alcohols 636a and 636b. Subsequent SNAr substitution by different aryl fluorides eventually generated the desired range of aryloxy ethers 637−642. These compounds were screened in vitro toward transgenic L. donovani promastigotes. When evaluated against an amastigote model, compounds 628−633 and 637−642 had IC50 values in the range of 0.47−4.83 μg/mL. Four of these compounds, viz., 628, 630, 637, and 641, had maximum SI (selectivity index) values of 36.68, 16.58, 13.85, and 31.89, respectively. Interestingly, the SI of these compounds was several times higher than that of the reference drugs pentamidine and sodium stibogluconate. All compounds in the aryloxyalkyl series (628−631 and 637−640) showed strong

activity toward amastigotes, displaying IC50 values in the range of 0.47−2.27 μg/mL. A further interesting finding was that compounds which have a linker of three carbons between the phenyl and the imidazole rings (628−633) showed a higher activity than those compounds with a two-carbon linker, viz., 637−642. It was also apparent from these results that the aryl ring was important for the leishmanicidal properties of tested compounds. Additionally, compounds with a further aryloxy group (641 and 642) showed an increase in IC50 values (from 0.47−2.83 to 4.82−5.62 μg/mL), except for compound 641, which showed an IC50 of 0.56 μg/mL.316 Furanyl azoles 646−652 and thiophenyl azoles 653−657 were prepared as outlined in Scheme 26.320 A Mannich protocol316 reaction between ketones (2-acetylthiophene or 2acetylfuran) 643a,b with pyrrolidine and paraformaldehyde provided the resulting Mannich products, which was followed by replacement of the pyrrolidine moiety by an imidazole-H1,2,4-triazole to provide a series of azolyl ketones 644a,b. Reduction (with NaBH4) of the latter compounds afforded the hydroxyl intermediates 645a,b, which were finally reacted with various substituted benzyl halides to furnish the desired series of benzyl ethers 646−657. The in vitro biological activities of thiophenyl and furanyl azole derivatives (646−657) toward L. donovani produced encouraging results, clearly suggesting that the furanyl azoles showed better activity than thiophenyl azoles. Additionally, the imidazole derivatives were more active than the triazole derivatives. The IC50 and SI values of the furanyl azoles (646−652) demonstrated that these compounds exhibit strong activities toward L. donovani amastigotes (IC50 = 3.04−9.39 μM) that are superior to the standard drug miltefosine (IC50 = 13.40 μM). Compounds 646 and 647 furthermore displayed promising selective activity toward amastigotes (SI > 10). 10403


Chemical Reviews

Review

Scheme 25. Synthesis of Aryloxyalkyl Imidazolesa

Scheme 26. Synthesis of Furanyl Azoles and Thiophenyl Azolesa

a

Reagents and conditions: (i) pyrrolidine, (HCHO)n, isopropanol, 90−95 °C, 6−8 h; (ii) corresponding Mannich salt, imidazole or 1H1,2,4-triazole, ethanol:H2O (3:2), 90 °C, 5−9 h; (iii) NaBH4, MeOH, 0 °C to rt, 2 h; (iv) K(t-OBu), DMSO, substituted benzyl halides, 5 °C to rt, 2−3 h.

Scheme 27. Synthesis of Bisbenzimidazolesa a

Reagents and conditions: (i) pyrrolidine, (HCHO)n, L-proline, DMSO, 6−8 h; (ii) corresponding Mannich salt, imidazole, ethanol:H2O (3:2), 5 h; (iii) NaBH4, MeOH, 2 h; (iv) K(t-OBu), DMSO, substituted aryl halides, 2−3 h; (v) imidazole, abs ethanol, reflux, 5 h.

Compound 646 demonstrated the highest activity of all of the tested compounds, showing an IC50 value of 3.04 μM and an SI of 19.80. Furthermore, it was the least toxic (CC50 = 60.21 μM) and several times more active than the reference compounds miconazole and miltefosine. All thiophenyl imidazole analogues (653−657) showed strong activity toward the amastigote form of the parasite with IC50 values evaluated to be in the range of 5.14−7.81 μM.320 Mayence et al.321 synthesized a number of bisbenzimidazoles, which are generally prepared by reaction between 1,2phenylenediamine and carboxylic acids. An alternative synthetic route322 involved condensation between 1,2-phenylenediamines and aldehydes, providing imines, which was followed by oxidation. Some more recent reports showed that starting from the aldehyde-derived bisulfite adducts 661a−c, the protocol renders the oxidation step unnecessary,323−325 and thus, this improved protocol was exploited to prepare bisbenzimidazoles 662−664 (Scheme 27). The pharmacological profiles of compounds 662−664 were established by testing them in vitro against L. donovani. Compounds 662 and 664 displayed strong antileishmanial activities (IC50 1.5 and 1.4 μM, respectively), and they were more potent than the standard pentamidine. Similarly, compound 663 exhibited an IC50 value of 4.9 μM. Compounds 662−664 were subsequently tested for cytotoxicity, where it was found that only 663 displayed no cytotoxicity in the assay

a

Reagents and conditions: (i) EtOH, K2CO3, reflux, 8 h; (ii) EtOH/ H2O (3/1), Na2S2O5; (iii) 1,2-phenylenediamine, MW 140 °C, 15 min.

used for this study. Compounds 662 and 664 were active against L. donovani, exhibiting modest selectivity indexes of approximately 20.321 Ferreira et al.326 synthesized various difluoromethyl azoles in their quest to discover novel compounds to test for antileishmanial activity. The N-aryl-amidine 666 and 2bromomalonaldehyde (667)327 were first synthesized to be used as starting materials in the preparation of N-aryl imidazole-5-carbaldehyde 668. The aldehyde moiety in 668 was readily converted into a difluoromethyl group by reaction with N,N-diethylaminosulfur trifluoride (DAST), generating compound 669 (Scheme 28).328 The 1,2,3-triazolic compound 673 was synthesized from diazomalonaldehyde (672)326 and the aromatic amine hydrochloride 671, and subsequent 10404


Chemical Reviews

Review

Scheme 28. Synthesis of Difluoromethyl Azolesa

The ethylenediamine derivative 678, which contains free amino groups, and compounds 679−682 all displayed significant antiproliferative activities against L. amazonensis and L. major. Of these compounds, 678 exhibited the highest activity toward the two Leishmania species (IC50 = less than 2 μg/mL). The L. amazonensis-infected BALB/c macrophage model was also used to confirm activity of the imidazolidine derivatives against the intracellular stage of the parasite. Compounds 678−682 were selected for further study due to their high activity against Leishmania promastigotes coupled with their low toxicity toward murine macrophages. Compounds 678−682 displayed a significant effect against the amastigote forms of L. amazonensis. Of these 678 and 679 displayed the best activities toward amastigotes, producing IC50 values of 2.0 and 9.4 μg/ mL, respectively. For compounds 678 and 679, the selectivity indices were calculated to be 2.2 and 0.0 at 45 μg/mL, 12.6 and 2.7 at 30 μg/mL, 15.7 and 17.8 at 15 μg/mL, 16.6 and 132.8 at 7.5 μg/mL, and 300.0 and 323.5 at 1.5 μg/mL respectively.329 8.8. Pyrimidines

Several 2-pyridyl pyrimidines were synthesized by Musonda et al.332 according to the general route outlined in Scheme 30. Scheme 30. Synthesis of 2-Pyridyl Pyrimidines a

Reagents and conditions: (i) HCl (gas), CH3CN, reflux; (ii) AcOH, Et3N, i-PrOH; (iii) DAST, CH2Cl2, rt, 24 h; (iv) HCl (gas), C3H6O, rt, 1 h; (v) H2O, rt, 1 h.

treatment with DAST produced the 4-difluoromethyl-1,2,3triazole 674. Interestingly, carbaldehyde 673 and the difluoromethylated azoles 669 and 674 showed leishmanicidal property toward promastigote forms of L. amazonensis with IC 50 values below 3.0 μM (2.8, 1.7, and 2.6 μM, respectively).326 Imidazolidines, N,N′-dibenzyl-2-arylimidazolidines, and N,N′-bisaminoalkylimidazolidines have been shown to possess fungicidal, antiparasitic, antibacterial, antiamoebic, and antiviral activities.329−331 Accordingly, Carvalho et al.329 synthesized a small library of imidazolidine derivatives (679−682) by condensing N,N′-disubstituted ethylenediamine 678 with a variety of aromatic aldehydes in EtOH (Scheme 29). The antileishmanial activities of compounds 678−682 were evaluated against L. amazonensis and L. major promastigotes. Scheme 29. Synthesis of Imidazolidine Derivativesa

The commercially available chloropyrimidine 683 was monoaminated with various amines in ethanol in the presence of Et3N, affording compounds 684−699, which were screened for antileishmanial activity in L. donovani using miltefosine as a standard. Compounds 684−699 showed activity with the same efficacy as the reference drug miltefosine, and some compounds of this series showed excellent selectivity against rat myoblast L6 cells.332 Agarwal et al.333 synthesized a small library of dihydropyrido[2,3-d]pyrimidines (701−709) in excellent yields by treating 6amino-1,3-dimethyl uracil (700) with various aldehydes in the

a

Reagents and conditions: (i) EtOH, 3 h, rt; (ii) NaBH4, MeOH, 2 h, rt; (iii) RCHO, EtOH, 1 h, 70 °C. 10405


Chemical Reviews

Review

Scheme 32. Synthesis of Terpenyl Pyrimidinesa

presence of 2,4-pentandione (Scheme 31). Compounds 701− 709 displayed encouraging in vitro biological activities toward Scheme 31. Synthesis of Dihydropyrido[2,3-d]pyrimidinesa

Reagents and conditions: (i) NaH, dimethyl carbonate, 110 °C, 3 h; (ii) guanidine, isopropanol, 90 °C, 16 h; (iii) POCl3, N,Ndiisopropylethylamine, rt, 8 h; (iv) isopropanol, various alcohols, rt, 12 h.

a a

Reagents and conditions: (i) RCHO, CH3COCH2COCH3, AcOH, Δ, 8 h.

a concentration of 1 μg/mL. The oxygen-substituted pyrimidines 721 and 722 displayed 99% inhibition at a concentration of 5 μg/mL.275

L. donovani coupled with a strong correlation between activity and structure. At a concentration of 50 μg/mL, four compounds (701−704) displayed 100% inhibition toward promastigotes while compounds (701 and 702) showed 100% inhibition in amastigotes. Compound 705 having a methyl group at the para position in R showed 97% and 74% inhibition against promastigotes and 80% and 62% inhibition against amastigotes at concentrations of 50 and 10 μg/mL, respectively. When an additional methyl moiety was present at the meta position in R, as in compound 706, a further increase in activity was observed. Similarly, the pisopropyl compound 701 exhibited 100% activity in both promastigotes and amastigotes. The para fluorinated compound 707 showed inhibition rates of 97% in promastigotes and 89% in amastigotes, and a further enhancement in activity was observed against both promastigotes and amastigotes by replacing the fluorine with a chlorine atom, as in compound 708.333 Compound 702, which has an additional chlorine substituted at C-3, showed 100% inhibition in promastigotes and amastigotes forms. The para-cyano-substituted compound 703 showed 100% and 99% inhibition toward promastigotes and 88% and 76% inhibition toward amastigotes at concentrations of 50 and 10 μg/mL, respectively. Compounds 704 and 709 having a nitro group at the meta or para position demonstrated inhibition rates of 100% each toward promastigotes, and 82% and 89%, respectively, toward amastigotes were observed at a concentration of 50 μg/mL.333 Chandra et al.275 prepared terpenyl pyrimidines 714−723 and evaluated their antileishmanial activity toward L. donovani promastigotes. Reaction between 710 and dimethyl carbonate and sodium hydride furnished 711,334 which upon condensation with a preprepared guanidine, produced pyrimidone 712. Further reaction with POCl3 in the presence of diisopropylethylamine generated significant amounts of chloride 713,335 which was used for synthesis of diaminopyrimidines 714−723 (Scheme 32). The library of pyrimidines 714−723 was evaluated for in vitro leishmanicidal screening using the promastigote model, and all showed 100% inhibition at a concentration of 10 μg/ mL. It was interesting to note that there was little difference in activity between the anilino-, morpholino-, and piperidinylsubstituted compounds. However, the p-anisidino-substituted compound 716 showed an improved inhibition rate of 98.8% at

8.9. Phospholipids

Ether-linked phospholipids have been synthesized by Coghi et al.336 as illustrated in Scheme 33. The easily accessible 2Scheme 33. Synthesis of Ether-Linked Phospholipidsa

a

Reagents and conditions: (i) PPTS, DCE; (ii) R1X, t-BuOK, DMA; (iii) PPTS, n-BuOH, 1,2-dichloroethane; (iv) 2-chloro-1,3,2-dioxaphospholane-2-oxide, Et3N; (v) Et3N.

alkyloxy-1,3-propanediols were first connected to Ellman’s dihydropyranyl linker using PPTS as the catalyst.337,338 Alkylation of the primary alcohol group of 726 was achieved via the Williamson protocol. In this case different conditions were evaluated to establish the best conditions for alkylation of primary alcohols, and the best results were obtained with DMA as the solvent and t-BuOK as the base.295 Finally, the crude alcohols obtained after removal from the linker were treated according to the known procedure for phosphorylation and provided the respective phosphocholines (729−731).336 10406


Chemical Reviews

Review

Scheme 34. Synthesis of Phospholipid Analoguesa

Reagents and conditions: (i) [(CH3)3Si]2NK, THF; (ii) MeOH, H+, 40 °C; (iii) LiAlH4, THF; (iv) NaBH3CN, BF3·Et2O, THF; (v) (a) P(O)Cl3, Et3N, THF; (b) H2O, 2-propanol; (vi) pyr., 40 °C; (vii) pyr., MSNT, or TIPS-Cl, HOCH2CH2NR1R2R3, 40 °C; (viii) H2 (1 atm), 10% Pd/C, EtOAc. a

cyclohexanone (732a) or adamantanone (732b) and 4carboxybutyltriphenylphosphonium bromide followed by H2SO4-catalyzed esterification of the unsaturated compounds 733a,b and subsequent reduction using LiAlH4 afforded the corresponding alcohols 735a,b (Scheme 34). Similarly, Wittig condensation between cyclohexanone (732a) or adamantanone (732b) and 10-methoxycarbonyldecyltriphenylphosphonium bromide provided compounds 736a,b, and subsequent reduction with LiAlH4 provided alcohols 737a,b. Finally, Wittig condensation between 1,4-cyclohexanedione monoethylene ketal and various alkyltriphenylphosphonium bromides led to formation of compounds 738a−c. Treatment of the latter compounds by BF3·Et2O and NaBH3CN340 reduction eventually produced compounds 739a−c. The aryloxyethanols and

The in vitro activities of the above library of molecules toward amastigote forms of L. donovani were determined where it was found that 729−731 displayed IC50 values in the range of 1.66−0.66 μM and were lower than the standard drug miltefosine (IC50 = 0.22 μM), which had an IC50 value similar to edelfosine. Compound 731 showed the highest activity with an IC50 value of 0.66 μM, similar to the one for miltefosine. Analogues 729 and 730 showed higher IC50 values (1.6 and 1.3 μM, respectively) compared to miltefosine. Compound 731 was further tested in macrophages infected with L. donovani and proved to be appreciably more active (IC50 0.78 μM) than the reference drug miltefosine (IC50 1.74 μM).336 Avlonitis et al.339 prepared a new and interesting library of phospholipids in the following way. Wittig reaction between 10407


Chemical Reviews

Review

Scheme 35. Synthesis of Buparvaquone Derivativesa

6-aryloxyhexanols which were used for preparation of the phospholipids 740−751 were synthesized according to previously published method.341 Catalytic hydrogenation of compounds 740, 742, 747, 748, and 749 using 10% Pd/C provided the saturated phospholipid ethers 752, 753, 754, 755, and 756, respectively. The new phospholipid analogues 740−756 were all screened in vitro for leishmanicidal properties toward promastigote forms of L. donovani and L. infantum. Interestingly, the ether functional phospholipids (740−746) showed pronounced activity toward both Leishmania strains. A further interesting finding was that compound 742 displays potent activity toward L. donovani (IC50 = 3.91 μM) and L. infantum (IC50 = 5.25 μM). It is noteworthy that the activity of compound 742 was higher than that of the standard miltefosine. Moreover, compounds 745 (IC50 = 6.5 μM) and 746 (IC50 = 3.7 μM) display better activity (toward L. infantum) than miltefosine. In the 2-(4-dodecylidene-cyclohexyloxy)ethyl series, compound 740 possessed a higher activity than miltefosine toward L. infantum (IC50 = 3.25 μM) and L. donovani (IC50 = 7.08 μM). A further interesting finding was that compounds 740 and 742−746 displayed better activity than toward miltefosine L. infantum. Furthermore, phospholipid ethers 740, 742, and 756 possessed better activities than miltefosine toward L. donovani. 11-Cyclohexylideneundecyloxy phospholipid ether 747 was more potent than miltefosine toward L. donovani (IC50 = 2.4 μM) and L. infantum (IC50 = 5.2 μM). Similarly, cholinecontaining compound 748 displays a higher activity than miltefosine toward L. donovani (IC50 = 4.99 μM), while phospholipid ether 749 possessed better activity than miltefosine toward both promastigote forms L. donovani (IC50 = 3.16 μM) and L. infantum (IC50 = 6.75 μM), respectively.339 Compared to compound 750, N-methylpiperidino compound 751 exhibited a decreased activity toward L. infantum (IC50 = 6.64 μM) but similar activity toward L. donovani (IC50 = 5.09 μM).339

a

Reagents and conditions: (i) (EtO)2POCl, NaH, THF; (ii) TMS−Br, CHCl3, MeOH; (iii) (t-BuO)2P(O)OCH2Cl, NaH, n-Bu4NI, DMF; (iv) EtOAc, HCl.

buparvaquone 757. The intracellular amastigotes demonstrated interspecies drug sensitivities that were similar to the promastigote form, exhibiting decreasing levels of inhibition in the following order 757 > 761 > 759 > Sbv. Moreover, buparvaquone displayed significant activity having IC50 values in the range of 0.37−5.50 μM. Buparvaquone-3-phosphate (759) and 3-phosphonooxymethylbuparvaquone (761) exhibited better water solubilities (>3.5 mg/mL) than the reference compound (≤0.03 μg/mL).342 Buparvaquone and its derivatives 759 and 761 exhibited micromolar ED50 values (in vitro) toward promastigotes form of L. donovani, L. aethiopica, L. major, L. amazonensis, L. mexicana, L. mexicana, and L. panamensis ranging from 0.001 to 0.124 μM. On the other hand, the range of ED50 values for amphotericin B was 0.022 to 0.124 μM. Buparvaquone and its derivatives 759 and 761 also showed micromolar ED50 values (in vitro) toward the amastigote forms of L. donovani, L. aethiopica, L. major, L. amazonensis, L. mexicana, and L. panamensis ranging from 0.037 to 15.731 μM. In conclusion, buparvaquone and its derivatives 759 and 761 displayed antileishmanial potential toward species that cause CL, viz., L. aethiopica, L. major, L. amazonensis, L. panamensis, and L. mexicana, and also toward L. donovani, which causes visceral leishmaniasis.342

