Recent Approaches to Chemical Discovery and Development Against

Jul 11, 2014 - Mathew Njoroge graduated with a Bachelor of Pharmacy degree from the University of Nairobi in 2008. He is currently completing his Ph.D...
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Recent Approaches to Chemical Discovery and Development Against Malaria and the Neglected Tropical Diseases Human African Trypanosomiasis and Schistosomiasis Mathew Njoroge,† Nicholas M. Njuguna,† Peggoty Mutai,† Dennis S. B. Ongarora,† Paul W. Smith,∥ and Kelly Chibale*,†,‡,§ †

Department of Chemistry, ‡Institute of Infectious Disease and Molecular Medicine, and §South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa ∥ Novartis Institute for Tropical Diseases, Singapore 138670, Singapore regression of child development and human productivity. Historically, they have collectively attracted much lower research investment than “first world diseases”.1 Between 1975 and 1999, for example, only 1% of the new drugs introduced were specifically for NTDs, as compared to central nervous system and cardiovascular diseases, which accounted for 15% and 12%, respectively, of the new drugs introduced in this period. This is despite NTDs contributing just about equally to the global morbidity burden.2 The development of drugs against these diseases to clinical stages is also sorely CONTENTS lacking; of the more than 148 000 clinical trials registered at the 1. Introduction 11138 end of 2011, only approximately 1% were focused on the 1.1. Malaria 11139 NTDs.3 The situation is, however, gradually changing, with 4% 1.2. Human African Trypanosomiasis 11141 of new drugs in the last 10 years being developed for NTDs and 1.3. Schistosomiasis 11142 projections from development pipelines predicting a doubling 2. Phenotypic Whole-Cell High-Throughput Screenin the current number of new chemical entities over the next 10 ing 11142 years.3 More recently, the London declaration was signed 3. Target Identification of Phenotypic Highcommitting governments, pharmaceutical companies, and other Throughput Screening Lead Compounds 11148 development partners to concerted efforts for NTD control and 4. Drug Repurposing, Repositioning, and Rescue 11148 eradication.4 4.1. Similarities in Cell Biology 11149 At present, the WHO lists 17 medical conditions as NTDs. 4.2. Similarities in Drug Targets and Exploitation These include: dengue fever, rabies, trachoma, buruli ulcer, of Genome Information 11150 endemic treponematoses, leprosy, Chagas disease, human 4.3. In Silico Approaches 11154 African trypanosomiasis (HAT), leishmaniases, taeniasis/ 4.4. Exploitation of Genome Information 11155 cystercercosis, guinea-worm disease, echinococcosis, foodborne 4.4.1. Exploitation of Coinfection Drug Effitrematodiases, lymphatic filariasis, onchocerciasis, schistosocacy 11155 miasis, and soil-transmitted helminthiases (Table 1).5 4.5. Nonhypothesis Driven Screening for RepurCollectively, it is estimated that these diseases afflict more posing and Repositioning 11155 than 1 billion of the world’s poorest 2.7 billion people living on 4.6. Drug Rescue 11157 less than 2 USD a day and are endemic in 149 countries 5. Conclusion and Future Outlook 11157 (Figure 1). These diseases contribute significantly to child Author Information 11158 mortality in the developing world and greatly undermine Corresponding Author 11158 economic development. In 2010, NTDs and malaria were Notes 11158 estimated to be the cause of 1.321 million deaths globally, an Biographies 11158 increase of 9.2% from 1990 and representing 2.5% of all deaths Acknowledgments 11159 that year.8 The socioeconomic impact of the NTDs is not References 11159 trivial. It is projected that 57 million disability adjusted life-years (DALYs) are lost every year due to these diseases, a figure widely believed to be an underestimate.9 Additionally, diseases 1. INTRODUCTION Neglected tropical diseases (NTDs) refer to a group of infectious diseases, which though treatable and/or preventable, remain a leading cause of morbidity and mortality among the world’s poorest populations. These diseases further fuel a vicious cycle because they are also big contributors to © 2014 American Chemical Society

Special Issue: 2014 Drug Discovery and Development for Neglected Diseases Received: February 19, 2014 Published: July 11, 2014 11138

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The first part of this Review focuses on drug discovery strategies for the selected NTDs through phenotypic whole-cell high-throughput screening (HTS) as a starting point for compound optimization and drug development. The identification of drug targets from hits derived from phenotypic HTS is also discussed. In the second part, we highlight the role played by drug repurposing, repositioning, and rescue as an alternative or complementary approach in the discovery and development of new drugs against the NTDs. A few examples of how both of these approaches have been successfully deployed and the progress made over the last 5 years will be highlighted. These approaches have been selected for highlighting in this Review due to the greater impact they have demonstrated in accelerating the delivery of optimized leads and preclinical drug development candidates relative to other approaches such as target-based HTS.

Table 1. Global Prevalence of and Mortality Due to Selected NTDs and Malaria6,7

lymphatic filariasis schistosomiasis trachoma onchocerciasis dengue fever leishmaniasis Chagas disease human African trypanosomiasis malaria

approx. global prevalence (million)

approx. deaths annually

120 200 84 37 50 12 8−9 6000 (Figure 32).