8.10. Buparvaquone Derivatives

The prodrug strategy of delivery of active agents to the targeted site is used to solve some inherent problems, viz., stability, permeability, and solubility. In drug discovery this approach is universally used to essentially enhance the cross-membrane delivery of different drugs.342−345 The prodrugs (759 and 761) of buparvaquone (757), which contains a hydroxynaphthoquinone moiety, were prepared and screened in vitro toward cutaneous and visceral leishmaniasis. Compound 757 was first deprotonated with NaH and the subsequent alkoxide anion reacted with a protected chlorophosphate, producing phosphate ester 758. Removal of the ethyl protecting groups of phosphate 758 was achieved using bromotrimethylsilane to yield the prodrug 759 (Scheme 35). Compound 761 was obtained by reacting buparvaquone (757) with a chloromethylphosphate,346 followed by deprotection of the di-tert-butyl protecting groups using a saturated solution of HCl in EtOAc. The ED 50 values obtained upon evaluation against promastigotes (L. major) showed that buparvaquone (757) and its prodrugs (759 and 761) in fact do display pronounced in vitro activities (2−124 nM), some of which are greater than the standard amphotericin B. Against the majority of the species investigated, decreasing levels of potency were observed in the order buparvaquone 757 > 761 > 759 > amphotericin B. The higher activities of prodrugs 759 and 761 compared to 757 may in part be ascribed to their ready hydrolysis to

8.11. N,C-Linked Arylisoquinolinium Salts

Naphthylisoquinoline alkaloids are axially chiral natural products reported from the two families, viz., Ancistrocladaceae and Dioncophyllaceae.347,348 These natural products exhibited very good and interesting biological activities.122,349−356 PonteSucre et al.347 synthesized a small library of N,C-coupled arylisoquinolinium salts, viz., 764−777 in good to excellent yields according to a known synthetic protocol122 in which the benzopyrylium salt 762356 was subjected to cyclocondensation with various substituted aromatic amines (Scheme 36). Interestingly, compounds 764−777 were very active against promastigotes of the pathogen L. major, exhibiting IC50 values ranging from 0.54 to 3.49 μM, comparable to that of amphotericin B (IC50 = 5.07 μM).347,357 Notably, all of these compounds (764−777) have a lipophilic aromatic subunit that either is unsubstituted or contains alkyl groups. Noteworthy 10408


Chemical Reviews

Review

Scheme 37. Synthesis of Amidoxime Derivativesa

Scheme 36. Synthesis of N,C-Coupled Arylisoquinolinium Saltsa

a

Reagents and conditions: (i) NaBH4, MeOH, H2O, 0 °C.

too is the fact that the steric demand of the aryl subunit, for example, naphthyl versus anthracenyl ring systems or methyl versus propyl substituents, does not seem to strongly influence the activity of these compounds toward L. major promastigotes. However, they play a crucial role in determining the toxicity of these compounds.347 For example, anthracenyl-substituted compound 767 was approximately 5 times more potent toward the parasite than its naphthalene derivatives 765, but it was up to 35 times more toxic to macrophages.347 8.12. Amidoxime Derivatives

Amidoxime derivatives were prepared using the Buchwald− Hartwig coupling protocol in conjunction with Heck reactions.358 The β-ketosulfone derivatives 780a−c underwent manganese(III) acetate359−362 promoted oxidative cyclization with various alkenes 781 to afford the 2,3-dihydrofuran intermediates, which were subsequently further transformed into the series of 2,3-dihydrofuran derivatives (782−784) (Scheme 37) in two steps, viz., (i) palladium-catalyzed Buchwald−Hartwig cross-coupling reactions of brominecontaining substrates with arylamine (in the presence of palladium acetate, BINAP, and Cs2CO3) and (ii) treatment of all synthesized nitrile derivatives with hydroxylamine hydrochloride and potassium tert-butoxide. All three amidoxime derivatives 782−784 were screened for their antileishmanial activity toward L. donovani. In particular, monoamidoxime 782 proved to be more potent than the standard pentamidine (IC50 = 8.3 μM, SI = 6.6),358 suggesting that a single amidoxime group on these compounds is sufficient for producing antileishmanial activity. Diamidoxime compounds 783 and 784 were also found to exhibit good activities (13.3 and 8.8 μM, respectively), and this may be attributed to the fact that the contain two amidoxime groups, one para to the sulfone group and the other ortho to the amine. A higher activity was observed for 784, which has a methyl and a benzyl group.358

Reagents and conditions: (i) (a) Na2SO3, NaHCO3, H2O, 100 °C, 500 W, 20 min; (b) water, 100 °C, 500 W, 10 min; (ii) Mn(OAc)3, Cu(OAc)2, AcOH, 80 °C, 200 W, 60 min; (iii) Pd(OAc)2 (4 mol %), BINAP (4 mol %), Cs2CO3 (1.4 equiv), tol., 80 °C, 18 h; (iv) NH2OH, HCl (10 equiv), t-BuOK (10 equiv) DMSO, 5 °C to rt. a

Scheme 38. Synthesis of Paullone Derivativesa

Reagents and conditions: (i) (a) AcOH, 70 °C, 1 h; (b) AcOH, H2SO4, 70 °C, 1 h; (ii) Pd(AcO)2, DMF, Et3N, PPh3, N2, 150 °C, 30 min.

a

8.13. Paullone Derivatives

The paullones are a class of protein kinase inhibitors which have demonstrated most interesting biological activities.363−372 Recently, Reichwald et al.363 synthesized a paullone series of analogues, viz., 789−796. Synthesis commenced with a Fischer indole cyclization using various phenyl hydrazines 786a−c and cyclic ketone 785373 to afford the new 2-iodo-substituted paullones 787a−c. These compounds were then heated with the ketone Mannich base 788 with Pd(OAc)2 and Et3N to afford the 2-vinylpaullones 789−796 (Scheme 38).

All of the compounds, viz., 789−796, showed strong antileishmanial activities against both axenic amastigotes and parasites in infected macrophages, producing GI50 values in the axenic amastigote model that were near or below 1 μM. Moreover, 790, 791, 793, and 794 did not show toxicity toward THP-1 macrophages. 10409


Chemical Reviews

Review

8.14. Piperine Derivatives

proved to be more active against promastigotes. Compound 801 was the most effective conjugate, displaying an IC50 of 0.075 mM against amastigotes. In contrast to the valine derivative 801, compounds 802 and 803 displayed significant activity toward amastigotes, with IC50 values of 0.168 and 0.119 mM, respectively.374 Similarly, piperine derivatives 804−808 demonstrated pronounced activity toward amastigotes (IC50 range 0.236−0.310 mM) and a better activity compared to piperine. Compounds of series 809−811, and 813, in which the double bonds were reduced, proved to be more active against promastigotes than their unsaturated analogues 799−803. Among these conjugates, tetrahydropiperoyl tryptophan methyl ester (813) was the most active, exhibiting an IC50 value of 0.473 mM. These results suggested that double bonds in the piperine subunit were crucial for antileishmanial activity. The most potent compounds (799 and 801) were also evaluated in vivo and at a dose of 250 mg/kg being administered intraperitoneally for 10 days. Data showed that compound 799 displayed a pronounced reduction of 35% and 30% in spleen parasitic burden and spleen weight, respectively. However, compound 801 also displayed a pronounced reduction of 24% in parasitic burden with no reduction in spleen weight. The reference drug miltefosine displayed pronounced reductions of 87% (in spleen parasitic burden) and 43% (in spleen weight) under the same in vivo conditions as described for compounds 799 and 801.374

Piperine (797) is a constituent of black pepper Piper nigrum. Piperic acid (798) has been synthesized by hydrolysis of piperine374,375 and can also be prepared by saponification of the CHCl3 extract of P. nigrum. On the basis of these observations, Singh et al.374 synthesized a library of selected piperine derivatives (797−813). First, the mesylate of piperic acid, prepared by treating piperic acid with methanesulfonyl chloride at 0 °C, was treated with different amino acid methyl esters to provide a series of methyl ester conjugates 799−803 in yields ranging from 40 to 75%375 (Scheme 39). Deprotection of the Scheme 39. Synthesis of Piperine Derivativesa

8.15. Pterocarpanquinones

Pterocarpanquinones 816−820 were prepared by oxyarylation of chromene quinone 814 with ortho-iodophenols 815a−e in refluxing acetone using 10 mol % of Pd(OAc)2 as catalyst and Ag2CO3 as a base (Scheme 40).378−380 Compounds 816−820 Scheme 40. Synthesis of Pterocarpanquinonesa a Reagents and conditions: (i) 20% KOH, CH3OH, 80 °C, 3 days, 88%; (ii) CH3SO2Cl, Et3N, CH2Cl2, 0 °C, 30 min, 85%; (iii) amino acid methyl ester, Et3N, CH2Cl2, rt, 40−75%; (iv) KF−Al2O3 (40%), Microwave, 1000 W, 3−4 min, 70−80%; (v) 5% Pd/C, H2 (40 psi), MeOH, 30 min, 75−80%.

carboxyl group in compounds 799−803 using a microwaveassisted solid-phase reaction with Al2O3 (40% KF) afforded compounds 804−808 in good yields of 70−80%.376,377 A third series of prepared conjugates comprised the corresponding saturated analogues of compounds 799−803. Thus, compounds 809−811 and 813 were synthesized via catalytic hydrogenation of compounds 799−801 and 803. For preparation of compound 812, tetrahydropiperic acid (798a) was synthesized via catalytic hydrogenation of compound 798, and this product was then coupled with the methyl ester of methionine. Compounds 797−813 were screened for activity toward the promastigote and amastigote forms of L. donovani. Piperine (797) exhibited antileishmanial activity toward promastigotes and amastigotes forms with IC50 values of 0.752 and 2.558 mM, respectively, whereas the piperine derivatives 799−803 demonstrated stronger activities than compound 797.374 All of these piperine derivatives were active against amastigotes with IC50 values ranging from 0.075 to 0.310 mM. However, the IC50 values were higher against promastigotes (0.473− 1.312 mM).374 Compounds 799−803 were thus found to be more active against amastigotes, while compounds 809−813

a

Reagents and conditions: (i) Pd(OAc)2, acetone, Ag2CO3, 12 h, reflux.

were evaluated on cultures of L. amazonensis (promastigote and amastigote forms) and demonstrated potent activities against the promastigote form of the parasite, with IC50 values ranging from 1.07 to 2.85 μM. With the exception of 817, the remaining compounds also displayed significant antileishmanial activity toward amastigote-infected macrophages (IC50 range 1.25−1.85 μM). The best selectivity indices for these pterocarpanquinones were exhibited by 816, 818, and 820.378 10410


Chemical Reviews

Review

8.16. Tetrahydronaphthyl Azoles

inhibition). Interestingly, compound 827 had a 38−72 times lower IC50 value than that of the reference compounds. A further interesting finding was that compound 827 was also 6 and 16 times more selective (SI = 34.78) than the standard sodium stibogluconate and paromomycin, respectively.381

381

Marrapu et al. synthesized some selected and novel tetrahydronaphthyl azoles (823−829 and 832−837) representing a new library of potentially active molecules as shown in Scheme 41. Ring opening of 1,2-epoxytetrahydronaphthalene

8.17. Quinazoline Derivatives

Scheme 41. Synthesis of Tetrahydronaphthyl Azolesa

Quinazoline-based compounds 841−847 were synthesized by Agarwal et al.383 according to the synthetic strategy illustrated in Scheme 42. Thus, reaction of 1-tetralone (838) with various Scheme 42. Synthesis of Quinazoline Derivativesa

a Reagents and conditions: (i) imidazole, EtOH, 90 °C, , 6 h or 1,2,3triazole, (But)4N+I−, rt, 8 h; (ii) NaH (60% oil), substituted aryl or benzyl halide, DMF, 0 °C → rt, 4−5 h; (iii) imidazole, abs. ethanol, 90 °C, 12 h.

a

(821)382 with imidazole or 1,2,3-triazole furnished trans-1imidazol-1-yl-1,2,3,4-tetrahydronaphthalen-2-ol (822a,b).382 Subsequent etherification of intermediates 822a,b with different aryl/benzyl halides provided the desired ethers 823−829. The related aryloxycyclohexyl imidazoles 832−837 were subsequently synthesized for SAR studies. Thus, treatment of imidazole with 1,2-epoxycyclohexane (830) in ethanol provided trans-2-imidazolylcyclohexanol (831), which when treated with different aryl halides in the presence of NaH provided the respective ethers 832−837.381 The series of compounds synthesized for this study (823− 829 and 832−837) were screened in vitro toward transgenic L. donovani promastigotes and amastigotes, and all exhibited higher activities toward L. donovani (IC50 0.64−6.52 μg/mL) than the standard sodium stibogluconate (IC50 = 46.54 μg/mL) and paromomycin (24.79 μg/mL). Among the series of tetrahydronaphthyl azoles, 823−829, compounds incorporating a benzyloxy moiety (827−829) were more potent than the aryloxy derivatives, showing better activity toward amastigotes and producing a significant selective activity toward amastigotes (SI > 10). To investigate the SAR effects of the fused aromatic ring, aryloxycyclohexyl azoles 832−837381 were subsequently synthesized. These tetrahydronaphthyl azoles possessed potent leishmanicidal activities toward the intracellular amastigotes, with IC50 values being in the range from 1.40 to 5.07 μg/mL. Two promising compounds (827 and 828) which had SI values above 10 were further evaluated for their in vivo activity in which 827 displayed a pronounced inhibition of 83.3%, whereas compound 828 displayed only moderate activity (32.1%

aldehydes (839a−d) in an alcoholic solution of KOH provided benzylidenes 840a−d.384 Cyclization of these latter compounds was achieved by treatment with various guanidine sulfates385 and potassium tert-butoxide in refluxing methanol for 24 h, producing the series of quinazoline-based compounds 841− 847. The in vitro efficacies of compounds 841−847 against promastigotes and amastigotes of L. donovani were subsequently assessed. All of these compounds inhibited promastigotes with IC50 values ranging from 2.65 to 8.95 μg/ mL, which were lower than that of the reference drug pentamidine (IC50 12.11 μg/mL). Among these tetrahydroquinazoline derivatives, compound 846, in which R3 is a pyridylpiperazinyl group and R1 is a chloro substituent, exhibited the lowest IC50 value (2.65 μg/mL). Replacement of the chlorine by the more electronegative fluorine atom, as in 844, resulted in an increase in the IC50 value (3.58 μg/mL).383 Insertion of an additional chlorine atom at the ortho position of 846 as in 847 had just the opposite effect of decreasing the activity by almost 2.5-fold. In a similar sense, replacement of the pyridylpiperazine moiety with a piperidinyl group resulted in a decrease in activity. On the other hand, compound 841, which has no substituents on its phenyl ring, displayed an IC50 value of 3.48 μg/mL. However, insertion of a fluorine atom at the ortho position, as in 842, introduced a slight decrease in the IC50 value (3.22 μg/mL). Fluoro-substituted compound 843 exhibited an IC50 value of 4.07 μg/mL, which was surprisingly lower than that of the dichlorinated compound 847, which in turn exhibited a relatively high IC50 value of 8.95 μg/mL.383

Reagents and conditions: (i) 5% alcoholic KOH, EtOH, 0 °C, rt, 2 h; (ii), t-BuOK, MeOH, reflux, 24 h.

10411


Chemical Reviews

Review

Scheme 43. Synthesis of Azaterphenyl Diamidinesa

a Reagents and conditions: (i) Pd(PPh3)4, Na2CO3, toluene, 80 °C; (ii) (a) LiN(TMS)2, THF, rt, overnight; (b) HCl, EtOH, rt, 15 h; (iii) 4cyanophenylboronic acid, Pd(PPh3)4, Na2CO3, toluene, 80 °C.

8.18. Azaterphenyl Diamidines

8.19. Pyridinones

Treatment of the commercially available γ-pyrone 871 with dibromopentane and dry potassium carbonate in dry DMF furnished 872 in almost quantitative yield.389 As shown in Scheme 44, the dimeric γ-pyrone 872 was treated with a series of different amines to produce pyridinones 873−879, which were tested for in vitro leishmanicidal potential toward promastigotes. These pyridinones displayed significant activity in this assay, with IC50 values in the range of 4.04−9.98 μg/mL.

386

Hu et al. prepared a series of azaterphenyl diamidines, beginning with the Suzuki coupling reaction between aryl halides and aryl boronic acids to afford teraryl bis-nitriles,387 and this was followed by conversion into diamidines using LiN(TMS)2. Scheme 43 illustrates the synthesis of the various azaterphenyl derivatives (851−853, 857−862, and 867−870). The entire library of these newly synthesized azaterphenyl diamidines, 851−853, 857−862, and 867−870, was tested against L. donovani.388 Nine of the compounds (851, 852, 857−860, 867, 869, and 870) displayed IC50 values of less than 1 μM of which five, viz., 851, 852, 857, 867, and 870, had values of 0.40 μM, and two (852 and 868) had the most encouraging values of less than 0.10 μM. Compounds 852 and 867 having a nitrogen atom ortho to both or one of the amidine moieties, respectively, showed a 3- and 4-fold increase in leishmanicidal potential over the parent compound. Interestingly, compounds 852 and 867 were the most potent, exhibiting excellent IC50 values of 0.084 and 0.063 μM, respectively. Introduction of two nitrogen atoms ortho to one of the amidine units, as in 869, resulted in a slight decrease of leishmanicidal potential compared to 852 (IC50 = 0.20 μM). Moreover, in compound 853, having two nitrogen atoms ortho to both amidine units, a pronounced decrease in leishmanicidal potential was observed (IC50 = 1.70 μM). Similar compounds 858−861 having additional nitrogen atoms in the central ring displayed a 2- to 4-fold decrease in activity.

Scheme 44. Synthesis of Pyridinonesa

a

Reagents and conditions: (i) Dibromopentane, K2CO3, DMF, rt, 12 h; (ii) EtOH, amine, 120−125 °C, 24 h.

10412


Chemical Reviews

Review

ophilic substitution reactions with various amines to yield the additional 2,4,6-trisubstituted pyrimidines 895−897.392 Compounds 885−897 demonstrated encouraging biological activities against L. donovani. Among the tested compounds, three, viz., 886, 887, and 889, displayed IC50 values against amastigotes in the range of 0.8−2.0 μg/mL and five, viz., 887, 890, 891, 893, and 896, had IC50 values in the range of 2.0−5.0 μg/mL. Compound 892 exhibited the lowest IC50 value (0.89 μg/mL) and the highest SI value (40.71), which was several times better than the reference drugs pentamidine and SSG. However, compound 886 had an IC50 of 1.80 μg/mL and was less cytotoxic (CC50 = 51.67 μg/mL) than compound 892. Similarly, compounds 913 and 914 displayed IC50 values of 5.12 and 4.99 μg/mL and cytotoxicity values (CC50) of 81.52 and 49.93 μg/mL, respectively. Interestingly, compounds 886, 895, and 896 showed lower cytotoxicity and better SI (28.70, 15.92 and 10.00). Compounds 886, 895, and 896 were consequently further screened for in vivo leishmanicidal potential in golden hamsters infected with L. donovani. Compounds 886 and 896 exhibited moderate inhibition percentages of 56.58% and 54.10%, respectively, whereas compound 895 has a slightly lower inhibitory effect (48.46%).390

Among these compounds, 873, 874, 878, and 879 demonstrated the most encouraging results. The activity of these compounds was found to be superior to that of miltefosine but inferior to that of amphotericin B.389 8.20. Triazines

Sunduru et al.390 synthesized a library of 2,4,6-trisubstituted1,3,5-triazine analogues (885−894) (Scheme 45). Substituted Scheme 45. Synthesis of 2,4,6-Trisubstituted-1,3,5-triazine Analoguesa

8.21. Triazole Derivatives

Patil et al.393 prepared a selected series of aryltriazolylhydroxamates and screened them for their antileishmanial activity. Reaction of the azido acids 898 and 899 with O-tritylhydroxylamine provided O-tritylated hydroxamates 900 and 901. Cu(I)catalyzed cycloaddition click reactions with various terminal alkynes produced the corresponding O-trityl-protected aryltriazolylhydroxamates 902−908.394 Removal of the trityl protecting group was accomplished with BF3·OEt2 or TFA to furnish the desired products 909−915 (Scheme 46). The in vitro leishmanicidal activities of the series of triazole derivatives 902−915 were screened toward the promastigote form of L. donovani, and compounds 902−908 showed moderate activity. However, compounds 909−915 displayed Scheme 46. Synthesis of Aryltriazolylhydroxamatesa Reagents and conditions: (i) CS2, NaH, MeI, THF, 0 °C to reflux; (ii) guanidine hydrochloride, NaH, DMF, reflux; (iii) cyanuric chloride, K2CO3, THF, reflux; (iv) various amines, K2CO3, THF, reflux; (v) m-CPBA, CH2Cl2, 0 °C to rt; (vi) various amines, THF, 100 °C, in a closed steel vessel. a

acetophenones were treated with CS2, followed by subsequent methylation,391 which produced the 3,3-bis-methylsulfanyl-1(substituted-phenyl)propenones 881a,b, cyclization of which was achieved by reaction with guanidine hydrochloride in the presence of NaH392 to afford the respective 4-(substitutedphenyl)-6-methylsulfanyl-pyrimidin-2-ylamines 882a,b. These were further treated with cyanuric chloride [(NCCl)3] to afford the (4,6-dichloro-[1,3,5]triazin-2-yl)-[4-(substituted-phenyl)-6methylsulfanyl-pyrimidin-2-yl]amines 883a,b. Subjection of these intermediate compounds to nucleophilic substitution with different amines afforded the target series of compounds 885−894 (Scheme 45). Compound 882a was additionally oxidized with m-CPBA to produce 4-(methylsulfonyl)-6-(3,4,5trimethoxyphenyl)pyrimidin-2-amine (884) followed by nucle-

Reagents and conditions: (i) NH2-O-trityl, IBCF, THF, −15 °C, 2 h; (ii) CuI, Hunig’s base, THF, rt; (iii) BF3·OEt2, THF, rt, 20 min or CH2Cl2, TFA/thioanisole (1:1), 0 °C, 3 h. Abbreviations: 3-Bp, 3biphenyl; DMA, p-N,N-dimethylanilyl; Ph, phenyl; 3-Py, 3-pyridyl; 2Tp, 2-thiophene; 2-Qn, 2-quinoline; 7-Qn, 7-quinoline. a

10413


Chemical Reviews

Review

potent activity toward promastigotes with IC50 values in the same range as miltefosin and 2- to 4-fold lower than that of suberoylanilide hydroxamic acid (SAHA).393

azomethines 919 (IC50 = 0.59 μg/mL) and 920 (IC50 = 0.57 μg/mL) displayed even more potent activity.395

8.22. Aryl Azomethines

Bakunov et al.396 synthesized several pentamidine congeners containing benzofuran moieties. Thus, starting from 4cyanophenol compound 926a was synthesized, and from 3hydroxybenzoic acid, 926b was prepared as described previously.397 Compounds 927a,b were also synthesized following a literature procedure.398 A modified coppermediated Castro reaction399 between o-iodophenols 926a,b and 927a,b afforded benzofurans 928a,b in 72−81% yields. Esters 928a,b were transformed into nitriles 929a (68%) and 929b (69%) by reaction with Me2AlNH2.400 Deprotection of these compounds with molten pyridine hydrochloride401 produced the cyanophenols 930a,b, which were then alkylated with 931a−d in the presence of K2CO3 to afford the isomeric dinitriles 932a−d and 933a−d in good to excellent yields (Scheme 48). Compounds 932a−d and 933a−d were transformed into imidate esters via the Pinner methodology.402 Further treatment with ethanolic solutions of isopropylamine, ammonia, or ethylenediamine yielded the benzofurans 934− 944. The new compounds (934−944) possessed potent activity toward L. donovani, and IC50 values were within the range of 0.48−3.0 μM. A further interesting finding was that four diamidines (934, 936, 939, and 940), three bis(N-isopropyl)amidines (935, 938, and 943), and one diimidazoline (941) display better or similar leishmanicidal potential than that of pentamidine (IC50 = 1.8 μM).396 Diamidine 936 and diimidazoline 941 display higher activity against L. donovani. Compounds having the benzofuran moiety connected to C-4′ display better activity than the C-3′ isomers. Compound 941 proved to be a promising candidate in this series because it

8.23. Pentamidine Congeners

Al-Kahraman et al.395 synthesized a fairly extensive library of the aryl azomethines 916−925 in good yields (55−87%) by reacting various substituted anilines with aromatic and/or heterocyclic aldehydes with methanolic glacial acetic acid, Scheme 47. Scheme 47. Synthesis of Aryl Azomethines

Arylimines 916−925 were screened against L. major, and all displayed strong antileishmanial activities with IC50 values (0.57−0.81 μg/mL) comparable to amphotericin B (IC50 = 0.56 μg/mL). Azomethines 917 (IC50 = 0.65 μg/mL), 922 (IC50 = 0.68 μg/mL), 923 (IC50 = 0.66 μg/mL), and 925 (IC50 = 0.62 μg/mL) all showed good activity against L. major, while Scheme 48. Synthesis of Pentamidine Congenersa

Reagents and conditions: (i) Cu2O, pyr, 100 °C; (ii) Me2AlNH2, o-xylene, 110−120 °C, 3 h; (iii) pyr. hydrochloride, 170−180 °C, 3 h; (iv) K2CO3, DMF, 80−100 °C, 14 h.

a

10414


Chemical Reviews

Review

possessed strong activity (IC50 = 0.48 μM). Moreover, diimidazoline 941 also demonstrating the highest selectivity against L. donovani (SI = 35) and its selectivity was higher than pentamidine.396

Scheme 50. Synthesis of Pyrazolopyridine Derivativesa

8.24. Glycosyl Ureides

Tiwari et al.403 synthesized the phenylene-bridged C2symmetric glycosyl ureides 947a,b by addition of β-glycosyl β-amino ester 945404,405 to 1,3- and 1,4-phenylene diisocyanates 946a,b.406 Subsequent reduction of the ureides with LiAlH4 furnished the respective phenylene-bridged glycosyl amino alcohols 948 and 949 in very good yields (Scheme 49). Scheme 49. Synthesis of Phenylene-Bridged C2-Symmetric Glycosyl Ureidesa

a

Reagents and conditions: (i) Diethyl ethoxymethylenemalonate, EtOH; (ii) POCl3, Δ; (iii) substituted aniline, Δ; (iv) 4-hydroxyaniline, Δ; (v) (CH3CH2)2NH, HCOH, 2-propanol.

8.26. Thiadiazoles a

A selected target library of compounds 966−975 was synthesized by an efficient process which began with the NH4Fe(SO4)2-mediated oxidative cyclization of 962a−c,414−416 yielding compounds 963a−c. Subsequent diazotization and chlorination with NaNO2 in hydrochloric acid afforded 964a− c, which were then treated with an equivalent of thiourea in refluxing EtOH to produce 965a−c.417 Finally, reaction of compounds 965a−c with various phenacyl bromides gave compounds 966−971, and treatment of 965a,b with the appropriate aromatic chlorides afforded the target compounds 973−975 (Scheme 51). All of the compounds (966−975) showed strong antileishmanial activities toward L. major, and IC50 values were determined to be in the range from 1.11 to 1.85 μM. In order to conduct a SAR study, various types of nitroheterocycles and bulky pendant groups attached to the 1,3,4-thiadiazole ring were selected. A comparison of the IC50 values for the different nitroaryl derivatives revealed that these compounds had very similar activities, and the observed differences as a function of any contribution by these groups were not very significant. Regioisomeric chlorine substitution and α-methyl branching on the pendant phenacylthio group did not improve the activity at concentrations less than 1.11 μM. The results for the α-methyl benzyl derivative (compound 975) and the α-methylphenacyl analogues (compounds 973 and 974) suggested that the carbonyl group may not be essential for optimum activity.414 In an attempt to optimize their antileishmanial activity, Tahghighi et al.418 prepared a series of 5-(5-nitrofuran-2-y1)1,3,4-thiadiazoles 982−985, and the synthetic route is illustrated in Scheme 52. First, 4-(piperazin-1-yl)benzonitrile

Reagents and conditions: (i) Dry CH2Cl2, Δ; (ii) LiAlH4, THF, 0 °C.

Interestingly, compound 949 showed 100% inhibition against promastigotes at concentrations of between 50 and 25 μg/mL. Similarly, compound 948 displayed 100% inhibition against promastigotes at a concentration of 50 μg/mL. 8.25. Pyrazolopyridine Derivatives

Mello et al.407 prepared a series of pyrazolopyridine derivatives and evaluated them against the promastigote form of L. amazonensis. Synthesis began by reacting 950, obtained from condensation between methylhydrazine and β-cyanocrotonitrile, with diethyl ethoxymethylenomalonate to yield compound 951,408 which was then treated with POCl3 following Lynch’s modified procedure409 to afford 952 (Scheme 50). The target compounds 953−955 were obtained by subsequent reaction with substituted anilines. Treatment of compounds 956 and 957409,410 with 4-hydroxyaniline hydrochloride led to 958 and 959, and compounds 960 and 961 were also subsequently obtained by a Mannich-type reaction or by nucleophilic displacement with diethylaminomethyl-4-acetylaminophenol.411−413 Compounds 953−956 and 958−961 were tested against the promastigote form of L. amazonensis. The most active compounds were 954 (IC50 = 1.23 μM), 955 (IC50 = 3.9 μM), and 953 (IC50 = 4.2 μM). Comparison of the IC50 values indicated that 958−961 were the most active compounds in this series, displaying IC50 values of 0.55, 0.75, 0.39, and 0.12 μM, respectively. For comparison, amodiaquine had an IC50 of 0.89 μM.407 10415


Chemical Reviews

Review

Scheme 51. Synthesis of Thiadiazolesa

(977) was prepared by reaction between piperazine and 4fluorobenzonitrile (976). The 2-chloro-1,3,4-thiadiazole (979) was prepared according to a known procedure.419 Condensation between chlorothiadiazole 979 and piperazine 977 in refluxing ethyl methyl ketone produced compound 980. This was transformed into imine hydrochloride 981 with acidic ethanol followed by final conversion into amidines 982−985 by the Pinner reaction.420,421 The antileishmanial screening of compounds 982−985 toward L. major was evaluated using the standard MTT assay.422 The potently active compounds of the series were found to be 982, 983, 984, and 985, which exhibited IC50 values after 72 h of 0.08 ± 0.01, 0.2 ± 0.1, 0.4 ± 0.2, and 2 ± 0.2 μM, respectively. Indeed, longer alkyl chains, such as npropyl and n-butyl (compounds 982 and 983), increased the antipromastigote activity. The benzyl derivative 984 had better activity (IC50 = 0.4 ± 0.2 μM) than the 4-methoxybenzyl derivative 985 (IC50 = 2 ± 0.2 μM). The in vitro cytotoxic activities of compounds 982−985 toward mouse peritoneal macrophages were also determined. Compound 982, which showed strong in vitro activity, displayed low toxicity toward macrophages (CC50 = 785 μM), resulting in the highest selectivity index (SI = 78.5).418 8.27. Miscellaneous Compounds

Esteves et al.423 synthesized a series of new trifluralin (986) based analogues (987−993) (Scheme 53) since pure trifluralin

a

Reagents and conditions: (i) NH4Fe(SO4)2, H2O, reflux; (ii) NaNO2, HCl, Cu; (iii) thiourea, EtOH, reflux, HCl; (iv) R−X, EtOH, KOH, rt.

Scheme 53. Synthesis of Trifluralin Derivatives Scheme 52. Synthesis of 5-(5-Nitrofuran-2-y1)-1,3,4thiadiazolesa

(986) has been reported for its activity against L. donovaniinfected mice and L. infantum-infected dogs.424,425 Furthermore, some trifluralin and oryzalin derivatives were active toward C. parvum426 and L. mexicana.427 It is noteworthy that compounds 987−993 demonstrated significant activity for the intracellular amastigotes of L. infantum with IC50 values in the range 1.1−9.1 μM. Interestingly, compound 988 displayed antileishmanial activity of an order of magnitude stronger than that of miltefosine (IC50 2.2 vs 23.9 μM for L. infantum promastigotes, 0.6 vs 8.7 μM for L. donovani promastigotes, and 1.8 vs 2.7 μM for intracellular amastigotes of L. infantum). It was observed that analogues 987, 990, and 992 showed significant activity toward intracellular amastigotes of L. infantum, exhibiting IC50 values in the range from 2.5- to 5-fold lower than the IC50 of miltefosine.423 However, compounds 987 and 989−993 did not show any activity toward the promastigote form of L. donovani and L. infantum.423 Compounds 996 and 998 were efficiently synthesized by Junior et al.428 DABCO-catalyzed Morita−Baylis−Hillman reaction between either 2-naphthaldehyde (994) or 4bromobenzaldehyde (997) (Scheme 54) and acrylonitrile at

a Reagents and conditions: (i) piperazine, ethyl methyl ketone, K2CO3, reflux; (ii) thiosemicarbazide, EtOH, reflux; (iii) NH4Fe(SO4)2· 12H2O, H2O, reflux; (iv) NaNO2, HCl, Cu, 0 °C to rt; (v) ethyl methyl ketone, K2CO3; (vi) CH2Cl2, EtOH, HCl, rt; (vii) appropriate amine, EtOH, reflux.

10416


Chemical Reviews

Review

Scheme 54. Synthesis of Compounds 996 and 998a

Scheme 55. Synthesis of 1-Phenyl-4-(β-L-threopentofuranos-4′-yl)dihydropyridinesa

Reagents and conditions: (i) DABCO, 0 °C, 10 h, 98%; (ii) DABCO, 0 °C, 4 h, 98%.

a

low temperature (0 °C) resulted in remarkably good yields of 996 and 998. The easy one-step synthesis and promising antileishmanial activities of these simple compounds toward L. amazonensis (996 IC50 = 6.88 μg/mL; 998 IC50 = 11.06 μg/ mL) and L. chagasi (996 IC50 = 9.58 μg/mL; 998 IC50 = 14.34 μg/mL) proved to be most encouraging, and thus, based on these data it was hypothesized that an intramolecular hydrogen bond (IHB) cannot form between the nitrogen atom of the nitrile group and the vicinal hydroxyl group in 996 and 998, resulting in these groups being able to efficiently bind to the hydrogen-bond donor and acceptor groups in the enzyme’s active site, and this could explain their potent biological activities.428 The series of compounds 1002−1006 was synthesized in a one-pot procedure between glycosyl aldehydes, β-keto derivatives, substituted or unsubstituted anilines, and tetrabutylammonium hydrogensulfate (TBAHS).429 The starting xylofuranosyl dialdoses 999a−c were prepared from D-glucose according to a known procedure.405,430,431 Compound 1002 was prepared from the TBAHS-catalyzed reaction between 999a, methylacetoacetate, and 4-methoxyaniline as reported previously.432 Furthermore, condensation of xylofuranosyl dialdoses 999a−c with various anilines (1000a−e) and methyl acetoacetate (1001a) or ethyl acetoacetate (1001b) was conducted under the previously mentioned conditions to produce the corresponding 1-phenyl-4-(β-L-threo-pentofuranos-4′-yl)dihydropyridines 1002−1006 in good yields (Scheme 55).429 These compounds were screened in vitro toward transgenic L. donovani promastigotes and amastigotes (concentration of 40 μg/mL) in order to identify the most potent molecule in the series. Compounds 1002−1006 had measured IC50 values in the range of 0.75−6.18 μg/mL, and selectivity index (SI) values were in the range of 7.43−18.93. The SI values of these glycosyl dihydropyridines were found to be several-fold better than the standard miltefosine and pentamidine. Compounds 1002− 1006 were also screened for their in vivo activity toward L. donovani in an intracellular hamster model. Compound 1004 displayed a better inhibition value (58.8%) than compounds 1003, 1005, and 1006, which exhibited lower inhibitions of 44.9%, 43.9%, and 49.7%, respectively. In contrast, compound 1002 possessed only marginal activity (26.7%). The glycosyl dihydropyridines 1002−1006 additionally had better SI values than the standard drugs. Rando et al.433 synthesized various 5-nitro-2-heterocyclic benzylidene hydrazides (1010−1015) based on the structure of nifuroxazide, which is an antibacterial agent. These novel synthesized hydrazides were evaluated for their antileishmanial activity.434 The library of compounds was prepared in three

Reagents and conditions: (i) TBAHS (20 mol %), digol, 80 °C, 5−6 h.

a

steps by solution-phase parallel syntheses via classical synthetic procedures, as illustrated in Scheme 56.435 Scheme 56. Synthesis of 5-Nitro-2-heterocyclic Benzylidene Hydrazidesa

a

Reagents and conditions: (i) MeOH, H2SO4, reflux; (ii) NH2NH2; (iii) EtOH:H2O (70:30).

Synthetic analogues 1010−1015 were screened in vitro toward the promastigote form of L. donovani at concentrations ranging from 10 to 0.01 μg/mL. The nitro derivatives all exhibited very encouraging antileishmanial activities. The nitrothiophene analogues 1010 (IC50 1.26 μM), 1011 (IC50 0.89 μM), 1012 (IC50 0.82 μM), and 1013 (IC50 0.41 μM) and the nitrofuran analogues 1014 (IC50 1.68 μM) and 1015 (IC50 0.62 μM) all exhibited activities that were higher than or comparable to the standard drugs.433 Dardari et al.436 synthesized 4-[2-(1-ethylamino-2-methylpropyl)-phenyl]-3-(4-methylphenyl)-1-phenylpyrazole (1019) from compound 1018, which in turn was prepared by reacting dipolarophile 1016 with (Z)-1-(chloro(p-tolyl)methylene)-2phenylhydrazine (1017) (Scheme 57). Interestingly, compound 1019 showed potent activity toward L. major (IC50 = 10417


Chemical Reviews

Review

0.63 μg/mL), L. tropica (IC50 = 0.48 μg/mL), and L. infantum (IC50 = 0.40 μg/mL).436

replicative helicases RepA and double-stranded DNA-unwinding potential of the enzyme.444,445 In a further study, Das et al.445 reported baicalein (1025), luteolin (1026), and quercetin (156) (Figure 59) displayed potent activity toward L. donovani

Scheme 57. Synthesis of Phenylpyrazole 1019a


bisubunit topoisomerase I. Interaction of flavones 1025, 1026, and 156 with the free enzyme was demonstrated in a range of experiments, and this observation was already reported in the literature.440,443−445 Some authors suggested that flavones 1025, 1026, and 156 were able to bind DNA because of the C2/C3 double bond of the C ring.442 Interestingly, compounds 1025, 1026, and 156 showed strong activity toward L. donovani topoisomerase I at low concentrations (3, 5, and 15 μM, respectively). Chowdhury and co-workers116 reported that dihydro betulinic acid (DHBA, 1027) (Figure 59), a derivative of betulinic acid, also displayed potent activity toward DNA topoisomerase I and II from of L. donovani promastigotes and amastigotes. It was shown that DHBA prevented interaction between the enzyme and the substrate DNA. The study also showed that DHBA was different from other topoisomerase inhibitors, such as camptothecin,446 etoposide,447 amsacrine,447 and doxorubicin,448 and its activity parallels the known class II inhibitors such as merbarone,449 aclarubicin,448 and chloroquine.450 DHBA demonstrated inhibitory effects toward L. donovani promastigotes with IC50 values of 4.1, 3.2, and 2.6 μM for a period of 24, 48, and 72 h. However, the 17decarboxylated analogue of DHBA known as dihydrolupeol exhibited no inhibitory effect on topoisomerases.116 Peganine hydrochloride (1028) is another example of a topoisomerase inhibitor which was isolated from Syrian Rue (Peganum harmala), an important medicinal plant used in India.451 Peganine hydrochloride (1028) (Figure 60) caused

a

Reagents and conditions: (i) Et3N, C6H6, reflux, 48 h; (ii) EtOH, reflux, 4 h.