patients. This is well exemplified in case of mutations in the cytochrome bc1 complex as the main resistance locus for atovaquone, which is what has been observed in the field.144 N-Myristoyltransferase (NMT) is an essential enzyme catalyzing the covalent myristoylation of various eukaryotic and viral proteins promoting protein−protein and protein− membrane associations.145 Because of the essential role of this process in cells, NMT inhibitors have been evaluated as anticancer, antiviral, and antifungal agents.146−148 In T. brucei, knockdown of NMT expression results in parasite death and avirulence, and NMT is therefore a potential target for the development of antitrypanosomal drugs.149 On the basis of this, a high-throughput screen of a 62 000 diversity-based compound library was performed against T. brucei NMT (TbNMT). Compound 98, an N-pyrazole arylsulfonamide, was selected from the hit compounds identified as a starting point for the SAR exploration of this series.150 Following medicinal chemistry optimization, Frearson et al. identified 99 as a potential lead compound, which cured all animals in a T. b. brucei acute model of HAT when dosed at 12.5 mg/kg twice a day for 4 days. Further work in this series will focus on improving selectivity and CNS permeation.151 In P. falciparum, NMT (PfNMT) is also a potential drug target with its inhibition associated with disruptions in the parasite life cycle.152 In an effort to discover NMT-based antiplasmodials, a focused library of hits consisting of Candida albicans and T. brucei inhibitors was screened against PfNMT. Compound 100, a C. albicans NMT inhibitor, was selected as a starting point for the design and synthesis of more potent NMT inhibitors. These optimization efforts led to the identification of a potential lead compound 101, which had >400-fold selectivity against human NMT and an EC50 of 1.2 μM against P. falciparum 3D7 trophozoites.153 A core-hopping approach starting from 100 and aiming to increase its ligand efficiency led to the identification of 102, which has a benzo[b]thiophene core and a 4-fold selectivity for PfNMT as compared to human NMT with an EC50 of 2.0 μM against P. falciparum 3D7.154 Further SAR explorations of this new scaffold have led to the identification of 103, which has an 8fold selectivity for PfNMT and an EC50 of 0.3 μM. Moreover

Figure 32. Fluoroquinolones with antitrypanosomal activity.

Although oral administration of this compound in T. b. rhodesiense-infected mice was not effective in curing the animals, it was hoped that modifications to enhance aqueous solubility or the preparation of a parenteral formulation may prove more successful in vivo.160 4.3. In Silico Approaches

In silico drug repositioning approaches have been proposed and are analogous to structure-based drug discovery in which in 11154

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28 in some patients.169 Current efforts are focused on the design and synthesis of analogues with better pharmacokinetic properties, a key drawback of this compound. In one such study, a reverse fosmidomycin derivative, 109, was demonstrated to have better in vitro activity against P. falciparum K1 (IC50 0.29 vs 3.7 μM for fosmidomycin). This difference in activity was, however, not seen in vivo with both compounds having comparable efficacy in the P. berghei mouse model. These efforts and other work on fosmidomycin and other reductoisomerase inhibitors have recently been reviewed.11,170 4.4.1. Exploitation of Coinfection Drug Efficacy. Studies have shown that most NTDs occur as coinfections. Coinfections can be exploited because the treatment of one infection could also clear the concurrent disease. An excellent example of this has recently been demonstrated based on the antimalarial effect of antiamoebic drugs that was first hypothesized during studies on the treatment of protozoan amoebiasis in patients coinfected with malaria. As a result, the 5-nitroimidazole derivative tinidazole (110, Figure 35) has been

silico screening is carried out using libraries of established drugs and/or clinical candidates. These approaches can be used complementarily with experimental techniques in repositioning studies; for example, virtual libraries can be created and screened in silico to help guide the potentially more resource intensive in vitro screening.161−164 Computational approaches may also be valuable in prioritizing drug targets and in predicting possible targets for active drugs. A prerequisite for in silico drug repositioning is availability and/or knowledge of the 3D structure of both the drugs and the molecular targets and pharmacophore modeling. While these approaches are slowly gaining traction, as in the section above, their potential is still hampered by the low number of reported active molecules in NTDs and by the relative absence of collaborative networks through which data and models can be shared.165 4.4. Exploitation of Genome Information

Exploitation of genome information for drug repositioning purposes typically involves identification of drug targets using genome homology between a potential target and a validated target in a different therapeutic area. One of the best examples of exploitation of genome information to drug repurposing and/or repositioning is the discovery of the antimalarial efficacy of fosmidomycin (107, Figure 33). Previous research had

Figure 35. Tinidazole.

evaluated in a pilot phase II clinical trial as a potential repositioning antimalarial candidate for radical cure of P. vivax malaria.171 While the compound showed modest activity against liver stages, it was ineffective at the dosage used against preventing relapse of P. vivax malaria.

Figure 33. Fosmidomycin and its derivatives.

4.5. Nonhypothesis Driven Screening for Repurposing and Repositioning

shown that fosmidomycin and its analogue FR-900089 (108) exert their antibacterial effects by inhibiting DOXP reductoisomerase, a key enzyme in the mevalonate-independent 1deoxy-D-xylulose-5-phosphate (DOXP) pathway of isoprenoid biosynthesis.166 Subsequent genome sequencing studies revealed that the DOXP pathway (Figure 34) is conserved in both bacteria and plasmodia. Fosmidomycin and FR-900089 were active in vitro at submicromolar levels across three P. falciparum strains tested and reduced parasitaemia to 10 mg/kg fosmidomycin or 5 mg/kg FR-90089 intraperitoneally.166 Because of the wealth of information available from the testing of fosmidomycin as an antibacterial, including phase II data, the compound has since been tested in trials where it has shown clinical and parasitological cure after administration at 1200 mg every 8 h for 7 days, although recrudescence occurred by day

Drug repurposing and repositioning may also be done by nonhypothesis driven compound screening where libraries of compounds with known properties are screened against the disease of interest. Compound libraries typically consist of drugs already approved for human use for potential “off-label” antiparasitic efficacy using in vitro target-based or/and phenotypic screening. Witschel et al. recently screened 600 commercial agrochemicals for their antiplasmodial, antitrypanosomal, and antileishmanial activities.172 Agrochemicals offer a number of potential advantages as repurposing and repositioning candidates, among them good selectivity, broad toxicological profiles, and low production cost. Submicromolar in vitro activity against P. falciparum was shown by 24 compounds with the most active having low nanomolar activity as

Figure 34. Abbreviated DOXP pathway showing point of action of fosmidomycin.167,168 11155

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Figure 36. Agrochemicals active against NTDs.

Figure 37. Nonhypothesis-based screening hits.

compared to much higher published LD50’s. Two compounds, azoxystrobin (111), a broad spectrum fungicide, and hydramethylon (112), an insecticide, were selected for in vivo activity profiling in the P. berghei mouse model. Azoxystrobin reduced parasitaemia by 98% at a dose of 4 × 100 mg/kg given subcutaneously and extended mice survival from 6 to 7 days in the control group to 13 days. At the same dose, hydramethylon reduced parasitaemia by 87% and extended mice survival to 14 days. In the T. brucei in vitro assay, zoxamide (113), a fungicide, had activity comparable to that of melarsoprol. The activity was, however, lower in vivo (Figure 36). While a dose of 4 × 200 mg/kg given intraperitoneally four times a day apparently cleared the parasitaemia for 24 h after treatment, all of the mice relapsed 3 days later. Although these compounds may require significant development before their use in humans, they nevertheless represent a unique starting point for discovery efforts.172 Other notable examples include the H1-histamine receptor antagonist astemizole (114), whose antimalarial activity was discovered through in vitro parasite-based HTS of a library of 2687 existing drugs. Astemizole and its principal human metabolite, desmethylastemizole (115), had in vivo antimalarial

efficacy in mouse models of malaria.173 A target-based HTS of a 4000-member compound library unraveled the antifungal agent acrisorcin (a mixture of 116), the anticancer agent harmine (117), and the metabotropic glutamate receptor agonist, (±)-2amino-3-phosphonopropionic acid (118), as synergistic inhibitors of P. falciparum heat shock protein 90.174 Although drug repurposing and/or repositioning has been applied more to malaria, NTDs are also starting to benefit from this approach. For example, a medium-throughput screen of about 2000 compounds, of which 41% had been approved for human use, on juvenile schistosome parasites led to identification of several hit compounds. These were filtered on the basis of activity and toxicity leading to the identification of anisomycin (119), lanaloscid sodium (120), and salicylanilide derivative (121) as lead-like compounds with activity in schistosomal animal models.175 More recently, a target-focused HTS of 1514 FDA-approved drugs against the Onchocerca volvulus Chitinase OvCHT1 identified closantel (122), a veterinary anthelmintic, for potential use in chemotherapy of onchocerciasis.176 On the other hand, tamoxifen (123), an established breast cancer antineoplastic, has been shown to be a potential repurposing candidate for the treatment of 11156

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hepatitis, aplastic anemia, and agranulocytosis, restricting its use in the treatment of malaria.181,182 These side effects have been proposed to occur from metabolic activation of the drug (Figure 39).183−186 Various analogues synthesized to overcome this liability while retaining the antimalarial activity have been reviewed.187,188 The most advanced derivative N-tert-butyl isoquine (126, Figure 40) has recently been withdrawn from clinical development because it showed low exposures at doses that would have demonstrated superior safety to chloroquine.188

leishmaniasis (Figure 37). This drug has been shown to possess both in vitro and in vivo efficacy against promastigotes and amastigotes of Leishmania.177 4.6. Drug Rescue

Rediscovery of the 5-nitro imidazole compound fexinidazole, 124, highlights the importance of drug rescue against the neglected diseases. Fexinidazole was initially developed in the late 1970s as a broad spectrum antimicrobial agent but was subsequently abandoned during preclinical development (Figure 38).178 Its antitrypanosomal activity has also been

Figure 38. Fexinidazole.

known since the 1980s.179 Following a systematic review and profiling of its pharmacological properties against HAT in recent years, fexinidazole was approved for clinical trials in 2009 and is currently undergoing phase II/III clinical studies as potentially the newest drug for the treatment of HAT.35,178 If successful, it would represent the first orally available agent for the treatment of both phase I and II HAT, in addition to enabling short-course therapy. Additionally, fexinidazole is currently undergoing phase II proof-of-concept studies to determine its efficacy against visceral leishmaniasis after having shown activity against L. donovani in vitro and against a murine model of the disease in vivo.180 Drug rescue can also occur on the basis of an understanding of the mechanisms of toxicity of existing drugs. Amodiaquine (125) has been reported to cause severe side effects including

Figure 40. Amodiaquine and N-tert-butyl isoquine.

5. CONCLUSION AND FUTURE OUTLOOK While phenotypic HTS has yielded many gains in neglected disease research, advances in genomics and proteomics have accelerated the discovery and validation of drug targets in neglected diseases, and target-based approaches may therefore increasingly contribute to the discovery of new agents. Successes in drug repurposing, repositioning, and rescue demonstrate the need for further screening of the known pharmacopoeia and also for similarities between known and new targets. At a higher level, drug discovery and development in neglected diseases will benefit from more collaborative

Figure 39. Bioactivation of amodiaquine. 11157

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approaches to maximize available resources and knowledge. Product development partnerships and open source drug discovery are among such approaches that are already bearing fruit.189−191 While the last five years have seen increases in funding and research on new drugs against neglected diseases, much still remains to be done for translation of this work into clinically available drugs. Given the increased participation of large pharmaceutical companies in drug discovery against NTDs, precompetitive research, wherein multidisciplinary collaborative research will be practiced by pharmaceutical companies who ordinarily are commercial competitors, will become a feature. In the field of NTDs, much of the current drug discovery efforts are driven by public-private partnerships (PPPs) such as Medicines for Malaria Venture (MMV) and Drugs for Neglected Disease initiative (DNDi). These PPPs have well developed and publicized criteria for selecting clinical development candidates through their respective Expert Scientific Advisory Committees (ESACs) comprising experienced senior scientists from academia and industry. An increasing collaborative landscape is emerging between these PPPs, while they facilitate formation of virtual discovery networks, improved collaborations between big pharma and academia, establishment of centers of excellence and incubators, as well as enhanced screening data and compound file sharing. However, to maximally benefit from economies of scale vis-à-vis resources, expertise, and reduction in duplication of efforts, there needs to be centralized coordination of the various PPPs through a joint precompetitive consortium that is more formalized and structured.