Hiam et al.437 evaluated various 3-haloacetamidobenzoıc acid derivatives (1020−1024) (Figure 58) for their antileishmanial

Figure 58. Structures of 3-haloacetamidobenzoıc acid derivatives (1020−1024).

activity against L. majori, L. mexicana, and L. infantum, and these compounds additionally showed strong activity against cancerous cells.437 Interestingly, compounds 1020−1024 all demonstrated potent activity toward promastigotes and intracellular amastigotes of L. mexicana, having IC50 values ranging between 0.3−1.8 and 0.1−1.2 μM, respectively. Compound 1022 also possessed leishmanicidal activity toward L. infantum, L. mexicana, and L. major and additionally exhibiting good IC50 values of lower than 1.8 μM. All of the compounds exhibited good activity (0.1−0.6 μM) toward the intracellular amastigote stage, and 1022 (IC50 = 0.33 μM) was between 3- and 400-fold more active than taxol (IC50 = 0.90 μM) and meglumine antimoniate (IC50 = 133 μM), respectively.437 The in vivo antileishmanial potential was performed (10 mg/kg) against L. major-infected BALB/c mice and showed potent infection reduction (liver 96%, spleen 97%, and poplitea ganglion 59%), which was better than the reference compound meglumine antimoniate (liver 74%, spleen 82%, and poplitea ganglion 44%).437


9. ACTIVITY AGAINST ESSENTIAL LEISHMANIAL ENZYMES Flavones are strong inhibitors of monomeric topoisomerase I and topoisomerase II.438−443 Sengupta et al.443 reported that luteolin displayed activity toward L. donovani topoisomerase II. Additionally, flavones also showed activity toward hexameric

DNA fragmentation in both promastigotes and internalized amastigote forms of L. donovani with IC50 values of 0.2 and 0.22 mM, respectively. A docking study demonstrated that the apoptosis processes were mediated by direct interaction with the enzyme topoisomerase I. The study showed that peganine hydrochloride (1028) formed a strong complex with the Ld10418


Chemical Reviews

Review

strated that LdTOP1Δ39LS had roughly a 15-fold decrease in the catalytic-center activity compared with LdTOP1LS.465 The results furthermore clearly illustrated that the N-terminal 39 residues of LdTOP1L were not critical for inhibition of relaxation activity by alkaloid 1030.455 Nerolidol (227) is a sesquiterpene present in many different plant species. Arruda and co-workers18,185 reported on the antileishmanial activity of nerolidol (226) and demonstrated that this compound had leishmanicidal activity for all of the Leishmania species tested. Furthermore, inhibition of isoprenoid biosynthesis was noticeable in nerolidol-treated promastigotes (30 μM). Possibly, the activity for compound (226) could be attributed to blockage of the mevalonate pathway.185

topo I enzyme and that this complex inhibited enzyme activity.451 Nafisi and co-workers452 showed that the alkaloid harmaline (1029) binds with DNA (Kharmaline−DNA = 3.82 × 105 M−1). However, Giorgio and co-workers453 demonstrated that the same alkaloid (1029) displayed potent antileishmanial activity toward the amastigote form. They also showed that 1029 was not able to induce nitric oxide production by infected macrophages but rather inhibited leishmanial PKC activity.453,454 3,3′-Di-indolylmethane (1030) is a type of novel topoisomerase inhibitor455 and has an anticarcinogenic effect on different cancer cells.456−462 Recently, Gong et al.463 showed that 1030 is a novel topoisomerase IIα catalytic inhibitor in human hepatoma HepG2 cells and also inhibited topoisomerase I at high concentrations. Roy et al.455 demonstrated that compound 1030 inhibited L. donovani topoisomerase I and displayed potent activity toward LdTOP1S (L. donovani topoisomerase I small subunit) and stabilized the cleavable complex similar to CPT. Subsequent cellular studies (SDS−K+ precipitation assay) revealed that in vivo alkaloid 1030 additionally induced stabilization of covalent topoisomerase I−DNA cleavable complex in the promastigote form of L. donovani. These results showed that in vivo a cleavable complex is induced by alkaloid 1030, which is a substrate for topoisomerase I. It has been confirmed from both in vitro and in vivo experiments that alkaloid 1030 is a class I inhibitor of topoisomerase I, which acts as a topoisomerase poison, and also that it inhibited the subsequent relegation reaction in a similar way to CPT. Furthermore, it was demonstrated that alkaloid 1030 is a noncompetitive inhibitor, as it binds both the enzyme (LdTOP1LS) and the enzyme−substrate complex (LdTOP1LS−DNA complex). Alkaloid 1030 also inhibited the catalytic activity of the enzyme (LdTOP1LS) in both simultaneous and preincubation relaxation assays. Experiments demonstrated that the KD value of alkaloid 1030−enzyme interaction was 9.73 × 10−9 M, which was indicative of a high affinity and strong binding of it to the enzyme. Alkaloid 1030 also exhibited a differential affinity toward LdTOP1L and LdTOP1S. The results showed that LdTOP1S had an 8.6-fold higher binding affinity for alkaloid 1030 compared with LdTOP1L. In 2006, Gong et al.463 reported alkaloid 1030 to be a catalytic inhibitor of human topoisomerase IIα. They also reported that 1030 cannot stabilize cleavable complexes with human topoisomerase I and topoisomerase II in human hepatoma (HepG2) cells.463 It has further been reported463 that alkaloid 1030 has a very high affinity for Leishmania topoisomerase I, and it also been proposed that apart from binding to the substrate-binding pocket, the drug also binds strongly to a region on LdTOP1S. In previous studies by Ganguly et al.,464 they reported that the subtle differences around the active site, viz., the tyrosine residue between L. donovani and human topoisomerase I, might affect their interactions with alkaloid 1030 in the same way that it affects their catalytic cycles in order to poison L. donovani topoisomerase but not human topoisomerase I. Due to the uncertainty of the exact mechanism of activity, Roy et al.455 investigated the effect of alkaloid 1030 on a CPTresistant mutant enzyme LdTOP1Δ39LS (N-terminal deletion of amino acids 1−39 of LdTOP1LS) lacking 1−39 amino acids of the N-terminus of LdTOP1L.465 Data obtained demon-

10. CONCLUSIONS AND FUTURE PROSPECTS Leishmaniasis is present in more than 88 countries and affects more than 12 million people. Therefore, safe, nontoxic, and highly specifically active drugs with the least side effects are urgently required for effective treatment of people suffering from leishmaniasis. The potential sources, namely, natural products and synthetically designed compounds as new antileishmanial hits, necessitate inclusion of a comprehensive discussion on biochemical differences between protozoa and their hosts. Further research by international groups is required to develop a precise and focused determination of leishmanial targets for development of plant-derived natural products and synthetic compounds which are described in this review. Importantly, natural products, viz., canthin-6-one (34) and 5methoxycanthin-6-one (35), γ-fagarine (97), 3,3′-di-indolylmethane (103), flavokavin B (125), quercetin (156), nerolidol (227), 16-hydroxy-clerod-3,13(14)-diene-15,16-olide (239), maesabalides III (265) and IV (266), and isoannonacin (270), displayed in vivo antileishmanial activities. Moreover, some synthetic compounds, viz., 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide (464), compounds 538a, 611, 618, 624, 799, 801, 827, 886, 896, 1002−1006, and 1022, also demonstrated in vivo antileishmanial activities. Appreciable activity and encouraging selectivity indices have been found in them. Some diverse and unusually active molecules have also been isolated from natural sources, and transformation of their structural scaffold features will lead the way for the design and construction of new synthetic compounds to be evaluated as future potential lead drug candidates. Discoveries that have been made to date are generally by the major research groups undertaking maximum exploration of natural sources using numerous advanced and sophisticated techniques for purification and characterization of novel molecules and their use as metabolites. There is little doubt that employing these modern techniques to their full potential will result in isolation of more specific antileishmanial drug candidates in the near future. There is, however, a critical need for inexpensive, rapid, and reproducible analytical techniques to screen as many new candidate compounds as possible for treatment of leishmaniasis. Considering these factors and the infrastructurally relatively poorly endowed countries of the affected populations of this disease, it is abundantly clear that large pharmaceutical companies will have to make huge efforts to strengthen their parasitic disease research programs. However, militating against this are the huge profit margins which drive such companies versus the cost of the research as well as the time needed for a new effective 10419


Chemical Reviews

Review

product to finally reach the patients. Therefore, to balance this urgency, any major drug discovery effort would have to come from academic research institutions, which is our finding based on the evidence of this current review. One would therefore hope that from the large library of compounds mentioned in this detailed review, when complemented by comprehensive studies (in vitro and in vivo), a reasonable range of new lead structures may enter and supplement the current leishmanicidal drug development pipeline.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected].

Ahmed Al-Harrasi received his B.Sc. degree in Chemistry from Sultan Qaboos University (Oman) in 1997. Then he moved to the Free University of Berlin from which he obtained his M.Sc. degree in Chemistry in 2002 and then his Ph.D. degree in Organic Chemistry in 2005 as a DAAD fellow under the supervision of Professor HansUlrich Reissig. His Ph.D. work was on New Transformations of Enantiopure 3,6-Dihydro-2H-1,2-oxazines. Then he received the Fulbright award in 2008 for postdoctoral research in chemistry for which he joined Professor Tadhg Begely’s group at Cornell University, where he worked on the synthesis of isotopically labeled thiamin pyrophosphate. His current research focuses on the drug discovery from Omani medicinal plants and marine species as well as on the synthesis of biologically active compounds. He is currently the Chairperson of the Chair of Oman’s Medicinal Plants and Marine Natural Products and Assistant Dean for Graduate Studies and Research at the University of Nizwa, Oman. He has several funded projects with a budget that exceeds $2,000,000 (US). He has authored and coauthored over 90 scientific papers.

Notes

The authors declare no competing financial interest. Biographies

Hidayat Hussain obtained his B.Sc. degree from the Post Graduate College Parachinar and his M.Sc. degree from Gomal University Dera Ismail Khan, Pakistan. He received his Ph.D. degree from the H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Pakistan, in Synthetic Organic Chemistry and Natural Product Chemistry. From June 2004 to September 2007 he was a postdoctoral fellow at the University of Paderborn, Germany, under the supervision of Professor Karsten Krohn. He was awarded a Region Pays de la Loire postdoctoral fellowship and worked at the Laboratory of Organic Synthesis, University of Maine, Le Mans, France, with Dr. Gilles Dujardin for 1 year. His research topic was asymmetric Robinson annulation via [4 + 2] heterocycloadditions and the design and synthesis of a tin catalyst for [4 + 2] heterocycloadditions. In December 2008, he rejoined the group of Professor Karsten Krohn as senior postdoctoral associate, working until October 2010. Currently, he is working at UoN as Chair of Oman’s Medicinal Plants and Marine Natural Products, University of Nizwa, Oman. His research interests include the design and synthesis of anticancer, antidiabetic, antimalarial, and antimicrobial compounds, asymmetric catalysis of [4 + 2] heterocycloadditions, total synthesis of anthrapyran antibiotics, and biodiversity and characterization of natural products produced by endophytic microorganisms and plants. To date he has authored and coauthored over 165 international publications with cumulative impact factor of more than 300 and given 15 podium lectures at International Conferences. He is a referee for over 20 international journals.

Ahmed Al Rawahi was born in Izki, Oman, in 1963 and received his primary and secondary education in Oman. Awarded a full scholarship from the Omani Government, he was awarded his B.Sc. degree in Biological Sciences with Honors from North Carolina State University in 1988. He joined Sultan Qaboos University (SQU) in 1988 as a technician and teaching assistant in the College of Agriculture. Two years later, he joined the University of California at Berkeley, where he received his M.Sc. in 1992 and Ph.D. degree in Plant Pathology in 1995. Upon his return to SQU he was appointed Lecturer, where he taught several courses in the field of Plant Pathology and Microbiology as well as conducted and initiated several research topics in soil-borne pathogens, biocontrol, and disease management programs. In December 1997 he was honored by his appointment as Minister of Agriculture and Fisheries, where he played a major role in developing various strategies and development plans for these vital sectors of the 10420


Chemical Reviews

Review

Pierre Fabre Prize for Phytochemistry and in 2012 was recipient of the Pharmanex Prize. He is founding Editor-in-Chief of Phytochemistry Letters and serves on the Editorial Boards of Natural Product Reports, Planta Medica, Phytochemical Analysis, Phytochemistry Reviews, Phytotherapy Research, Fitoterapia, Progress in the Chemistry of Organic Natural Products, The Chinese Journal of Natural Medicine, and Scientia Pharmaceutica. His research is on antimicrobial phytochemicals, natural product bacterial-resistance modifying agents, and novel psychoactive substances and has authored over 150 publications in these areas.

Omani economy. From 2001, he has served as a member of the State Council holding several positions, such as Chairman of the Economic Committee and Development Plans Implementation Follow-up Committee, where he has served energetically in the conduct of important studies and issuing reports for the government. From April 2000 onwards, he has served as a core-founding member, Chairman of the Academic Foundation Committee, and General Secretary of the Higher Foundation Committee for the University of Nizwa Project. In 2004, he was appointed as Chancellor of the University of Nizwa, where he embarked on bringing the project to reality, creating a functioning campus that adheres to quality standards, ethics, and procedures. In December 2006, he was promoted to the academic position of Founding Professor by the scholarly independent academic committee.

REFERENCES (1) Renslo, A. R.; McKerrow, J. H. Nat. Chem. Biol. 2006, 2, 701. (2) Mishra, B. B.; Kale, R. R.; Singh, R. K.; Tiwari, V. K. Fitoterapia 2009, 80, 81. (3) Balana-Fouce, R.; Reguera, R. M.; Cubria, J. C.; Ordonez, D. Gen. Pharmacol. 1998, 30, 435. (4) Jean-Robert, I. Curr. Org. Chem. 2008, 12, 643. (5) Rahman, A. U.; Samreen; Wahab, A. T.; Choudhary, M. I. Pure Appl. Chem. 2008, 80, 1783. (6) Delorenzi, J. C.; Attias, M.; Gattass, C. R.; Andrade, M.; Rezende, C.; Pinto, A. D.; Henriques, A. T.; Bou-Habib, D. C.; Saraiva, E. M. B. Antimicrob. Agents Chemother. 2001, 45, 1349. (7) Gontijo, C. M. F.; Melo, M. N. Rev. Bras. Epidemiol. 2004, 7, 338. (8) Santos, D. O.; Coutinho, C. E. R.; Madeira, M. F.; Bottino, C. G.; Vieira, R. T.; Nascimento, S. B.; Bernardino, A.; Bourguignon, S. C.; Corte-Real, S.; Pinho, R. T.; Rodrigues, C. R.; Castro, H. C. Parasitol. Res. 2008, 103, 1. (9) Weniger, B.; Robledo, S.; Arango, G. J.; Deharo, E.; Aragon, R.; Munoz, V.; Callapa, J.; Lobstein, A.; Anton, R. J. Ethnopharmacol. 2001, 78, 193. (10) Gontijo, B.; Carvalho, M. L. R. Rev. Soc. Bras. Med. Trop. 2003, 36, 71. (11) Pal, S.; Ravindran, R.; Ali, N. Antimicrob. Agents Chemother. 2004, 48, 3591. (12) Oliveira, C. C.; Lacerda, H. G.; Martins, D. R.; Barbosa, J. D.; Monteiro, G. R.; Queiroz, J. W.; Sousa, J. M.; Ximenesf, M. F.; Jerônimo, S. M. Acta Trop. 2004, 90, 155. (13) Chan-Bacab, M. J.; Pena-Rodríguez, L. M. Nat. Prod. Rep. 2001, 18, 674. (14) Rocha, L. G.; Almeida, J. R. G. S.; Macedo, R. O.; Barbosa-Filho, J. M. Phytomedicine 2005, 12, 514. (15) Tempone, A. G.; Oliveira, C. M.; Berlinck, R. G. S. Planta Med. 2011, 77, 572. (16) Sen, R.; Chatterjee, M. Phytomedicine 2011, 18, 1056. (17) Fotie, J. Natural Products and Protozoan Neglected Diseases: Malaria, Trypanosomiasis and Leishmaniasis. In Natural Products: Chemistry, Biochemistry and Pharmacology; Brahmachari, G., Ed.; Narosa Publishing House PVT. LTD and Alphascience International: New Delhi and Oxford, 2008; pp 137−193. (18) Polonio, T.; Efferth, T. Int. J. Mol. Med. 2008, 22, 277. (19) Rodrigues, I. A.; Amaral, A. C. F.; Rosa, M. S. S. Curr. Enzyme Inhib. 2011, 7, 32. (20) Assche, T. V.; Deschacht, M.; Inocêncio da Luz, R. A.; Maes, L.; Cos, P. Free Radical Biol. Med. 2011, 51, 337. (21) Bern, C.; Maguire, J. H.; Alvar, J. PLoS Neglected Trop. Dis. 2008, 2, e313. (22) Eissa, M. M.; Amer, E. I.; El Sawy, S. M. F. Exp. Parasitol. 2011, 128, 382. ́ Smith, C. D., (23) Vande Waa, E. A.; Tracy, J. W. In Farmacologia; Reynard, A. M., Eds.; Médica Panamericana: Argentina, 1993; pp 875−877. (24) Singh, S. P.; Reddy, D. C.; Rai, M.; Sundar, S. Trop. Med. Int. Health 2006, 11, 899. (25) Singh, V. P.; Ranjan, A.; Topno, R. K.; Verma, R. B.; Siddique, N. A.; Ravidas, V. N.; Kumar, N.; Pandey, K.; Das, P. Am. J. Trop. Med. Hyg. 2010, 82, 9.

Ivan R. Green graduated with his Ph.D. degree in Organic Chemistry in 1973 from the University of Cape Town. He was made a Full Professor in 1986 and Senior Professor in 1990 at the University of the Western Cape, where he lectured for 39 years until his retirement in July 2011.To date he has authored and coauthored over 130 scientific publications, given 40 podium lectures at international conferences, and supervised 30 M.Sc. and 18 Ph.D. students locally and 6 Ph.D. students internationally. He is a referee for 8 international journals. Upon retirement he moved to the University of Stellenbosch, where he is involved in mentoring research students, writing articles, giving seminars, and alkaloid and kinase inhibition research.