Nicholas Njuguna obtained his undergraduate degree in pharmacy from the University of Nairobi, Kenya, and worked as a regulatory pharmaceutical quality control analyst before receiving his Master of Pharmacy degree in Pharmaceutical Analysis at the same university in 2009. He is currently a Ph.D. candidate at the University of Cape Town, studying under the supervision of Prof. Kelly Chibale and Dr. Collen Masimirembwa, conducting research on the bioactivation of natural products to reactive metabolic intermediates.

AUTHOR INFORMATION Corresponding Author

*Phone: +27-21-6502553. Fax: +27-21-6505195. E-mail: kelly. chibale@uct.ac.za. Peggoty Mutai holds a Bachelor of Pharmacy degree and a Master of Pharmacy degree from the University of Nairobi. She has been pursuing a Ph.D. in Chemistry at the University of Cape Town under the guidance of Prof. Kelly Chibale since 2010 and is due for the award of the degree in 2014. Peggoty is currently lecturing at the School of Pharmacy, University of Nairobi.

Notes

The authors declare no competing financial interest. Biographies

Mathew Njoroge graduated with a Bachelor of Pharmacy degree from the University of Nairobi in 2008. He is currently completing his Ph.D. work with Prof. Kelly Chibale at the University of Cape Town. His research interests are in drug discovery and drug metabolism, in particular, the role of metabolites in drug efficacy and toxicity, and structure−metabolism relationships.

Dennis Ongarora obtained his Bachelor and Master of Pharmacy degrees from the University of Nairobi (Kenya) in 2004 and 2009, respectively. Dennis conducted his doctoral research in Chemistry at the University of Cape Town (South Africa) under the supervision of Prof. Kelly Chibale and Dr. Collen Masimirembwa between 2010 and 11158

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Fellow with K. C. Nicolaou (1994−96). He was a Sandler Sabbatical Fellow at the University of California, San Francisco, CA (2002), a U.S. Fulbright Senior Research Scholar at the University of Pennsylvania School of Medicine in PA (2008), and a Visiting Professor at Pfizer in the UK (2008). His research is in the field of drug discovery.

2014. His research focused on the synthesis and evaluation of antimalarial analogues with improved safety profiles as compared to existing 4-aminoquinolines. He has recently taken up a position as a faculty member in the Department of Pharmaceutical Chemistry at the University of Nairobi. His research focus is on drug discovery and the quality of medicines available in the Kenyan market.

ACKNOWLEDGMENTS We thank the University of Cape Town, South African Medical Research Council, and South African Research Chairs Initiative of the Department of Science and Technology, administered through the South African National Research Foundation, for their support. REFERENCES (1) World Health Organization. Working to Overcome the Global Impact of Neglected Tropical Diseases: First WHO Report on Neglected Tropical Diseases; World Health Organization: Geneva, 2010. (2) Trouiller, P.; Olliaro, P.; Torreele, E.; Orbinski, J.; Laing, R.; Ford, N. Lancet 2002, 359, 2188. (3) Pedrique, B.; Strub-Wourgaft, N.; Some, C.; Olliaro, P.; Trouiller, P.; Ford, N.; Pécoul, B.; Bradol, J.-H. Lancet Global Health 2013, 1, e371. (4) London declaration on neglected tropical diseases; http://www. unitingtocombatntds.org/downloads/press/london_declaration_on_ ntds.pdf (accessed May 31, 2014). (5) The 17 Neglected Tropical Diseases - World Health Organization; http://www.who.int/neglected_diseases/diseases/en/ (accessed May 31, 2014). (6) Hotez, P. J.; Fenwick, A.; Savioli, L.; Molyneux, D. H. Lancet 2009, 373, 1570. (7) World Health Organization. World Malaria Report 2013; Geneva, 2013. (8) Lozano, R.; Naghavi, M.; Foreman, K.; Lim, S.; Shibuya, K.; Aboyans, V.; Abraham, J.; Adair, T.; Aggarwal, R.; Ahn, S. Y.; Alvarado, M.; Anderson, H. R.; Anderson, L. M.; Andrews, K. G.; Atkinson, C.; Baddour, L. M.; Barker-Collo, S.; Bartels, D. H.; Bell, M. L.; Benjamin, E. J.; Bennett, D.; Bhalla, K.; Bikbov, B.; Bin Abdulhak, A.; Birbeck, G.; Blyth, F.; Bolliger, I.; Boufous, S.; Bucello, C.; Burch, M.; Burney, P.; Carapetis, J.; Chen, H.; Chou, D.; Chugh, S. S.; Coffeng, L. E.; Colan, S. D.; Colquhoun, S.; Colson, K. E.; Condon, J.; Connor, M. D.; Cooper, L. T.; Corriere, M.; Cortinovis, M.; de Vaccaro, K. C.; Couser, W.; Cowie, B. C.; Criqui, M. H.; Cross, M.; Dabhadkar, K. C.; Dahodwala, N.; De Leo, D.; Degenhardt, L.; Delossantos, A.; Denenberg, J.; Des Jarlais, D. C.; Dharmaratne, S. D.; Dorsey, E. R.; Driscoll, T.; Duber, H.; Ebel, B.; Erwin, P. J.; Espindola, P.; Ezzati, M.; Feigin, V.; Flaxman, A. D.; Forouzanfar, M. H.; Fowkes, F. G. R.; Franklin, R.; Fransen, M.; Freeman, M. K.; Gabriel, S. E.; Gakidou, E.; Gaspari, F.; Gillum, R. F.; Gonzalez-Medina, D.; Halasa, Y. A.; Haring, D.; Harrison, J. E.; Havmoeller, R.; Hay, R. J.; Hoen, B.; Hotez, P. J.; Hoy, D.; Jacobsen, K. H.; James, S. L.; Jasrasaria, R.; Jayaraman, S.; Johns, N.; Karthikeyan, G.; Kassebaum, N.; Keren, A.; Khoo, J.-P.; Knowlton, L. M.; Kobusingye, O.; Koranteng, A.; Krishnamurthi, R.; Lipnick, M.; Lipshultz, S. E.; Ohno, S. L.; Mabweijano, J.; MacIntyre, M. F.; Mallinger, L.; March, L.; Marks, G. B.; Marks, R.; Matsumori, A.; Matzopoulos, R.; Mayosi, B. M.; McAnulty, J. H.; McDermott, M. M.; McGrath, J.; Mensah, G. A.; Merriman, T. R.; Michaud, C.; Miller, M.; Miller, T. R.; Mock, C.; Mocumbi, A. O.; Mokdad, A. A.; Moran, A.; Mulholland, K.; Nair, M. N.; Naldi, L.; Narayan, K. M. V.; Nasseri, K.; Norman, P.; O’Donnell, M.; Omer, S. B.; Ortblad, K.; Osborne, R.; Ozgediz, D.; Pahari, B.; Pandian, J. D.; Rivero, A. P.; Padilla, R. P.; Perez-Ruiz, F.; Perico, N.; Phillips, D.; Pierce, K.; Pope, C. A.; Porrini, E.; Pourmalek, F.; Raju, M.; Ranganathan, D.; Rehm, J. T.; Rein, D. B.; Remuzzi, G.; Rivara, F. P.; Roberts, T.; De León, F. R.; Rosenfeld, L. C.; Rushton, L.; Sacco, R. L.; Salomon, J. A.; Sampson, U.; Sanman, E.; Schwebel, D. C.; Segui-Gomez, M.; Shepard, D. S.; Singh, D.; Singleton, J.; Sliwa, K.; Smith, E.; Steer, A.; Taylor, J. A.; Thomas, B.;