Simon Gibbons is Professor of Medicinal Phytochemistry and Head of the Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy. He is a member of the U.K. Government’s Advisory Council on the Misuse of Drugs (ACMD) and Chairman of the Novel Psychoactive Substances Committee. He attended Kingston Polytechnic (B.Sc. degree in Chemistry 1989), Britannia Royal Naval College Dartmouth, and Strathclyde University (Ph.D. degree). In 2005 he was the recipient of the Phytochemical Society of Europe− 10421


Chemical Reviews

Review

(26) Dujardin, J. C.; Campino, L.; Cañavate, C.; Dedet, J. P.; Gradoni, L.; Soteriadou, K.; Mazeris, A.; Ozbel, Y.; Boelaert, M. Emerging Infect. Dis. 2008, 14, 1013. (27) Ready, P. D. Euro Surveill. 2010, 15, 19505. (28) Maroli, M.; Rossi, L.; Baldelli, R.; Capelli, G.; Ferroglio, E.; Genchi, C.; Gramiccia, M.; Mortarino, M.; Pietrobelli, M.; Gradoni, L. Trop. Med. Int. Health 2008, 13, 256. (29) Morosetti, G.; Bongiorno, G.; Beran, B.; Scalone, A.; Moser, J.; Gramiccia, M.; Gradoni, L.; Maroli, M. Geospat. Health 2009, 4, 115. (30) Biglino, A.; Bolla, C.; Concialdi, E.; Trisciuoglio, A.; Romano, A.; Ferroglio, E. J. Clin. Microbiol. 2010, 48, 131. (31) Naucke, T. J.; Schmitt, C. Int. J. Med. Microbiol. 2004, 293, 179. (32) Naucke, T. J.; Menn, B.; Massberg, D.; Lorentz, S. Parasitol. Res. 2008, 103, S65. (33) Postigo, J. A. Int. J. Antimicrob. Agents 2010, 36, S62. (34) Mosleh, I. M.; Geith, E.; Natsheh, L.; Abdul-Dayem, M.; Abotteen, N. Trop. Med. Int. Health 2008, 13, 855. (35) Romero, G. A.; Boelaert, M. PLoS Neglected Trop. Dis. 2010, 4, e584. (36) Killick-Kendrick, R.; Molineux, W. Trans R. Soc. Trop. Med. Hyg. 1981, 75, 152. (37) Ponte-Sucre, A. Kinetoplastid Biol. Dis. 2003, 2, 14. (38) Chang, K. P.; Reed, S. G.; McGwire, B. S.; Soong, L. Acta Trop. 2003, 85, 375. (39) DosReis, G. An. Acad. Bras. Cienc. 2000, 72, 79. (40) Ismaeel, A. Y.; Garmson, J. C.; Molyneux, D. H.; Bates, P. A. Am. J. Trop. Med. Hyg. 1998, 59, 421. (41) Zilberstein, D.; Shapira, M. Annu. Rev. Microbiol. 1994, 48, 449. (42) Marchesini, N.; Docampo, R. Mol. Biochem. Parasitol. 2002, 119, 225. (43) Turco, S. J.; Sacks, D. L. Mol. Biochem. Parasitol. 1991, 45, 91. (44) Muylder, G. D.; Ang, K. K. H.; Chen, S.; Arkin, M. R.; Engel, J. C.; McKerrow, J. H. PLoS Neglected Trop. Dis. 2011, 5, e1253. (45) Fumarola, L.; Spinelli, R.; Brandonisio, O. Res. Microbiol. 2004, 155, 224. (46) Siqueira-Neto, J. L.; Song, O. R.; Oh, H.; Sohn, J. H.; Yang, G. PLoS Neglected Trop. Dis. 2010, 4, e675. (47) Sharlow, E. R.; Close, D.; Shun, T.; Leimgruber, S.; Reed, R. PLoS Neglected Trop. Dis. 2009, 3, e540. (48) Croft, S. L.; Coombs, G. H. Trends Parasitol. 2003, 19, 502. (49) Pratt, D. M.; David, J. R. Nature 1981, 291, 581. (50) Lainson, R.; Shaw, J. J. The leishmaniases in biology and medicine. In Evolution, classification and geographical distribution; Peters, W., Killick-Kendrick, R., Eds.; Academic Press: London, 1987; pp 1−120. (51) Antinori, S.; Schifanella, S.; Corbellino, M. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 109. (52) Rioux, J. A.; Lanotte, G.; Serres, E.; Pratlong, F.; Bastien, P.; Perieres, J. Ann. Parasitol. Hum. Comp. 1990, 65, 111. (53) Pearson, R. D.; Jeronimo, S. M. B.; Sousa, A. Q. In Principles and Practices of Clinical Parasitology. Leishmaniasis; Gillespie, S., Pearson, R. D., Eds.; John Wiley and Sons Ltd.: New York, 2001; pp 287−313. (54) Fraga, J.; Montalvo, A. M.; De Doncker, S.; Dujardin, J. C.; Van der Auwera, G. Infect. Genet. Evol. 2010, 10, 238. (55) Seifert, K. Open Med. Chem. J. 2011, 5, 31. (56) Croft, S. L.; Sundar, S.; Fairlamb, A. H. Clin. Microbiol. Rev. 2006, 19, 111. (57) Sundar, S.; More, D. K.; Singh, M. K.; Singh, V. P.; Sharma, S.; Makharia, A.; Kumar, P. C.; Murray, H. W. Clin. Infect. Dis. 2000, 31, 1104. (58) Alvar, J.; Croft, S.; Olliaro, P. Adv. Parasitol. 2006, 61, 223. (59) Olliaro, P. L.; Guerin, P. J.; Gerstl, S.; Haaskjold, A. A.; Rottingen, J. A.; Sundar, S. Lancet Infect. Dis. 2005, 5, 763. (60) Sundar, S.; Sinha, P. R.; Agrawal, N. K.; Srivastava, R.; Rainey, P. M.; Berman, J. D.; Murray, H. W.; Singh, V. P. Am. J. Trop. Med. Hyg. 1998, 59, 139. (61) Chulay, J. D.; Fleckenstein, L.; Smith, D. H. Trans. R. Soc. Trop. Med. Hyg. 1988, 82, 69.

(62) Frezard, F.; Martins, P. S.; Barbosa, M. C.; Pimenta, A. M.; Ferreira, W. A.; de Melo, J. E.; Mangrum, J. B.; Demicheli, C. J. Inorg. Biochem. 2008, 102, 656. (63) Berman, J. D.; Waddell, D.; Hanson, B. D. Antimicrob. Agents Chemother. 1985, 27, 916. (64) Berman, J. D.; Gallalee, J. V.; Best, J. M. Biochem. Pharmacol. 1987, 36, 197. (65) Wyllie, S.; Cunningham, M. L.; Fairlamb, A. H. J. Biol. Chem. 2004, 279, 39925. (66) Meyerhoff, A. Clin. Infect. Dis. 1999, 28, 42. (67) Sundar, S.; Mehta, H.; Suresh, A. V.; Singh, S. P.; Rai, M.; Murray, H. W. Clin. Infect. Dis. 2004, 38, 377. (68) Sundar, S.; Agrawal, G.; Rai, M.; Makharia, M. K.; Murray, H. W. BMJ [Br. Med. J.] 2001, 323, 419. (69) Sundar, S.; Jha, T. K.; Thakur, C. P.; Mishra, M.; Singh, V. P.; Buffels, R. Clin. Infect. Dis. 2003, 37, 800. (70) Sundar, S.; Chakravarty, J.; Agarwal, D.; Rai, M.; Murray, H. W. N. Engl. J. Med. 2010, 362, 504. (71) Sundar, S.; Mehta, H.; Chhabra, A.; Singh, V.; Chauhan, V.; Desjeux, P.; Rai, M. Clin. Infect. Dis. 2006, 42, 608. (72) Bern, C.; Adler-Moore, J.; Berenguer, J.; Boelaert, M.; den Boer, M.; Davidson, R. N.; Figueras, C.; Gradoni, L.; Kafetzis, D. A.; Ritmeijer, K.; Rosenthal, E.; Royce, C.; Russo, R.; Sundar, S.; Alvar, J. Clin. Infect. Dis. 2006, 43, 917. (73) WHO, Report of a WHO informal consultation on liposomal amphotericin B in the treatment of visceral leishmaniasis. WHO/ CDS/NTD/IDM/2007.4 2007. (74) Gradoni, L.; Davidson, R. N.; Orsini, S.; Betto, P.; Giambenedetti, M. J. Drug Targeting 1993, 1, 311. (75) Pourshafie, M.; Morand, S.; Virion, A.; Rakotomanga, M.; Dupuy, C.; Loiseau, P. M. Antimicrob. Agents Chemother. 2004, 48, 2409. (76) Brajtburg, J.; Bolard, J. Clin. Microbiol. Rev. 1996, 9, 512. (77) Sindermann, H.; Engel, J. Trans. R. Soc. Trop. Med. Hyg. 2006, 100, S17. (78) Bhattacharya, S. K.; Sinha, P. K.; Sundar, S.; Thakur, C. P.; Jha, T. K.; Pandey, K.; Das, V. R.; Kumar, N.; Lal, C.; Verma, N.; Singh, V. P.; Ranjan, A.; Verma, R. B.; Anders, G.; Sindermann, H.; Ganguly, N. K. J. Infect. Dis. 2007, 196, 591. (79) Seifert, K.; Matu, S.; Javier Perez-Victoria, F.; Castanys, S.; Gamarro, F.; Croft, S. L. Int. J. Antimicrob. Agents 2003, 22, 380. (80) Seifert, K.; Perez-Victoria, F. J.; Stettler, M.; Sanchez-Canete, M. P.; Castanys, S.; Gamarro, F.; Croft, S. L. Int. J. Antimicrob. Agents 2007, 30, 229. (81) Lux, H.; Hart, D. T.; Parker, P. J.; Klenner, T. Adv. Exp. Med. Biol. 1996, 416, 201. (82) Lux, H.; Heise, N.; Klenner, T.; Hart, D.; Opperdoes, F. R. Mol. Biochem. Parasitol. 2000, 111, 1. (83) Luque-Ortega, J. R.; Rivas, L. Antimicrob. Agents Chemother. 2007, 51, 1327. (84) Rakotomanga, M.; Blanc, S.; Gaudin, K.; Chaminade, P.; Loiseau, P. M. Antimicrob. Agents Chemother. 2007, 51, 1425. (85) Sundar, S.; Agrawal, N.; Arora, R.; Agarwal, D.; Rai, M.; Chakravarty, J. Clin. Infect. Dis. 2009, 49, 914. (86) Davidson, R. N.; den Boer, M.; Ritmeijer, K. Trans. R. Soc. Trop. Med. Hyg. 2009, 103, 653. (87) Maarouf, M.; Lawrence, F.; Croft, S. L.; Robert-Gero, M. Parasitol. Res. 1995, 81, 421. (88) Maarouf, M.; de Kouchkovsky, Y.; Brown, S.; Petit, P. X.; Robert-Gero, M. Exp. Cell. Res. 1997, 232, 339. (89) Maarouf, M.; Lawrence, F.; Brown, S.; Robert-Gero, M. Parasitol. Res. 1997, 83, 198. (90) Maarouf, M.; Adeline, M. T.; Solignac, M.; Vautrin, D.; RobertGero, M. Parasite 1998, 5, 167. (91) Jhingran, A.; Chawla, B.; Saxena, S.; Barrett, M. P.; Madhubala, R. Mol. Biochem. Parasitol. 2009, 164, 111. (92) Vercesi, A. E.; Docampo, R. Biochem. J. 1992, 284, 463. (93) Vercesi, A. E.; Rodrigues, C. O.; Catisti, R.; Docampo, R. FEBS Lett. 2000, 473, 203. 10422


Chemical Reviews

Review

(125) Bringmann, G.; Dreyer, M.; Faber, J. H.; Dalsgaard, P. W.; Staerk, D.; Jaroszewski, J. W.; Ndangalasi, H.; Mbago, F.; Brun, R.; Christensen, S. B. J. Nat. Prod. 2004, 67, 743. (126) Cazorla, D.; Yepez, J.; Anez, N.; Sanchez, M. A. Invest. Clin. 2001, 42, 5. (127) Muhammad, I.; Dunbar, D. C.; Khan, S. I.; Tekwani, B. L.; Bedir, E.; Takamatsu, S.; Ferreira, D.; Walker, L. A. J. Nat. Prod. 2003, 66, 962. (128) Camacho, M. R.; Phillipson, J. D.; Croft, S. L.; Rock, P.; Marshall, S. J.; Schiff, P. L. Phytother. Res. 2002, 16, 432. (129) Gonzaleza, P.; Marına, C.; Rodrıguez-Gonzaleza, I.; Hitosa, A. B.; Rosalesa, M. J.; Reinab, M.; Dıazc, J. G.; Gonzalez-Colomad, A.; Sanchez-Morenoa, M. Int. J. Antimicrob. Agents 2005, 25, 136. (130) Salem, M. M.; Werbovetz, K. A. Curr. Med. Chem. 2006, 13, 2571. (131) Ahua, K. M.; Ioset, J. R.; Ransijn, A.; Mauel, J.; Mavi, S.; Hostettmann, K. Phytochemistry 2004, 65, 963. (132) Mwangi, E. S. K.; Keriko, J. M.; Machocho, A. K.; Wanyonyi, A. W.; Malebo, H. M.; Chhabra, S. C.; Tarus, P. K. J. Med. Plants Res. 2010, 4, 726. (133) Ferreira, M. E.; Rojas, A. A.; Torres, O. S.; Inchausti, A.; Nakayama, H.; Thouvenel, C.; Hocquemiller, R.; Fournet, A. J. Ethnopharmacol. 2002, 80, 199. (134) Giorgio, C. D.; Lamidi, M.; Delmas, F.; Balansard, G.; Ollivier, E. Planta Med. 2006, 72, 1396. (135) Rao, K. V.; Santarsiero, B. D.; Mesecar, A. D.; Schinazi, R. F.; Tekwani, B. L.; Hamann, M. T. J. Nat. Prod. 2003, 66, 823. (136) Rao, K. V.; Kasanah, N.; Wahyuono, S.; Tekwani, B. L.; Schinazi, R. F.; Hamann, M. T. J. Nat. Prod. 2004, 67, 1314. (137) Rao, K. V.; Donia, M. S.; Peng, J.; Garcia-Palomero, E.; Alonso, D.; Martinez, A.; Medina, M.; Franzblau, S. G.; Tekwani, B. L.; Khan, S. I.; Wahyuono, S.; Willett, K. L.; Hamann, M. T. J. Nat. Prod. 2006, 69, 1034. (138) Tanaka, J. C. A.; da Silva, C. C.; Ferreira, I. C. P.; Machado, G. M. C.; Leon, L. L.; de Oliveira, A. J. B. Phytomedicine 2007, 14, 377. (139) Copp, B. R.; Kayser, O.; Brun, R.; Kiderlen, A. F. Planta Med. 2003, 69, 527. (140) Hua, H. M.; Peng, J.; Dunbar, D. C.; Schinazi, R. F.; de Castro Andrews, A. G.; Cuevas, C.; Garcia-Fernandez, L. F.; Kelly, M.; Hamann, M. T. Tetrahedron 2007, 63, 11179. (141) Devkota, K. P.; Choudhary, M. I.; Ranjit, R.; Samreen; Sewald, N. Nat. Prod. Res. 2007, 21, 292. (142) Devkota, K. P.; Lenta, B. N.; Wansi, J. D.; Choudhary, M. I.; Kisangau, D. P.; Naz, Q.; Samreen; Sewald, N. J. Nat. Prod. 2008, 71, 1481. (143) Devkota, K. P.; Wansi, J. D.; Lenta, B. N.; Khan, S.; Choudhary, M. I.; Sewald, N. Planta Med. 2010, 76, 1022. (144) Scala, F.; Fattorusso, E.; Menna, M.; Taglialatela-Scafati, O.; Tierney, M.; Kaiser, M.; Tasdemir, D. Mar. Drugs 2010, 8, 2162. (145) Ferreira, M. E.; Arias, A. R.; Yaluff, G.; Bilbao, N. V.; Nakayama, H.; Torres, S.; Schinini, A.; Guy, I.; Heinzen, H.; Fournet, A. Phytomedicine 2010, 17, 375. (146) Rahman, A. A.; Samoylenko, V.; Jacob, M. R.; Sahu, R.; Jain, S. K.; Khan, S. I.; Tekwani, B. L.; Muhammad, I. Planta Med. 2011, 77, 1639. (147) Kerr, R. G.; Kerr, S. S. Expert Opin. Ther. Pat. 1999, 9, 1207. (148) Nakao, Y.; Shiroiwa, T.; Murayama, S.; Matsunaga, S.; Goto, Y.; Matsumoto, Y.; Fusetani, N. Mar. Drugs 2004, 2, 55. (149) Kayser, O.; Kiderlen, A. F. Phytother. Res. 2001, 15, 148. (150) Hermoso, A.; Jimenez, I. A.; Mamani, Z. A.; Bazzocchi, I. L.; Pinero, J. E.; Ravelo, A. G.; Valladares, B. Bioorg. Med. Chem. 2003, 11, 3975. (151) Flores, N.; Cabrera, G.; Jimenez, I. A.; Pinero, J.; Gimenez, A.; Bourdy, G.; Cortes-Selva, F.; Isabel, L. Planta Med. 2007, 73, 206. (152) Chen, M.; Zhai, L.; Christensen, S. B.; Theander, T. G.; Khatrazmi, A. Antimicrob. Agents Chemother. 2001, 45, 2023. (153) Salem, M. M.; Werbovetz, K. A. J. Nat. Prod. 2006, 69, 43. (154) Salem, M. M.; Werbovetz, K. A. J. Nat. Prod. 2005, 68, 108.

(94) Mukherjee, A.; Padmanabhan, P. K.; Sahani, M. H.; Barrett, M. P.; Madhubala, R. Mol. Biochem. Parasitol. 2006, 145, 1. (95) Basselin, M.; Denise, H.; Coombs, G. H.; Barrett, M. P. Antimicrob. Agents Chemother. 2002, 46, 3731. (96) Yeates, C.; Sitamaquine, S. Curr. Opin. Invest. Drugs 2002, 3, 1446. (97) Tekwani, B. L.; Walker, L. A. Curr. Opin. Infect. Dis. 2006, 19, 623. (98) Wasunna, M. K.; Rashid, J. R.; Mbui, J.; Kirigi, G.; Kinoti, D.; Lodenyo, H. Am. J. Trop. Med. Hyg. 2005, 73, 871. (99) Jha, T. K.; Sunder, S.; Thakur, C. P.; Felton, J. M.; Sabin, A. J.; Horton, J. Am. J. Trop. Med. Hyg. 2005, 73, 1005. (100) Idowu, O. R.; Peggins, J. O.; Brewer, T. G. Drug Metab. Dispos. 1995, 23, 18. (101) Lopez-Martin, C.; Perez-Victoria, J. M.; Carvalho, L.; Castanys, S.; Gamarro, F. Antimicrob. Agents Chemother. 2008, 52, 4030. (102) Carvalho, P. B.; Arribas, M. A. G.; Ferreira, E. I. Braz. J. Pharm. Sci. 2000, 36, 69. (103) Chawla, B.; Madhubala, R. J. Parasit. Dis. 2010, 34, 1. (104) Barrett, M. P.; Mottram, J. C.; Coombs, G. H. Trends Microbiol. 1999, 7, 82. (105) Hassan, P.; Fergusson, D.; Grant, K. M.; Mottram, J. C. Mol. Biochem. Parasitol. 2001, 113, 189. (106) Grant, K. M.; Hassan, P.; Anderson, J. S.; Mottram, J. C. J. Biol. Chem. 1998, 273, 10153. (107) Alexander, J.; Coombs, G. H.; Mottram, J. C. J. Immunol. 1998, 161, 6794. (108) Neal, R. A.; Croft, S. L. J. Antimicrob. Chemother. 1984, 14, 463. (109) Hardy, L. W.; Matthews, W.; Nare, B.; Beverley, S. M. Exp. Parasitol. 1997, 87, 157. (110) Das, A.; Dasgupta, A.; Sengupta, T.; Majumder, H. K. Trends Parasitol. 2004, 20, 381. (111) Das, B. B.; Sen, N.; Ganguly, A.; Majumder, H. K. FEBS Lett. 2004, 565, 81. (112) Hoet, S.; Opperdoes, F.; Brun, R.; Quetin-Leclercq, J. Nat. Prod. Rep. 2004, 21, 353. (113) Strauss, P. R.; Wang, J. C. Biochem. Parasitol. 1990, 38, 141. (114) Fragoso, S. P.; Goldenberg, S. Biochem. Parasitol. 1992, 55, 127. (115) Das, A.; Dasgupta, A.; Sharma, S.; Ghosh, M.; Sengupta, T.; Bandopadhyay, S.; Majumder, H. K. Nucleic Acids Res. 2001, 29, 1844. (116) Chowdhury, A. R.; Mandal, S.; Goswami, A.; Ghosh, M.; Mandal, L.; Chakraborty, D.; Ganguly, A.; Tripathi, G.; Mukhopadhyay, S.; Bandyopadhyay, S.; Majumder, H. K. Mol. Med. 2003, 9, 26. (117) Costa, E. V.; Pinheiro, M. L. B.; Xavier, C. M.; Silva, J. R. A.; Amaral, A. C. F.; Souza, A. D. L.; Barison, A.; Campos, F. R.; Ferreire, A. G.; Machado, G. M. C.; Leon, L. L. P. J. Nat. Prod. 2006, 69, 292. (118) Correa, J. E.; Rios, C. H.; Castillo, A. R.; Romero, L. I.; Barria, E. O.; Coley, P. D.; Kursar, T. A.; Heller, M. V.; Gerwick, W. H.; Rajos, L. C. Planta Med. 2006, 72, 270. (119) Montenegro, H.; Gutierrez, M.; Romero, L. I.; Ortega-Barria, E.; Capson, T. L.; Rios, L. C. Planta Med. 2003, 69, 677. (120) da Silva, D. B.; Tulli, E. C. O.; Militao, G. C. G.; Costa-Lotufo, L. V.; Pessoa, C.; de Moraes, M. O.; Albuquerque, S.; de Siqueira, J. M. Phytomedicine 2009, 16, 1059. (121) Maurya, R.; Gupta, P.; Chand, K.; Kumar, M.; Dixit, P.; Singh, N.; Dube, A. Nat. Prod. Resp. 2009, 23, 1134. (122) Ponte-Sucre, A.; Faber, J. H.; Gulder, T.; Kajahn, I.; Pedersen, S. E. H.; Schultheis, M.; Bringmann, G.; Moll, H. Antimicrob. Agents Chemother. 2007, 51, 188. (123) Bringmann, G.; Kajahn, I.; Reichert, M.; Pedersen, S. E. H.; Faber, J. H.; Gulder, T.; Brun, R.; Christensen, S. B.; Ponte-Sucre, A.; Moll, H.; Heubl, G.; Mudogo, V. J. Org. Chem. 2006, 71, 9348. (124) Bringmann, G.; Dreyer, M.; Faber, J. H.; Dalsgaard, P. W.; Staerk, D.; Jaroszewski, J. W.; Ndangalasi, H.; Mbago, F.; Brun, R.; Christensen, S. B. J. Nat. Prod. 2003, 66, 1159. 10423