Paul W. Smith is the head of chemistry at the Novartis Institute for Tropical Diseases in Singapore and has spent 25 years in smallmolecule drug discovery research. Before embarking on his career in the pharmaceutical industry, he obtained his first degree and Ph.D. in synthetic organic chemistry at Oxford University and then spent a further 2 years training at Columbia University, New York, as an SERC-NATO postdoctoral fellow. The focus of research at NITD is the identification of new medicines for the treatment of neglected tropical diseases (including dengue fever and malaria).

Kelly Chibale is a full Professor of Organic Chemistry at the University of Cape Town (UCT). He joined UCT in 1996. He is a Full Member of the UCT Institute of Infectious Disease & Molecular Medicine (IDM). In 2008 he was awarded a Tier 1 South Africa Research Chair in Drug Discovery under the South Africa Research Chairs Initiative (SARChI) of the Department of Science and Technology (DST) and administered through the National Research Foundation (NRF). In 2009 he became the founding Director of the Medical Research Council (MRC) Drug Discovery and Development Research Unit at UCT. In the same year (2009) he was elected a Life Fellow of UCT and a Fellow of the Royal Society of South Africa. In 2010 he became the Founder and Director of the UCT Drug Discovery and Development Centre (H3-D). Kelly obtained his Ph.D. in Synthetic Organic Chemistry from the University of Cambridge in the UK with Stuart Warren (1989−1992). This was followed by postdoctoral stints at the University of Liverpool in the UK as a British Ramsay Research Fellow with Nick Greeves (1992−94) and at the Scripps Research Institute in the U.S. as a Wellcome Trust International Prize Research 11159

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Tleyjeh, I. M.; Towbin, J. A.; Truelsen, T.; Undurraga, E. A.; Venketasubramanian, N.; Vijayakumar, L.; Vos, T.; Wagner, G. R.; Wang, M.; Wang, W.; Watt, K.; Weinstock, M. A.; Weintraub, R.; Wilkinson, J. D.; Woolf, A. D.; Wulf, S.; Yeh, P.-H.; Yip, P.; Zabetian, A.; Zheng, Z.-J.; Lopez, A. D.; Murray, C. J. L.; AlMazroa, M. A.; Memish, Z. A. Lancet 2012, 380, 2095. (9) Conteh, L.; Engels, T.; Molyneux, D. H. Lancet 2010, 375, 239. (10) Treatment and Prevention of Malaria: Antimalarial Drug Chemistry, Action and Use; Staines, H. M., Krishna, S., Eds.; Springer Basel AG: Basel, 2012. (11) Calderón, F.; Wilson, D. M.; Gamo, F.-J. Prog. Med. Chem. 2013, 52, 97. (12) Jacobs, R. T.; Nare, B.; Phillips, M. A. Curr. Top. Med. Chem. 2011, 11, 1255. (13) Garcia-Salcedo, J. A.; Munday, J. C.; Unciti-Broceta, J. D.; de Koning, H. P. In Trypanosomes and Trypanosomiasis; Magez, S., Radwanska, M., Eds.; Springer: Vienna, 2014; pp 217−238. (14) Caffrey, C. R.; Secor, W. E. Curr. Opin. Infect. Dis. 2011, 24, 410. (15) Da Rocha Pitta, M. G.; da Rocha Pitta, M. G.; de Melo Rêgo, M. J. B.; Galdino, S. L. Mini-Rev. Med. Chem. 2013, 13, 493. (16) Bannister, L.; Mitchell, G. Trends Parasitol. 2003, 19, 209. (17) Trampuz, A.; Jereb, M.; Muzlovic, I.; Prabhu, R. M. Crit. Care 2003, 7, 315. (18) Miller, L. H.; Baruch, D. I.; Marsh, K.; Doumbo, O. K. Nature 2002, 415, 673. (19) Seder, R. A.; Chang, L.-J.; Enama, M. E.; Zephir, K. L.; Sarwar, U. N.; Gordon, I. J.; Holman, L. A.; James, E. R.; Billingsley, P. F.; Gunasekera, A.; Richman, A.; Chakravarty, S.; Manoj, A.; Velmurugan, S.; Li, M.; Ruben, A. J.; Li, T.; Eappen, A. G.; Stafford, R. E.; Plummer, S. H.; Hendel, C. S.; Novik, L.; Costner, P. J. M.; Mendoza, F. H.; Saunders, J. G.; Nason, M. C.; Richardson, J. H.; Murphy, J.; Davidson, S. A.; Richie, T. L.; Sedegah, M.; Sutamihardja, A.; Fahle, G. A.; Lyke, K. E.; Laurens, M. B.; Roederer, M.; Tewari, K.; Epstein, J. E.; Sim, B. K. L.; Ledgerwood, J. E.; Graham, B. S.; Hoffman, S. L. Science 2013, 341, 1359. (20) Raj, D. K.; Nixon, C. P.; Nixon, C. E.; Dvorin, J. D.; DiPetrillo, C. G.; Pond-Tor, S.; Wu, H.-W.; Jolly, G.; Pischel, L.; Lu, A.; Michelow, I. C.; Cheng, L.; Conteh, S.; McDonald, E. A.; Absalon, S.; Holte, S. E.; Friedman, J. F.; Fried, M.; Duffy, P. E.; Kurtis, J. D. Science 2014, 344, 871. (21) World Health Organization. Guidelines For The Treatment of Malaria, 2nd ed.; World Health Organization: Geneva, 2010. (22) World Health Organization. Global Report on Antimalarial Drug Efficacy and Drug Resistance: 2000−2010; World Health Organization: Geneva, 2011. (23) Feasey, N.; Wansbrough-Jones, M.; Mabey, D. C. W.; Solomon, A. W. Br. Med. Bull. 2010, 93, 179. (24) Malvy, D.; Chappuis, F. Clin. Microbiol. Infect. 2011, 17, 986. (25) Simarro, P. P.; Cecchi, G.; Franco, J. R.; Paone, M.; Diarra, A.; Ruiz-Postigo, J. A.; Fèvre, E. M.; Mattioli, R. C.; Jannin, J. G. PLoS Neglected Trop. Dis. 2012, 6, e1859. (26) Brun, R.; Blum, J.; Chappuis, F.; Burri, C. Lancet 2010, 375, 148. (27) Docampo, R.; Moreno, S. N. J. Parasitol. Res. 2003, 90, S10. (28) Delespaux, V.; de Koning, H. P. Drug Resist. Updates 2007, 10, 30. (29) World Health Organization. Schistosomiasis Fact Sheet No 115 http://www.who.int/mediacentre/factsheets/fs115/en/ (accessed Feb 12, 2014). (30) Scélo, G.; Brennan, P. Nat. Clin. Pract. Urol. 2007, 4, 205. (31) Meltzer, E.; Schwartz, E. Curr. Infect. Dis. Rep. 2013, 15, 211. (32) World Health Organization. WHO Model List of Essential Medicines - 18th List (April 2013); World Health Organization: Geneva, 2013; pp 1−45. (33) Wang, W.; Wang, L.; Liang, Y.-S. Parasitol. Res. 2012, 111, 1871. (34) Medicines for Malaria Venture - R&D portfolio; http://www. mmv.org/research-development/rd-portfolio (accessed May 31, 2014).