Chemical Reviews

Review

(155) Tasdemir, D.; Kaiser, M.; Brun, R.; Yardley, V.; Schmidt, T. J.; Tosun, F.; Rüedi, P. J. Antimicrob. Agents Chemother. 2006, 50, 1352. (156) Muzitano, M. F.; Tinoco, L. W.; Guette, C.; Kaiser, C. R.; Rossi-Bergmann, B.; Costa, S. S. Phytochemistry 2006, 67, 2071. (157) Bonzue, J. A.; Parthasarathy, N.; Phillips, L. R.; Cote, C. K.; Fellows, P. F. Microb. Pathog. 2005, 38, 1. (158) Radwan, M. M.; ElSohly, M. A.; Slade, D.; Ahmed, S. A.; Wilson, L.; El-Alfy, A. T.; Khan, I. A.; Ross, S. A. Phytochemistry 2008, 69, 2627. (159) Kirmizibekmez, H.; Calis, I.; Perozzo, R.; Brun, R.; Dönmez, A. A.; Linden, A.; Rüedi, P.; Tasdemir, D. Planta Med. 2004, 70, 711. (160) Salem, M. M.; Capers, J.; Rito, S.; Werbovetz, K. A. Phytother. Res. 2011, 25, 1246. (161) Sartorelli, P.; Carvalho, C. S.; Reimao, J. Q.; Ferreira, M. J. P.; Tempone, A. G. Parasitol. Res. 2009, 104, 311. (162) Ganapaty, S.; Pannakal, S. T.; Srilakshmi, G. V. K.; Lakshmi, P.; Waterman, P. G.; Brun, R. Phytochem. Lett. 2008, 1, 175. (163) Kapingu, M. C.; Mbwambo, Z. H.; Moshi, M. J.; Magadula, J. J.; Cos, P.; Vanden, B. D.; Maes, L.; Theunis, M.; Apers, S.; Pieters, L.; Vlietinck, A. Planta Med. 2006, 72, 1341. (164) Iranshahi, M.; Arfa, P.; Ramezani, M.; Jaafari, M. R.; Sadeghian, H.; Bassarello, C.; Piacente, S.; Pizza, C. Phytochemistry 2007, 68, 554. (165) Brenzan, M. A.; Nakamura, C. V.; Dias-Filho, B. P.; UedaNakamura, T.; Young, M. C. M.; Cortez, D. A. G. Parasitol. Res. 2007, 101, 715. (166) Azebaze, A. G. B.; Ouahouo, B. M. W.; Vardamides, J. C.; Valentin, A.; Kuete, V.; Acebey, L.; Beng, V. P.; Nkengfack, A. E.; Meyer, M. Chem. Nat. Compd. 2008, 44, 582. (167) Pontius, A.; Krick, A.; Kehraus, S.; Brun, R.; König, G. M. J. Nat. Prod. 2008, 71, 1579. (168) Hay, A. E.; Merza, J.; Landreau, A.; Litaudon, M.; Pagniez, F.; Pape, P. L.; Richomme, P. Fitoterapia 2008, 79, 42. (169) Filho, A. A. S.; Costa1, E. S.; Cunha, W. R.; Silva, M. L. A.; Nanayakkara, N. P. D.; Bastos, J. K. Phytother. Res. 2008, 22, 1307. (170) Muhammad, I.; Li, X. C.; Jacob, M. R.; Tekwani, B. L.; Dunbar, D. C.; Ferreira, D. J. Nat. Prod. 2003, 66, 804. (171) Ankisetty, S.; ElSohly, H. N.; Li, X. C.; Khan, S. I.; Tekwani, B. L.; Smillie, T.; Walker, L. J. Nat. Prod. 2006, 69, 692. (172) Jin, W.; Zjawiony, J. K. J. Nat. Prod. 2006, 69, 704. (173) Jimenez-Romero, C.; Torres-Mendoza, D.; Gonzalez, L. D. U.; Ortega-Barrıa, E.; McPhail, K. L.; Gerwick, W. H.; Cubilla-Rios, L. J. Nat. Prod. 2007, 70, 1249. (174) Flores, N.; Jimenez, I. A.; Gimenez, A.; Ruiz, G.; Gutierrez, D.; Bourdy, G.; Bazzocchi, I. L. J. Nat. Prod. 2008, 71, 1538. (175) Radwan, M. M.; ElSohly, M. A.; Slade, D.; Ahmed, S. A.; Khan, I. A.; Ross, S. A. J. Nat. Prod. 2009, 72, 906. (176) Giddens, A. C.; Nielsen, L.; Boshoff, H. I.; Tasdemir, D.; Perozzo, R.; Kaiser, M.; Wang, F.; Sacchettini, J. C.; Copp, B. R. Tetrahedron 2008, 64, 1242. (177) Getti, G. T.; Aslam, S. N.; Humber, D. P.; Stevenson, P. C.; Cheke, R. A. Planta Med. 2006, 72, 907. (178) Duarte, N.; Kayser, O.; Abreu, P.; Ferreira1, M. J. U. Phytother. Res. 2008, 22, 455. (179) Cabanillas, B. J.; Le Lamer, A. C.; Castillo, D.; Arevalo, J.; Rojas, R.; Odonne, G.; Bourdy, G.; Moukarzel, B.; Sauvain, M.; Fabre, N. J. Nat. Prod. 2010, 73, 1884. (180) Gupta, S.; Raychaudhuri, B.; Banerjee, S.; Das, B.; Mukhopadhaya, S.; Datta, S. C. Parasitol. Int. 2010, 59, 192. (181) Castillo, D.; Arevalo, J.; Herrera, F.; Ruiz, C.; Rojas, R.; Rengifo, E.; Vaisberg, A.; Lock, O.; Lemesre, J.-L.; Gornitzka, H.; Sauvain, M. J. Ethnopharmacol. 2007, 112, 410. (182) Fuchino, H.; Koide, T.; Takahashi, M.; Sekita, S.; Satake, M. Planta Med. 2001, 67, 647. (183) Nunez, M. J.; Cortes-Selva, F.; Bazzocchi, I. L.; Jimenez, I. A.; Gonzalez, A. G.; Ravelo, A. G.; Gavin, J. A. J. Nat. Prod. 2003, 66, 572. (184) Tiuman, T. S.; Ueda-Nakamura, T.; Cortez, D. A. G.; Dias, D. F. B.; Morgado-Diaz, J. A.; de Souza, W.; Nakamura, C. V. Antimicrob. Agents Chemother. 2005, 49, 176.

(185) Arruda, D. C.; D’Alexandri, F. L.; Katzin, A. M.; Uliana, S. R. B. Antimicrob. Agents Chemother. 2005, 49, 1679. (186) dos Santos, A. O.; Veiga-Santos, P.; Ueda-Nakamura, T.; Filho, B. P. D.; Sudatti, D. B.; Bianco, É. M.; Pereira, R. C.; Nakamura, C. V. Mar. Drugs 2010, 8, 2733. (187) Odonne, G.; Herbette, G.; Eparvier, V.; Bourdy, G.; Rojas, R.; Sauvain, M.; Stien, D. J. Ethnopharmacol. 2011, 137, 875. (188) Wu, H.; Fronczek, F. R.; Burandt, C. L.; Zjawiony, J. K. Planta Med. 2011, 77, 749. (189) Machado, F. L. S.; Pacienza-Lima, W.; Rossi-Bergmann, B.; Gestinari, L. M. S.; Fujii, M. T.; Paula, J. C.; Costa, S. S.; Lopes, N. P.; Kaiser, C. R.; Soares, A. R. Planta Med. 2011, 77, 733. (190) Habtemariam, S. BMC Pharmacol. 2003, 3, 6. (191) Misra, P.; Sashidhara, K. V.; Singh, S. P.; Kumar, A.; Gupta, R.; Chaudhaery, S. S.; Gupta, S. S.; Majumder, H. K.; Saxena, A. K.; Dube, A. Br. J. Pharmacol. 2010, 159, 1143. (192) Fokialakis, N.; Kalpoutzakis, E.; Tekwani, B. L.; Skaltsounis, A. L.; Duke, S. O. Biol. Pharm. Bull. 2006, 29, 1775. (193) Samoylenko, V.; Dunbar, D. C.; Gafur, M. A.; Khan, S. I.; Ross, S. A.; Mossa, J. S.; El-Feraly, F. S.; Tekwani, B. L.; Bosselaers, J.; Muhammad, I. Phytother. Res. 2008, 22, 1570. (194) Moein, M. R.; Pawar, R. S.; Khan, S. I.; Tekwani, B. L.; Khan, I. A. Phytother. Res. 2008, 22, 283. (195) Filho, A.A. S.; Resende, D. O.; Fukui, M. J.; Santos, F. F.; Pauletti, P. M.; Cunha, W. R.; Silva, M. L. A.; Gregório, L. E.; Bastos, J. K.; Nanayakkara, N. P. D. Fitoterapia 2009, 80, 478. (196) Sairafianpour, M.; Christensen, J.; Stærk, D.; Budnik, B. A.; Kharazmi, A.; Bagherzadeh, K.; Jaroszewski, J. W. J. Nat. Prod. 2001, 64, 1398. (197) Khalid, S. A.; Friedrichsen, G. M.; Christensen, S. B.; Tahir, A. E.; Sattic, G. M. ARKIVOC 2007, IX, 129. (198) Thiem, D. A.; Sneden, A. T.; Khan, S. I.; Tekwani, B. L. J. Nat. Prod. 2005, 68, 251. (199) Moulisha1, B.; Bikash, M. N.; Partha, P.; Kumar, G. A.; Sukdeb, B.; Kanti, H. P. Trop. J. Pharm. Res. 2009, 8, 127. (200) Mandal, D.; Panda, N.; Kumar, S.; Banerjee, S.; Mandal, N. B.; Sahu, N. P. Phytochemistry 2006, 67, 183. (201) Germonprez, N.; Puyvelde, L. V.; Maes, L.; Trib, M. V.; Kimpe, N. D. Tetrahedron 2004, 60, 219. (202) Germonprez, N.; Maes, L.; Puyvelde, L. V.; Tri, M. V.; Tuan, D. A.; Kimpe, N. D. J. Med. Chem. 2005, 48, 32. (203) Encarnacion-Dimayuga, R.; Murillo-Alvarez, J. I.; Christophersen, C.; Chan-Bacab, M.; Reiriz, M. L. G.; Zacchino, S. Nat. Prod. Commun. 2006, 1, 541. (204) Grandic, S. R.; Fourneau, C.; Laurens, A.; Bories, C.; Hocquemiller, R.; Loiseau, P. M. Biomed. Pharmacother. 2004, 58, 388. (205) Simmons, T. L.; Engene, N.; Urena, L. D.; Romero, L. I.; Ortega-Barrıa, E.; Gerwick, L.; Gerwick, W. H. J. Nat. Prod. 2008, 71, 1544. (206) Linington, R. G.; Edwards, D. J.; Shuman, C. F.; McPhail, K. L.; Matainaho, T.; Gerwick, W. H. J. Nat. Prod. 2008, 71, 22. (207) Nakao, Y.; Kawatsu, S.; Okamoto, C.; Okamoto, M.; Matsumoto, Y.; Matsunaga, S.; van Soest, R. W. M.; Fusetani, N. J. Nat. Prod. 2008, 71, 469. (208) Balunas, M. J.; Linington, R. G.; Tidgewell, K.; Fenner, A. M.; Urena, L. D.; Togna, G. D.; Kyle, D. E.; Gerwick, W. H. J. Nat. Prod. 2010, 73, 60. (209) Donia, M. S.; Wang, B.; Dunbar, D. C.; Desai, P. V.; Patny, A.; Avery, M.; Hamann, M. T. J. Nat. Prod. 2008, 71, 941. (210) Linington, R. G.; Clark, B. R.; Trimble, E. E.; Almanza, A.; Urena, L. D.; Kyle, D. E.; Gerwick, W. H. J. Nat. Prod. 2009, 72, 14. (211) Martınez-Luis, S.; Della-Togna, G.; Coley, P. D.; Kursar, T. A.; Gerwick, W. H.; Cubilla-Rios, L. J. Nat. Prod. 2008, 71, 2011. (212) Martınez-Luis, S.; Cherigo, L.; Spadafora, C.; Gerwick, W. H.; ́ 2009, 37, 104. Cubilla-Rios, L. Rev. Latinoam. Quim. (213) Mbwambo, Z. H.; Apers, S.; Moshi, M. J.; Kapingu, M. C.; Miert, S. V.; Claeys, M.; Brun, R.; Cos, P.; Pieters, L.; Vlietinck, A. Planta Med. 2004, 70, 706. 10424


Chemical Reviews

Review

(214) Bringmann, G.; Rüdenauer, S.; Irmer, A.; Bruhn, T.; Brun, R.; Heimberger, T.; Stühmer, T.; Bargou, R.; Chatterjee, M. Phytochemistry 2008, 69, 2501. (215) Ali, A.; Assimopoulou, A. N.; Papageorgiou, V. P.; Kolodziej, H. Planta Med. 2011, 77, 2003. (216) Sartorelli, P.; Andrade, S. P.; Melhem, M. S. C.; Prado, F. O.; Tempone, A. G. Phytother. Res. 2007, 21, 644. (217) Kayser, O.; Kiderlen, A. F.; Croft, S. L. Acta Trop. 2003, 86, 105. (218) Mori, K.; Kawano, M.; Fuchino, H.; Ooi, T.; Satake, M.; Agatsuma, Y.; Kusumi, T.; Sekita, S. J. Nat. Prod. 2008, 71, 18. (219) Choudhary, M. I.; Yousuf, S.; Ahmed, S.; Samreen; Yasmeen, K.; Rahman, A. U. Chem. Biodiversity 2005, 2, 1164. (220) Cardona, D.; Quinones, W.; Torres, F.; Robledo, S.; Velez, I. D.; Cruz, V.; Notariod, R.; Echeverri, F. Tetrahedron 2006, 62, 6822. (221) Martín-Quintal, Z.; Moo-Puc, R.; González-Salazar, F.; ChanBacab, M. J.; Torres-Tapia, L. W.; Peraza-Sánchez, S. R. J. Ethnopharmacol. 2009, 122, 463. (222) Ghaffarifar, F. Exp. Parasitol. 2010, 126, 126. (223) Morales-Yuste, M.; Morillas-Marquez, F.; Martın-Sanchez, J.; Valero-Lo pez, A.; Navarro-Moll, M. C. Phytomedicine 2010, 17, 279. (224) Zhai, L.; Chen, M.; Blom, J.; Theander, T. G.; Christensen, S. B.; Kharazmi, A. J. Antimicrob. Chemother. 1999, 43, 793. (225) Andrighetti-Frohner, C. R.; de Oliveira, K. N.; Gaspar-Silva, D.; Pacheco, L. K.; Joussef, A. C.; Steindel, M.; Simoes, C. M. O.; de Souza, A. M. T.; Magalhaes, U. O.; Afonso, I. F.; Rodrigues, C. R.; Nunes, R. J.; Castro, H. C. Eur. J. Med. Chem. 2009, 44, 755. (226) Narender, T.; Shweta; Gupta, S. Bioorg. Med. Chem. Lett. 2004, 14, 3913. (227) Narender, T.; Khaliq, T.; Shweta; Nishi; Goyal, N.; Gupta, S. Bioorg. Med. Chem. 2005, 13, 6543. (228) Nazarian, Z.; Emami, S.; Heydari, S.; Ardestani, S. K.; Nakhjiri, M.; Poorrajab, F.; Shafiee, A.; Foroumadi, A. Eur. J. Med. Chem. 2010, 45, 1424. (229) Bello, M. L.; Chiaradia, L. D.; Dias, L. R. S.; Pacheco, L. K.; Stumpf, T. R.; Mascarello, A.; Steindel, M.; Yunes, R. A.; Castro, H. C.; Nunes, R. J.; Rodrigues, C. R. Bioorg. Med. Chem. 2011, 19, 5046. (230) Chiaradia, L. D.; dos Santos, R.; Vitor, C. E.; Vieira, A. A.; Leal, P. C.; Nunes, R. J.; Calixto, J. B.; Yunes, R. A. Bioorg. Med. Chem. 2008, 16, 658. (231) Rizvi, S. U. F.; Siddiqui, H. L.; Parvez, M.; Ahmed, M.; Siddiqui, W. A.; Yasinzai, M. M. Chem. Pharm. Bull. 2010, 58, 301. (232) Herencia, F.; Ferrándiz, M. L.; Ubeda, A.; Domínguez, J. N.; Charris, J. E.; Lobo, G.; Alcaraz, M. J. Bioorg. Med. Chem. Lett. 1998, 8, 1169. (233) Li, R.; Kenyon, G. L.; Cohen, F. E.; Chen, X.; Gong, B.; Dominguez, D. E.; Kurzban, G.; Miller, R. E.; Nuzum, E. O.; Rosenthal, P. J.; McKerrow, J. H. J. Med. Chem. 1995, 38, 5031. (234) Boeck, P.; Falcao, C. A. B.; Leal, P. C.; Yunes, R. A.; Filho, V. C.; Torres-Santos, E. C.; Rossi-Bergmann, B. Bioorg. Med. Chem. 2006, 14, 1538. (235) Torres-Santos, E. C.; Moreira, D.; Kaplan, M. A.; RossiBergmann, B. Antimicrob. Agents Chemother. 1999, 43, 1234. (236) Torres-Santos, E. C.; Rodrigues, J. M., Jr.; Moreira, D. L.; Kaplan, M. A.; Rossi-Bergmann, B. Antimicrob. Agents Chemother. 1999, 43, 1776. (237) Calixto, J. B.; Yunes, R. A.; Miguel, O. G.; Era, G. A. Planta Med. 1986, 6, 444. (238) Cechinel, V. F.; Vaz, Z. R.; Zunino, L.; Calixto, J. B.; Yunes, R. A. Eur. J. Med. Chem. 1996, 31, 833. (239) Sundar, S.; Jha, T. K.; Sindermann, H.; Junge, K.; Bachmann, P.; Berman, J. Pediatr. Infect. Dis. J. 2003, 22, 434. (240) Foroumadi, A.; Emami, S.; Sorkhi, M.; Nakhjiri, M.; Nazarian, Z.; Heydari, S.; Ardestani, S. K.; Poorrajab, F.; Shafiee, A. Chem. Biol. Drug Des. 2010, 75, 590. (241) Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1. (242) Fine, S. A.; Pulaski, P. D. J. Org. Chem. 1973, 38, 1747. (243) Nielsen, S. F.; Christensen, S. B.; Cruciani, G.; Kharazmi, A.; Liljefors, T. J. Med. Chem. 1998, 41, 4819.

(244) Zhai, L.; Blom, J.; Chen, M.; Christensen, S. B.; Kharazmi, A. Antimicrob. Agents Chemother. 1995, 39, 2742. (245) Jain, M.; Khan, S. I.; Tekwani, B. L.; Jacob, M. R.; Singh, S.; Singh, P. P.; Jain, R. Bioorg. Med. Chem. 2005, 13, 4458. (246) Jain, R.; Jain, S.; Gupta, R. C.; Anand, N.; Dutta, G. P.; Puri, S. K. Indian J. Chem. 1994, 33B, 251. (247) Carroll, F. I.; Berrang, B.; Linn, C. P. J. Med. Chem. 1985, 28, 1564. (248) Jain, M.; Vangapandu, S.; Sachdeva, S.; Singh, S.; Singh, P. P.; Jena, G. B.; Tikoo, K.; Ramarao, P.; Kaul, C. L.; Jain, R. J. Med. Chem. 2004, 47, 285. (249) Kaur, K.; Patel, S. R.; Patil, P.; Jain, M.; Khan, S. I.; Jacob, M. R.; Ganesan, S.; Tekwani, B. L.; Jain, R. Bioorg. Med. Chem. 2007, 15, 915. (250) Chu, T. H. L. C. K.; Yang, C. S.; Lu, X. T.; Chang, C. C. Yao Hsueh Hsueh Pao 1956, 4, 197. (251) Sahu, N. P.; Pal, C.; Mandal, N. B.; Banerjee, S.; Raha, M.; Kundu, A. P.; Basu, A.; Ghosh, M.; Roy, K.; Bandyopadhyay, S. Bioorg. Med. Chem. 2002, 10, 1687. (252) Chakrabarti, G.; Basu, A.; Manna, P. P.; Mahato, S. B.; Mandal, N. B.; Bandyopadhyay, S. J. Antimicrob. Agents Chemother. 1999, 43, 359. (253) Tempone, A. G.; Silva, A. C. M. P.; Brandt, C. A.; Martinez, F. S.; Borborema, S. E. T.; Silveira, M. A. B.; Andrade, H. F. Antimicrob. Agents Chemother. 2005, 49, 1076. (254) Loiseau, P. M.; Gupta, S.; Verma, A.; Srivastava, S.; Puri, S. K.; Sliman, F.; Normand-Bayle, M.; Desmaele, D. Antimicrob. Agents Chemother. 2011, 51, 1777. (255) Nakayama, H.; Loiseau, P. M.; Bories, C.; Torres de Ortiz, S.; Schinini, A.; Serna, E.; Fakhfakh, M. A.; Franck, X.; Figadere, B.; Hocquemiller, R.; Fournet, A. Antimicrob. Agents Chemother. 2005, 49, 4950. (256) Mouscadet, J. F.; Desmaele, D. Molecules 2010, 15, 3048. (257) Zouhiri, F.; Normand-Bayle, M.; Danet, M.; Desmaele, D.; Leh, H. J. Med. Chem. 2000, 43, 1533. (258) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem. 1967, 32, 2358. (259) Trecourt, F.; Mallet, M.; Mongin, F.; Quéguiner, G. Synthesis 1995, 9, 1159. (260) Normand-Bayle, M.; Benard, C.; Zouhiri, F.; Mouscadet, J. F.; Leh, H.; Thomas, C. M.; Mbemba, G.; Desmaele, D.; Angelo, J. Bioorg. Med. Chem. Lett. 2005, 15, 4019. (261) Khan, M. O. F.; Levi, M. S.; Tekwani, B. L.; Wilson, N. H.; Borne, R. F. Bioorg. Med. Chem. 2007, 15, 3919. (262) Chauhan, S. S.; Gupta, L.; Mittal, M.; Vishwakarma, P.; Gupta, S.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett. 2010, 20, 6191. (263) Tseng, M. C.; Liang, Y. M.; Chu, Y. H. Tetrahedron Lett. 2005, 46, 6131. (264) Wang, L. T.; Huang, H.; Ye, Z. L.; Wu, Y.; Wang, X. C. Synth. Commun. 2006, 36, 2627. (265) (a) Muthukrishnan, M.; More, S. V.; Garud, D. R.; Ramana, C. V. J. Heterocycl. Chem. 2006, 43, 767. (b) Saha, B.; Sharma, S.; Sawant, D.; Kundu, B. Tetrahedron Lett. 2007, 48, 1379. (266) Gupta, L.; Sunduru, N.; Verma, A.; Srivastava, S.; Gupta, S.; Goyal, N.; Chauhan, P. M. S. Eur. J. Med. Chem. 2010, 45, 2359. (267) Elederfield, R. C.; Rembges, H. H. J. Org. Chem. 1967, 32, 3809. (268) Zhang, W. Org. Lett. 2003, 5, 1011. (269) Kgokong, J. L.; Smith, P. P.; Matsabisa, G. M. Bioorg. Med. Chem. 2005, 13, 2935. (270) Kumar, R.; Khan, S.; Verma, A.; Srivastava, S.; Viswakarma, P.; Gupta, S.; Meena, S.; Singh, N.; Sarkar, J.; Chauhan, P. M. S. Eur. J. Med. Chem. 2010, 45, 3274. (271) Kam, T.-S.; Sim, K.-M.; Koyano, T.; Komiyama, K. Phytochemistry 1999, 50, 75. (272) Lala, S.; Pramanick, S.; Mukhopadhyay, S.; Bandyopadhyay, S.; Basu, M. K. J. Drug Targeting 2004, 12, 165. (273) Suryawanshi, S. N.; Bhat, B. A.; Pandey, S.; Chandra, N.; Gupta, S. Eur. J. Med. Chem. 2007, 42, 1211. 10425


Chemical Reviews

Review

(307) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. (308) Guillon, J.; Forfar, I.; Desplat, V.; Fabre, S. B.; Thiolat, D.; Massip, S.; Carrie, H.; Mossalayi, D.; Jarry, C. J. Enzyme Inhib. Med. Chem. 2007, 22, 541. (309) Guillon, J.; Dallemagne, P.; Pfeiffer, B.; Renard, P.; Manechez, D.; Kervran, A.; Rault, S. Eur. J. Med. Chem. 1998, 33, 293. (310) Yoo, S.; Lee, S. Synlett 1990, 7, 419. (311) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (312) Satoh, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1986, 15, 1329. (313) Srinivas, N.; Palne, S.; Nishi; Gupta, S.; Bhandari, K. Bioorg. Med. Chem. Lett. 2009, 19, 324. (314) Cordova, A. Acc. Chem. Res. 2004, 372, 102. (315) Xanthakis, E.; Zarevúcka, M.; Šaman, D.; Wimmerová, M.; Kolisis, F. N.; Wimmer, Z. Tetrahedron: Asymmetry 2006, 17, 2987. (316) Bhandari, K.; Srinivas, N.; Marrapu, V. K.; Verma, A.; Srivastava, S.; Gupta, S. Bioorg. Med. Chem. Lett. 2010, 20, 291. (317) Ibrahem, I.; Casas, J.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 6528. (318) Srinivas, N.; Bhandari, K. Tetrahedron Lett. 2008, 49, 7070. (319) Srivastava, S.; Bhandari, K.; Shankar, G.; Singh, H. K.; Saxena, A. K. Med. Chem. Res. 2004, 13, 631. (320) Marrapu, V. K.; Mittal, M.; Shivahare, R.; Gupta, S.; Bhandari, K. Eur. J. Med. Chem. 2011, 46, 1694. (321) Mayence, A.; Pietka, A.; Collins, M. S.; Cushion, M. T.; Tekwani, B. L.; Huang, T. L.; Eynde, J. J. V. Bioorg. Med. Chem. Lett. 2008, 18, 2658. (322) Preston, P. N. Chem. Rev. 1974, 74, 279. (323) Ridley, H. F.; Spickett, R. G.; Timmis, G. M. J. Heterocycl. Chem. 1965, 2, 1965. (324) Paglietti, G.; Pirisi, M.; Loriga, M.; Grella, G.; Sparatore, F.; Satta, M.; Manca, P. Farmaco, Ed. Sci. 1988, 43, 215. (325) Maquestiau, A.; Berte, L.; Mayence, A.; Vanden Eynde, J. J. Synth. Commun. 1991, 21, 2171. (326) Ferreira, S. B.; Costa, M. S.; Boechat, N.; Bezerra, R. J. S.; Genestra, M. S.; Canto-Cavalheiro, M. M.; Kover, W. B.; Ferreira, V. F. Eur. J. Med. Chem. 2007, 42, 1388. (327) Trofimenko, S. J. Org. Chem. 1963, 28, 3243. (328) Ferreira, S. B. Synlett 2006, 7, 1130. (329) Carvalho, G. S. G.; Machado, P. A.; Paula, D. T. S.; Coimbra, E. S.; Silva, A. D. Sci. World J. 2010, 10, 1723. (330) Caterina, M. C.; Perillo, I. A.; Boiani, L.; Pezaroglo, H.; Cerecetto, H.; González, M.; Salerno, A. Bioorg. Med. Chem. 2008, 16, 2226. (331) Sharma, V.; Khan, M. S. Eur. J. Med. Chem. 2001, 36, 651. (332) Musonda, C. C.; Whitlock, G. A.; Witty, M. J.; Brun, R.; Kaiser, M. Bioorg. Med. Chem. Lett. 2009, 19, 401. (333) Agarwal, A.; Ramesh, A.; Goyal, N.; Chauhan, P. M. S.; Gupta, S. Bioorg. Med. Chem. 2005, 13, 6678. (334) Herlem, D.; Kervagoret, J.; Yu, D.; Huu, F.; Kende, A. S. Tetrahedron 1993, 49, 607. (335) Osmo Hormi, E. O.; Paakkanen, A. M. J. Org. Chem. 1987, 52, 5275. (336) Coghi, P.; Vaiana, N.; Pezzano, M. G.; Rizzi, L.; Kaiser, M.; Brun, R.; Romeo, S. Bioorg. Med. Chem. Lett. 2008, 18, 4658. (337) Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333. (338) Rampy, M. A.; Pinchuk, A. N.; Weichert, J. P.; Skinner, R. W. S.; Fisher, S. J.; Wahl, R. L.; Gross, M. D.; Counsell, R. E. J. Med. Chem. 1995, 38, 3156. (339) Avlonitis, N.; Lekka, E.; Detsi, A.; Koufaki, M.; Calogeropoulou, T.; Scoulica, E.; Siapi, E.; Kyrikou, I.; Mavromoustakos, T.; Tsotinis, A.; Grdadolnik, S. G.; Makriyannis, A. J. Med. Chem. 2003, 46, 755. (340) Srikrishna, A.; Viswajanani, R. Tetrahedron 1995, 51, 3339. (341) Tsotinis, A.; Calogeropoulou, T.; Koufaki, M.; Souli, C.; Balzarini, J.; De Clercq, E.; Makriyannis, A. J. Med. Chem. 1996, 39, 3418.

(274) Pandey, S.; Suryawanshi, S. N.; Gupta, S.; Srivastava, V. M. L. Eur. J. Med. Chem. 2004, 39, 969. (275) Chandra, N.; Ramesh, Ashutosh; Goyal, N.; Suryawanshi, S. N.; Gupta, S. Eur. J. Med. Chem. 2005, 40, 552. (276) Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.; Agarwal, S. K.; Bhaduri, A. P. S.; Singh, N.; Fatima, N.; Chatterjee, R. K. Bioorg. Med. Chem. 1999, 7, 1223. (277) Na, Y. M.; Lebouvier, N.; Borgne, M.; Pagniez, F.; Alvarez, N.; Pape, P.; Baut, A. G. J. Enzyme Inhib. Med. Chem. 2004, 19, 451. (278) Porwal, S.; Chauhan, S. S.; Chauhan, P. M. S.; Shakya, N.; Verma, A.; Gupta, S. J. Med. Chem. 2009, 52, 5793. (279) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329. (280) Newman, D. J. J. Med. Chem. 2008, 51, 2589. (281) Changtam, C.; de Koning, H. P.; Ibrahim, H.; Sajid, M. S.; Gould, M. K.; Suksamrarn, A. Eur. J. Med. Chem. 2010, 45, 941. (282) Maheshwari, R. K.; Singh, A. K.; Gaddipatti, J.; Srimal, R. C. Life Sci. 2006, 78, 2081. (283) Ruby, A. J.; Kuttan, G.; Babu, K. D.; Rajasekharan, K. N.; Kuttan, R. Cancer Lett. 1995, 911, 79. (284) Gringberg, L. N.; Shalev, O.; Tonnesen, H. H.; Lachmillewitz, E. A. Int. J. Pharm. 1996, 132, 251. (285) Chan, M. M. -Y.; Ho, C.-T.; Huang, H.-I. Cancer Lett. 1995, 96, 23. (286) Chan, M. M.-Y.; Huang, H.-I.; Fenton, M. R.; Fong, D. Biochem. Pharmacol. 1998, 55, 1955. (287) Inano, H.; Onoda, M.; Inafuku, N.; Kubota, M.; Kamada, Y.; Osawa, T.; Kobayashi, H.; Wakabayashi, K. Carcinogenesis 2000, 21, 1835. (288) Thapliyal, R.; Maru, G. B. Food Chem. Toxicol. 2001, 39, 541. (289) Araujo, C. A. C.; Alegrio, L. V.; Gomes, D. C. F.; Lima, M. E. F.; Gomes-Cardoso, L.; Leon, L. L. Mem. Inst. Oswaldo Cruz 1999, 94, 791. (290) Mazumder, A.; Raghavan, K.; Weinstein, J.; Kohn, K. W.; Pommier, Y. Biochem. Pharmacol. 1995, 49, 1165. (291) Nose, M.; Koide, T.; Ogihara, Y.; Yabu, Y.; Ohta, N. Biol. Pharm. Bull. 1998, 21, 643. (292) Koide, T.; Nose, M.; Ogihara, Y.; Yabu, Y.; Ohta, N. Biol. Pharm. Bull. 2002, 25, 131. (293) Park, S.-Y.; Kim, D. H. L. J. Nat. Prod. 2002, 65, 1227. (294) Giorgio, C. D.; Shimi, K.; Boyer, G.; Delmas, F.; Galy, J. P. Eur. J. Med. Chem. 2007, 42, 1277. (295) Albert, A.; Linnell, W. H. J. Org. Chem. 1938, 55, 1614. (296) Carole, D. G.; Michel, D. M.; Julien, C.; Florence, D.; Anna, N.; Severine, J.; Gerard, D.; Pierre, T. D.; Jean-Pierre, G. Bioorg. Med. Chem. 2005, 13, 5560. (297) Hess, F. K.; Stewart, P. B. J. Med. Chem. 1975, 18, 320. (298) Barea, C.; Pabón, A.; Castillo, D.; Zimic, M.; Quiliano, M.; Galiano, S.; Pérez-Silanes, S.; Monge, A.; Deharo, E.; Aldana, I. Bioorg. Med. Chem. Lett. 2011, 21, 4498. (299) Ortega, M. A.; Sainz, Y.; Montoya, M. E.; Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. Arzneim.-Forsch. 2002, 52, 113. (300) González, M.; Cerecetto, H. Benzofuraxane and furaxane, chemistry and biology, bioactive heterocyclic IV; Springer: Berlin/ Hiedelberg, 2007; Vol. 10, pp 265−308. (301) Ley, K.; Seng, F. Synthesis 1975, 7, 415. (302) Guillon, J.; Forfar, I.; Mamani-Matsuda, M.; Desplat, V.; Saliege, M.; Thiolat, D.; Massip, S.; Tabourier, A.; Leger, J. M.; Dufaure, B.; Haumont, G.; Jarry, C.; Mossalayi, D. Bioorg. Med. Chem. 2007, 15, 194. (303) Kaufman, J. M.; Litak, P. T.; Boyko, W. J. J. Heterocycl. Chem. 1995, 32, 1541. (304) Zhang, Z.; Tillekeratne, L. M. V.; Hudson, R. A. Synthesis 1996, 3, 377. (305) Guillon, J.; Grellier, P.; Labaied, M.; Sonnet, P.; Leger, J.-M.; Deprez-Poulain, R.; Forfar-Bares, I.; Dallemagne, P.; Lemaıtre, N.; Péhourcq, F.; Rochette, J.; Sergheraert, C.; Jarry, C. J. Med. Chem. 2004, 47, 1997. (306) Kelin, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. 10426


Chemical Reviews

Review

(342) Mantyla, A.; Garnier, T.; Rautio, J.; Nevalainen, T.; Vepsalainen, J.; Koskinen, A.; Croft, S. L.; Jarvinen, T. J. Med. Chem. 2004, 47, 188. (343) Krise, J. P.; Zygmunt, J.; Georg, G. I.; Stella, V. J. J. Med. Chem. 1999, 42, 3094. (344) Rautio, J.; Nevalainen, T.; Taipale, H.; Vepsalainen, J.; Gynther, J.; Pedersen, T.; Jarvinen, T. Pharm. Res. 1999, 16, 1172. (345) Rautio, J.; Nevalainen, T.; Taipale, H.; Vepsalainen, J.; Gynther, J.; Laine, K.; Jarvinen, T. J. Med. Chem. 2000, 43, 1489. (346) Mantyla, A.; Vepsalainen, J.; Jarvinen, T.; Nevalainen, T. A. Tetrahedron Lett. 2002, 43, 3793. (347) Ponte-Sucre, A.; Gulder, T.; Wegehaupt, A.; Albert, C.; Rikanovic, C.; Schaeflein, L.; Frank, A.; Schultheis, M.; Unger, M.; Holzgrabe, U.; Bringmann, G.; Moll, H. J. Med. Chem. 2009, 52, 626. (348) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. Biaryls in Nature: A Multi-facetted Class of Stereochemically, Biosynthetically, and Pharmacologically Intriguing Secondary Metabolites. In Progress in the Chemistry of Organic Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore, R. E., Eds.; Springer-Verlag: New York, 2001; Vol. 82, pp 1−293. (349) Francois, G.; Bringmann, G.; Dochez, C.; Schneider, C.; Timperman, G.; Assi, L. J. Ethnopharmacol. 1995, 46, 115. (350) Francois, G.; Timperman, G.; Holenz, J.; Aké Assi, L.; Geuder, T.; Maes, L.; Dubois, J.; Hanocq, M.; Bringmann, G. Ann. Trop. Med. Parasitol. 1996, 90, 115. (351) Francois, G.; Timperman, G.; Eling, W.; Assi, L.; Holenz, J.; Bringmann, G. Antimicrob. Agents Chemother. 1997, 41, 2533. (352) Bringmann, G.; Horr, V.; Holzgrabe, U.; Stich, A. Pharmazie 2003, 58, 343. (353) Bringmann, G.; Hamm, A.; Guenther, C.; Michel, M.; Brun, R.; Mudogo, V. J. Nat. Prod. 2000, 63, 1465. (354) Bringmann, G.; Messer, K.; Brun, R.; Mudogo, V. J. Nat. Prod. 2002, 65, 1096. (355) Yang, L.-K.; Glover, R. P.; Yonganathan, K.; Sarnaik, J. P.; Godbole, A. J.; Soejarto, D. D.; Buss, A. D.; Butler, M. S. Tetrahedron Lett. 2003, 44, 5827. (356) Unger, M.; Frank, A. Rapid Commun. Mass Spectrom. 2004, 18, 2273. (357) Mikus, J.; Steverding, D. Parasitol. Int. 2000, 48, 265. (358) Bouhlel, A.; Curti, C.; Dumètre, A.; Laget, M.; Crozet, M. D.; Azas, N.; Vanelle, P. Bioorg. Med. Chem. 2010, 18, 7310. (359) Snider, B. B. Chem. Rev. 1996, 96, 339. (360) Demir, A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 321. (361) Paloque, L.; Bouhlel, A.; Curti, C.; Dumètre, A.; Verhaeghe, P.; Azas, N.; Vanelle, P. Eur. J. Med. Chem. 2011, 46, 2984. (362) Curti, C.; Crozet, M. D.; Vanelle, P. Tetrahedron 2009, 65, 200. (363) Reichwald, C.; Shimony, O.; Dunkel, U.; Sacerdoti-Sierra, N.; Jaffe, C. L.; Kunick, C. J. Med. Chem. 2008, 51, 659. (364) Kunick, C. Arch. Pharm. (Weinheim, Ger.) 1992, 325, 297. (365) Kunick, C.; Lauenroth, K.; Wieking, K.; Xie, X.; Schultz, C.; Gussio, R.; Zaharevitz, D.; Leost, M.; Meijer, L.; Weber, A.; Jorgensen, F. S.; Lemcke, T. J. Med. Chem. 2004, 47, 22. (366) Kunick, C.; Zeng, Z.; Gussio, R.; Zaharevitz, D.; Leost, M.; Totzke, F.; Schächtele, C.; Kubbutat, M.; Meijer, L.; Lemcke, T. ChemBioChem 2005, 6, 541. (367) Xie, X.; Lemcke, T.; Gussio, R.; Zaharevitz, D. W.; Leost, M.; Meijer, L.; Kunick, C. Eur. J. Med. Chem. 2005, 40, 655. (368) Phiel, C. J.; Wilson, C. A.; Lee, V. M.-Y.; Klein, P. S. Nature 2003, 423, 435. (369) Leost, M.; Schultz, C.; Link, A.; Wu, Y.-Z.; Biernat, J.; Mandelkow, E.-M.; Bibb, J. A.; Snyder, G. L.; Greengard, P.; Zaharevitz, D. W.; Gussio, R.; Senderowicz, A. M.; Sausville, E. A.; Kunick, C.; Meijer, L. Eur. J. Biochem. 2000, 267, 5983. (370) Mussmann, R.; Geese, M.; Harder, F.; Kegel, S.; Andag, U.; Lomow, A.; Burk, U.; Onichtchouk, D.; Dohrmann, C.; Austen, M. J. Biol. Chem. 2007, 282, 12030. (371) Grant, K.; Dunion, M.; Yardley, V.; Skaltsounis, A.; Marko, D.; Eisenbrand, G.; Croft, S.; Meijer, L.; Mottram, J. Antimicrob. Agents Chemother. 2004, 48, 3033.