(35) Drugs for Neglected Diseases Initiative - Human African Trypanosomiasis; http://www.dndi.org/diseases-projects/diseases/ hat.html (accessed May 31, 2014). (36) Pink, R.; Hudson, A.; Mouriès, M.-A.; Bendig, M. Nat. Rev. Drug Discovery 2005, 4, 727. (37) Burrows, J. N.; van Huijsduijnen, R. H.; Möhrle, J. J.; Oeuvray, C.; Wells, T. N. C. Malar. J. 2013, 12, 187. (38) Geary, T. G. Curr. Opin. Infect. Dis. 2012, 25, 709. (39) Swinney, D. C.; Anthony, J. Nat. Rev. Drug Discovery 2011, 10, 507. (40) Butera, J. A. J. Med. Chem. 2013, 56, 7715. (41) Kotz, J. Sci. Exch. 2012, 5, 1. (42) Wells, T. N. C. Science 2010, 329, 1153. (43) Gilbert, I. H. J. Med. Chem. 2013, 56, 7719. (44) Chatterjee, A. K.; Yeung, B. K. S. Curr. Top. Med. Chem. 2012, 12, 473. (45) Hart, C. P. Drug Discovery Today 2005, 10, 513. (46) Jeffery, D. A.; Bogyo, M. Curr. Opin. Biotechnol. 2003, 14, 87. (47) Cong, F.; Cheung, A. K.; Huang, S.-M. A. Annu. Rev. Pharmacol. Toxicol. 2012, 52, 57. (48) Sykes, M. L.; Avery, V. M. J. Med. Chem. 2013, 56, 7727. (49) Guiguemde, W. A.; Shelat, A. A.; Garcia-Bustos, J. F.; Diagana, T. T.; Gamo, F.; Guy, R. K. Chem. Biol. 2012, 19, 116. (50) Paquet, T.; Gordon, R.; Waterson, D.; Witty, M. J.; Chibale, K. Future Med. Chem. 2012, 4, 2265. (51) Younis, Y.; Douelle, F.; Feng, T.; Cabrera, D. G.; Manach, C.; Le Nchinda, A. T.; Duffy, S.; White, K. L.; Shackleford, D. M.; Morizzi, J.; Mannila, J.; Katneni, K.; Bhamidipati, R.; Zabiulla, K. M.; Joseph, J. T.; Bashyam, S.; Waterson, D.; Witty, M. J.; Hardick, D.; Wittlin, S.; Avery, V. M.; Charman, S. A.; Chibale, K. J. Med. Chem. 2012, 55, 3479. (52) González Cabrera, D.; Douelle, F.; Younis, Y.; Feng, T.-S.; Le Manach, C.; Nchinda, A. T.; Street, L. J.; Scheurer, C.; Kamber, J.; White, K. L.; Montagnat, O. D.; Ryan, E.; Katneni, K.; Zabiulla, K. M.; Joseph, J. T.; Bashyam, S.; Waterson, D.; Witty, M. J.; Charman, S. A.; Wittlin, S.; Chibale, K. J. Med. Chem. 2012, 55, 11022. (53) Younis, Y.; Douelle, F.; González Cabrera, D.; Le Manach, C.; Nchinda, A. T.; Paquet, T.; Street, L. J.; White, K. L.; Zabiulla, K. M.; Joseph, J. T.; Bashyam, S.; Waterson, D.; Witty, M. J.; Wittlin, S.; Charman, S. A.; Chibale, K. J. Med. Chem. 2013, 56, 8860. (54) González Cabrera, D.; Douelle, F.; Feng, T.-S.; Nchinda, A. T.; Younis, Y.; White, K. L.; Wu, Q.; Ryan, E.; Burrows, J. N.; Waterson, D.; Witty, M. J.; Wittlin, S.; Charman, S. A.; Chibale, K. J. Med. Chem. 2011, 54, 7713. (55) González Cabrera, D.; Le Manach, C.; Douelle, F.; Younis, Y.; Feng, T.-S.; Paquet, T.; Nchinda, A. T.; Street, L. J.; Taylor, D.; de Kock, C.; Wiesner, L.; Duffy, S.; White, K. L.; Zabiulla, K. M.; Sambandan, Y.; Bashyam, S.; Waterson, D.; Witty, M. J.; Charman, S. A.; Avery, V. M.; Wittlin, S.; Chibale, K. J. Med. Chem. 2014, 57, 1014. (56) Chatterjee, A. K. J. Med. Chem. 2013, 56, 7741. (57) Wu, T.; Nagle, A.; Kuhen, K.; Gagaring, K.; Borboa, R.; Francek, C.; Chen, Z.; Plouffe, D.; Goh, A.; Lakshminarayana, S. B.; Wu, J.; Ang, H. Q.; Zeng, P.; Kang, M. L.; Tan, W.; Tan, M.; Ye, N.; Lin, X.; Caldwell, C.; Ek, J.; Skolnik, S.; Liu, F.; Wang, J.; Chang, J.; Li, C.; Hollenbeck, T.; Tuntland, T.; Isbell, J.; Fischli, C.; Brun, R.; Rottmann, M.; Dartois, V.; Keller, T.; Diagana, T.; Winzeler, E.; Glynne, R.; Tully, D. C.; Chatterjee, A. K. J. Med. Chem. 2011, 54, 5116. (58) Nagle, A.; Wu, T.; Kuhen, K.; Gagaring, K.; Borboa, R.; Francek, C.; Chen, Z.; Plouffe, D.; Lin, X.; Caldwell, C.; Ek, J.; Skolnik, S.; Liu, F.; Wang, J.; Chang, J.; Li, C.; Liu, B.; Hollenbeck, T.; Tuntland, T.; Isbell, J.; Chuan, T.; Alper, P. B.; Fischli, C.; Brun, R.; Lakshminarayana, S. B.; Rottmann, M.; Diagana, T. T.; Winzeler, E.; Glynne, R.; Tully, D. C.; Chatterjee, A. K. J. Med. Chem. 2012, 55, 4244. (59) Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; González-Páez, G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.; 11160