(372) Knockaert, M.; Wieking, K.; Schmitt, S.; Leost, M.; Grant, K. M.; Mottram, J. C.; Kunick, C.; Meijer, L. J. Biol. Chem. 2002, 277, 25493. (373) Kunick, C.; Schultz, C.; Lemcke, T.; Zaharevitz, D. W.; Gussio, R.; Jalluri, R. K.; Sausville, E. A.; Leost, M.; Meijer, L. Bioorg. Med. Chem. Lett. 2000, 10, 567. (374) Singh, I. P.; Jain, S. K.; Kaur, A.; Singh, S.; Kumar, R.; Garg, P.; Sharma, S. S.; Arora, S. K. Eur. J. Med. Chem. 2010, 45, 3439. (375) Venkatswamy, R.; Faas, L.; Young, A. R.; Raman, A.; Hider, R. C. Bioorg. Med. Chem. 2004, 12, 1905. (376) Kamawaki, J.; Ando, T. Chem. Lett. 1979, 8, 755. (377) Blass, B. E. Tetrahedron 2002, 58, 9301. (378) Buarque, C. D.; Militão, G. C. G.; Lima, D. J. B.; Costa-Lotufo, L. V.; Pessoa, C.; de Moraes, M. O.; Cunha-Junior, E. F.; TorresSantos, E. C.; Netto, C. D.; Costa, P. R. R. Bioorg. Med. Chem. 2011, 19, 6885. (379) Netto, C. D.; da Silva, A. J. M.; Salustiano, E. J. S.; Bacelar, T. S.; Riça, I. G.; Cavalcante, M. C. M.; Rumjanek, V. M.; Costa, P. R. R. Bioorg. Med. Chem. 2010, 18, 1610. (380) Lehmann, T.; Köhler, C.; Weidauer, E.; Taege, C. Toxicology 2001, 167, 59. (381) Marrapu, V. K.; Srinivas, N.; Mittal, M.; Shakya, N.; Gupta, S.; Bhandari, K. Bioorg. Med. Chem. Lett. 2011, 21, 1407. (382) Bhandari, K.; Sharma, V. L.; Singh, C. M.; Shanker, G.; Singh, H. K. Indian J. Chem. 2000, 39B, 468. (383) Agarwal, K. C.; Sharma, V.; Shakya, N.; Gupta, S. Bioorg. Med. Chem. Lett. 2009, 19, 5474. (384) El-Rayyes, N. R.; Al-Jawhary, A. J. Heterocycl. Chem. 1986, 23, 135. (385) Short, G. H.; Biermacher, U.; Dunnigan, D. A.; Leth, T. D. J. Med. Chem. 1963, 6, 273. (386) Hu, L.; Arafa, R. K.; Ismail, M. A.; Wenzler, T.; Brun, R.; Munde, M.; Wilson, W. D.; Nzimiro, S.; Samyesudhas, S.; Werbovetz, K. A.; Boykin, D. W. Bioorg. Med. Chem. Lett. 2008, 18, 247. (387) Ismail, M. A.; Arafa, R. K.; Brun, R.; Wenzler, T.; Miao, Y.; Wilson, W. D.; Generaux, C.; Bridges, A.; Hall, J. E.; Boykin, D. W. J. Med. Chem. 2006, 49, 5324. (388) Delfın, D. A.; Bhattacharjee, A. K.; Yakovich, A. J.; Werbovetz, K. A. J. Med. Chem. 2006, 49, 4196. (389) Pandey, S.; Suryawanshi, S. N.; Nishi; Goyal, N.; Gupta, S. Eur. J. Med. Chem. 2007, 42, 669. (390) Sunduru, N.; Nishi; Palne, S.; Chauhan, P. M. S.; Gupta, S. Eur. J. Med. Chem. 2009, 44, 2473. (391) Katiyar, S. B.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett. 2005, 15, 4957. (392) Katiyar, S. B.; Bansal, I.; Saxena, J. K.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett. 2005, 15, 47. (393) Patil, V.; Guerrant, W.; Chen, P. C.; Gryder, B.; Benicewicz, D. B.; Khan, S. I.; Tekwani, B. L.; Oyelere, A. K. Bioorg. Med. Chem. 2010, 18, 415. (394) Chen, P. C.; Patil, V.; Guerrant, W.; Green, P.; Oyelere, A. K. Bioorg. Med. Chem. 2008, 16, 4839. (395) Al-Kahraman, Y. M. S. A.; Madkour, H. M. F.; Ali, D.; Yasinzai, M. Molecules 2010, 15, 660. (396) Bakunov, S. A.; Bakunova, S. M.; Bridges, A. S.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.; Tidwell, R. R. J. Med. Chem. 2009, 52, 5763. (397) Bakunova, S. M.; Bakunov, S. A.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.; Hall, J. E.; Tidwell, R. R. J. Med. Chem. 2007, 50, 5807. (398) Dulog, L.; Korner, B.; Heinze, J.; Yang, J. Liebigs Ann. Chem. 1995, 9, 1663. (399) Doad, G. J. S.; Barltrop, J. A.; Petty, C. M.; Owen, T. C. Tetrahedron Lett. 1989, 30, 1597. (400) Wood, J. L.; Khatri, N. A.; Weinreb, S. M. Tetrahedron Lett. 1979, 20, 4907. (401) Bakunov, S. A.; Bakunova, S. M.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.; Tidwell, R. R. J. Med. Chem. 2008, 51, 6927. 10427


Chemical Reviews

Review

(434) Raether, W.; Hänel, H. Parasitol. Res. 2003, 90, S19. (435) Rando, D. G.; Sato, D. N.; Siqueira, L. J. A.; Malvezzi, A.; Leite, C. Q. F.; do Amaral, A. T.; Ferreira, E. I.; Tavares, L. C. Bioorg. Med. Chem. 2002, 10, 557. (436) Dardari, Z.; Lemrani, M.; Sebban, A.; Bahloul, A.; Hassar, M.; Kitane, S.; Berrada, M.; Boudouma, M. Arch. Pharm. Chem. Life Sci. 2006, 339, 291. (437) Hiam, B.; Sebastien, D.; George, B.; Arlette, F.; Kalil, J.; Pape, P. J. Enzyme Inhib. Med. Chem. 2006, 21, 305. (438) Mittra, B.; Saha, A.; Chowdhury, A. R.; Pal, C.; Mandal, S.; Mukhopadhyay, S.; Bandopadhyay, S.; Majumder, H. K. Mol. Med. 2000, 6, 527. (439) Austin, C. A.; Patel, S.; Ono, K.; Nakane, H.; Fisher, L. M. Biochem. J. 1992, 282, 883. (440) Chowdhury, A. R.; Sharma, S.; Mandal, S.; Goswami, A.; Mukhopadhyay, S.; Majumder, H. K. Biochem. J. 2002, 366, 653. (441) Boege, F.; Straub, T.; Kehr, A.; Bosenberg, C.; Christiansen, K.; Anderson, A.; Jacob, F.; Kohrle, J. J. Biol. Chem. 1996, 271, 2262. (442) Webb, M. R.; Ebeller, S. E. Biochem. J. 2004, 384, 527. (443) Sengupta, T.; Mukherjee, M.; Das, A.; Mandal, C.; Das, R.; Mukherjee, T.; Majumder, H. K. Biochem. J. 2005, 390, 419. (444) Xu, H.; Ziegelin, G.; Schroder, W.; Frank, J.; Ayora, S.; Alonso, J. C.; Lanka, E.; Saenger, W. Nucleic Acids Res. 2001, 29, 5058. (445) Das, B. B.; Sen, N.; Roy, A.; Dasgupta, S. B.; Ganguly, A.; Mohanta, B. C.; Dinda, B.; Majumder, H. K. Nucleic Acids Res. 2006, 34, 1121. (446) Hsiang, Y. H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol. Chem. 1985, 260, 14873. (447) Shapiro, T. A.; Klein, V. A.; Englund, P. T. J. Biol. Chem. 1989, 264, 4173. (448) Bridewell, D. J.; Finlay, G. J.; Baguley, B. C. Oncol. Res. 1997, 9, 535. (449) Fortune, J. M.; Osheroff, N. J. Biol. Chem. 1998, 273, 17643. (450) O’Brien, R. L.; Allison, J. L.; Hahn, F. E. Biochim. Biophys. Acta 1966, 129, 622. (451) Misra, P.; Khaliq, T.; Dixit, A.; SenGupta, S.; Samant, M.; Kumari, S.; Kumar, A.; Kushawaha, P. K.; Majumder, H. K.; Saxena, A. K.; Narender, T.; Dube, A. J. Antimicrob. Chemother. 2008, 62, 998. (452) Nafisi, S.; Bonsaii, M.; Maali, P.; Khalilzadeh, M. A.; Manouchehri, F. J. Photochem. Photobiol., B 2010, 100, 84. (453) Di Giorgio, C.; Delmas, F.; Ollivier, E.; Elias, R.; Balansard, G.; Timon-David, P. Exp. Parasitol. 2004, 106, 67. (454) Vannier-Santos, M. A.; Martiny, A.; Meyer-Fernandes, J. R.; de Souza, W. Eur. J. Cell. Biol. 1995, 67, 112. (455) Roy, A.; Das, B. B.; Ganguly, A.; Dasgupta, S. B.; Khalkho, N. V. M; Pal, C.; Dey, S.; Giri, V. S.; Jaisankar, P.; Dey, S.; Majumder, H. K. Biochem. J. 2008, 409, 611. (456) Tiwari, R. K.; Guo, L.; Bradlow, H. L.; Telang, N. T.; Osborne, M. P. J. Natl. Cancer Inst. 1994, 86, 126. (457) Hong, C.; Kim, H. A.; Firestone, G. L.; Bjeldanes, L. F. Carcinogenesis 2002, 23, 1297. (458) Chen, I.; McDougal, A.; Wang, F.; Safe, S. Carcinogenesis 1998, 19, 1631. (459) Xue, L.; Firestone, G. L.; Bjeldanes, L. F. Oncogene 2005, 24, 2343. (460) Hong, C.; Firestone, G. L.; Bjeldanes, L. F. Biochem. Pharmacol. 2002, 63, 1085. (461) Rahman, K. W.; Sarkar, F. H. Cancer Res. 2005, 65, 364. (462) Riby, J. E.; Xue, L.; Chatterji, U.; Bjeldanes, E. L.; Firestone, G. L.; Bjeldanes, L. F. Mol. Pharmacol. 2006, 69, 430. (463) Gong, Y.; Firestone, G. L.; Bjeldanes, L. F. Mol. Pharmacol. 2006, 69, 1320. (464) Ganguly, A.; Das, B. B.; Sen, N.; Roy, A.; Dasgupta, S. B.; Majumder, H. K. Nucleic Acids Res. 2006, 34, 6286. (465) Das, B. B.; Sen, N.; Dasgupta, S. B.; Ganguly, A.; Majumder, H. K. J. Biol. Chem. 2005, 280, 16335.

(402) Dox, A. W.; Whitmore, F. C. Acetamidine hydrochloride. In Organic Syntheses, 2nd ed.; Blatt, A. H., Ed.; John Wiley and Sons: New York, 1941; Vol. 1, pp 5. (403) Tewari, N.; Mishra, R. C.; Tripathi, R. P.; Srivastava, V. M. L.; Gupta, S. Bioorg. Med. Chem. Lett. 2004, 14, 4055. (404) Tripathi, R. P.; Tripathi, R.; Tiwari, V. K.; Bala, L.; Sinha, S. A.; Srivastava, R.; Srivastava, B. S. Eur. J. Med. Chem. 2002, 37, 773. (405) Khan, A. R.; Tripathi, R. P.; Tiwari, V. K.; Mishra, R. C.; Reddy, V. J. M.; Saxena, J. K. J. Carbohydr. Chem. 2002, 21, 591. (406) Tewari, N.; Mishra, R. C.; Tiwari, V. K.; Tripathi, R. P. Synlett 2002, 11, 1779. (407) Mello, H.; Echevarria, A.; Bernardino, A. M.; CantoCavalheiro, M.; Leon, L. L. J. Med. Chem. 2004, 47, 5427. (408) Taylor, E. C.; Hart, K. J. Am. Chem. Soc. 1959, 81, 2456. (409) Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti, F. Can. J. Chem. 1988, 66, 420. (410) Hohn, H.; Denzel, T.; Janssen, W. J. Heterocycl. Chem. 1972, 9, 235. (411) Omura, Y.; Taruno, Y.; Irisa, Y.; Morimoto, M.; Saimoto, H.; Shigemasa, Y. Tetrahedron Lett. 2001, 42, 7273. (412) Bernardino, A. M. R.; Mello, H.; Romeiro, G. A.; Ferreira, V. F.; Souza, M. C. B. Heterocycl. Commun. 1996, 12, 415. (413) Bernardino, A. M. R.; Mello, H.; Romeiro, G. A.; Ferreira, V. F.; Souza, M. C. B. V.; Carvalho, M. G. Magn. Reson. Chem. 1996, 34, 730. (414) Alipour, E.; Emami, S.; Yahya-Meymandi, A.; Nakhjiri, M.; Johari, F.; Ardestani, S. K.; Poorrajab, F.; Hosseini, M.; Shafiee, A.; Alireza, F. J. Enzyme Inhib. Med. Chem. 2011, 26, 123. (415) Foroumadi, A.; Mirzaei, M.; Shafiee, A. Farmaco 2001, 56, 621. (416) Foroumadi, A.; Daneshtalab, M.; Shafiee, A. Arzneim-Forsch. Drug Res. 1999, 49, 1035. (417) Foroumadi, A.; Rineh, A.; Emami, S.; Siavoshi, F.; Massarrat, S.; Safari, F.; Rajabalian, S.; Falahati, M.; Lotfali, E.; Shafiee, A. Bioorg. Med. Chem. Lett. 2008, 18, 3315. (418) Tahghighi, A.; Marznaki, F. R.; Kobarfard, F.; Dastmalchi, S.; Mojarrad, J. S.; Razmi, S.; Ardestani, S. K.; Emami, S.; Shafiee, A.; Foroumadi, A. Eur. J. Med. Chem. 2011, 46, 2602. (419) Foroumadi, A.; Pournourmohammadi, S.; Soltani, F.; Rezaee, M. A.; Dabiri, S.; Kharazmi, A.; Shafiee, A. Bioorg. Med. Chem. Lett. 2005, 15, 1983. (420) Shriner, R. L.; Neumann, F. W. Chem. Rev. 1944, 35, 351. (421) Roger, R.; Neilson, D. G. Chem. Rev. 1961, 61, 179. (422) Dutta, A.; Bandyopadhyay, S.; Mandal, C.; Chatterjee, M. Parasitol. Int. 2005, 54, 119. (423) Esteves, M. A.; Fragiadaki, I.; Lopes, R.; Scoulica, E.; Cruz, M. E. M. Bioorg. Med. Chem. 2010, 18, 274. (424) Carvalheiro, M.; Jorge, J.; Eleutério, C.; Pinhal, A. F.; Sousa, A. C.; Morais, J. G.; Cruz, M. E. M. Eur. J. Pharm. Biopharm. 2009, 71, 292. (425) Marques, C.; Carvalheiro, M.; Pereira, M. A.; Jorge, J.; Cruz, M. E. M.; Santos-Gomes, G. M. Vet. J. 2008, 178, 133. (426) Benbow, J. W.; Bernberg, E. L.; Korda, A.; Mead, J. R. Antimicrob. Agents Chemother. 1998, 42, 339. (427) Chan, M. M.; Tzeng, J.; Emge, T. J.; Ho, C. T.; Fong, D. Antimicrob. Agents Chemother. 1993, 37, 1909. (428) Junior, C. G. L.; de Assis, P. A. C.; Silva, F. P. L.; Sousa, S. C.O.; de Andrade, N. G.; Barbosa, T. P.; Nerís, P. L. N.; Segundo, L. V. G.; Anjos, I.́ C.; Carvalho, G. A. U.; Rocha, G. B.; Oliveira, M. R.; Vasconcellos, M. L. A. A. Bioorg. Chem. 2010, 38, 279. (429) Pandey, V. P.; Bisht, S. S.; Mishra, M.; Kumar, A.; Siddiqi, M. I.; Verma, A.; Mittal, M.; Sane, S. A.; Gupta, S.; Tripathi, R. P. Eur. J. Med. Chem. 2010, 45, 2381. (430) Wolform, M. L.; Hanessian, S. J. Org. Chem. 1962, 27, 1800. (431) Freudenberg, K.; Dun, W.; Von Hochstetter, H. Ber. Dtsch. Chem. Ges 1928, 61, 1732. (432) Bisht, S. S.; Dwivedi, N.; Tripathi, R. P. Tetrahedron Lett. 2007, 48, 1187. (433) Rando, D. G.; Avery, M. A.; Tekwani, B. L.; Khan, S. I.; Ferreira, E. I. Bioorg. Med. Chem. 2008, 16, 6724. 10428


Fruitful Decade for Antileishmanial Compounds ... - ACS Publications

Recommend Documents