dx.doi.org/10.1021/cr500098f | Chem. Rev. 2014, 114, 11138−11163

Chemical Reviews

Review

Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.; Winzeler, E.; Diagana, T. T. Science 2010, 329, 1175. (60) Gamo, F.; Sanz, L. M.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J.; Vanderwall, D. E.; Green, D. V. S.; Kumar, V.; Hasan, S.; Brown, J. R.; Peishoff, C. E.; Cardon, L. R.; Garcia-Bustos, J. F. Nature 2010, 465, 305. (61) Calderón, F.; Barros, D.; Bueno, J. M.; Coterón, J. M.; Fernández, E.; Gamo, F. J.; Lavandera, J. L.; León, M. L.; Macdonald, S. J. F.; Mallo, A.; Manzano, P.; Porras, E.; Fiandor, J. M.; Castro, J. ACS Med. Chem. Lett. 2011, 2, 741. (62) Sanz, L. M.; Jiménez-Díaz, M. B.; Crespo, B.; De-Cozar, C.; Almela, M. J.; Angulo-Barturen, I.; Castañ eda, P.; Ibañ ez, J.; Fernández, E. P.; Ferrer, S.; Herreros, E.; Lozano, S.; Martínez, M. S.; Rueda, L.; Burrows, J. N.; García-Bustos, J. F.; Gamo, F.-J. Antimicrob. Agents Chemother. 2011, 55, 5740. (63) Rueda, L.; Castellote, I.; Castro-Pichel, J.; Chaparro, M. J.; de la Rosa, J. C.; Garcia-Perez, A.; Gordo, M.; Jimenez-Diaz, M. B.; Kessler, A.; Macdonald, S. J. F.; Martinez, M. S.; Sanz, L. M.; Gamo, F. J.; Fernandez, E. ACS Med. Chem. Lett. 2011, 2, 840. (64) Spangenberg, T.; Burrows, J. N.; Kowalczyk, P.; McDonald, S.; Wells, T. N. C.; Willis, P. PLoS One 2013, 8, e62906. (65) Lucantoni, L.; Duffy, S.; Adjalley, S. H.; Fidock, D. A.; Avery, V. M. Antimicrob. Agents Chemother. 2013, 57, 6050. (66) Murugesan, D.; Mital, A.; Kaiser, M.; Shackleford, D. M.; Morizzi, J.; Katneni, K.; Campbell, M.; Hudson, A.; Charman, S. A.; Yeates, C.; Gilbert, I. H. J. Med. Chem. 2013, 56, 2975. (67) Murugesan, D.; Kaiser, M.; White, K. L.; Norval, S.; Riley, J.; Wyatt, P. G.; Charman, S. A.; Read, K. D.; Yeates, C.; Gilbert, I. H. ChemMedChem 2013, 8, 1537. (68) Nwaka, S.; Besson, D.; Ramirez, B.; Maes, L.; Matheeussen, A.; Bickle, Q.; Mansour, N. R.; Yousif, F.; Townson, S.; Gokool, S.; ChoNgwa, F.; Samje, M.; Misra-Bhattacharya, S.; Murthy, P. K.; Fakorede, F.; Paris, J.-M.; Yeates, C.; Ridley, R.; Van Voorhis, W. C.; Geary, T. PLoS Neglected Trop. Dis. 2011, 5, e1412. (69) Sykes, M. L.; Baell, J. B.; Kaiser, M.; Chatelain, E.; Moawad, S. R.; Ganame, D.; Ioset, J.-R.; Avery, V. M. PLoS Neglected Trop. Dis. 2012, 6, e1896. (70) Ferrins, L.; Rahmani, R.; Sykes, M. L.; Jones, A. J.; Avery, V. M.; Teston, E.; Almohaywi, B.; Yin, J.; Smith, J.; Hyland, C.; White, K. L.; Ryan, E.; Campbell, M.; Charman, S. A.; Kaiser, M.; Baell, J. B. Eur. J. Med. Chem. 2013, 66, 450. (71) Tatipaka, H. B.; Gillespie, J. R.; Chatterjee, A. K.; Norcross, N. R.; Hulverson, M. A.; Ranade, R. M.; Nagendar, P.; Creason, S. A.; McQueen, J.; Duster, N. A.; Nagle, A.; Supek, F.; Molteni, V.; Wenzler, T.; Brun, R.; Glynne, R.; Buckner, F. S.; Gelb, M. H. J. Med. Chem. 2014, 57, 828. (72) Vodnala, S. K.; Lundbäck, T.; Sjöberg, B.; Svensson, R.; Rottenberg, M. E.; Hammarström, L. G. J. Antimicrob. Agents Chemother. 2013, 57, 1012. (73) Nare, B.; Wring, S.; Bacchi, C.; Beaudet, B.; Bowling, T.; Brun, R.; Chen, D.; Ding, C.; Freund, Y.; Gaukel, E.; Hussain, A.; Jarnagin, K.; Jenks, M.; Kaiser, M.; Mercer, L.; Mejia, E.; Noe, A.; Orr, M.; Parham, R.; Plattner, J.; Randolph, R.; Rattendi, D.; Rewerts, C.; Sligar, J.; Yarlett, N.; Don, R.; Jacobs, R. Antimicrob. Agents Chemother. 2010, 54, 4379. (74) Ding, D.; Zhao, Y.; Meng, Q.; Xie, D.; Nare, B.; Chen, D.; Bacchi, C. J.; Yarlett, N.; Zhang, Y.-K.; Hernandez, V.; Xia, Y.; Freund, Y.; Abdulla, M.; Ang, K.-H.; Ratnam, J.; McKerrow, J. H.; Jacobs, R. T.; Zhou, H.; Plattner, J. J. ACS Med. Chem. Lett. 2010, 1, 165. (75) Jacobs, R. T.; Nare, B.; Wring, S. A.; Orr, M. D.; Chen, D.; Sligar, J. M.; Jenks, M. X.; Noe, R. A.; Bowling, T. S.; Mercer, L. T.; Rewerts, C.; Gaukel, E.; Owens, J.; Parham, R.; Randolph, R.; Beaudet, B.; Bacchi, C. J.; Yarlett, N.; Plattner, J. J.; Freund, Y.; Ding, C.; Akama, T.; Zhang, Y.-K.; Brun, R.; Kaiser, M.; Scandale, I.; Don, R. PLoS Neglected Trop. Dis. 2011, 5, e1151. (76) Vodnala, S. K.; Ferella, M.; Lundén-Miguel, H.; Betha, E.; van Reet, N.; Amin, D. N.; Oberg, B.; Andersson, B.; Kristensson, K.; Wigzell, H.; Rottenberg, M. E. PLoS Neglected Trop. Dis. 2009, 3, e495.

(77) Vodnala, S. K.; Lundbäck, T.; Yeheskieli, E.; Sjöberg, B.; Gustavsson, A.-L.; Svensson, R.; Olivera, G. C.; Eze, A. A.; de Koning, H. P.; Hammarström, L. G. J.; Rottenberg, M. E. J. Med. Chem. 2013, 56, 9861. (78) Renslo, A. R.; McKerrow, J. H. Nat. Chem. Biol. 2006, 2, 701. (79) Kuntz, A. N.; Davioud-Charvet, E.; Sayed, A. A.; Califf, L. L.; Dessolin, J.; Arnér, E. S. J.; Williams, D. L. PLoS Med. 2007, 4, e206. (80) Cioli, D.; Valle, C.; Angelucci, F.; Miele, A. E. Trends Parasitol. 2008, 24, 379. (81) Song, L.; Li, J.; Xie, S.; Qian, C.; Wang, J.; Zhang, W.; Yin, X.; Hua, Z.; Yu, C. PLoS One 2012, 7, e31456. (82) Sayed, A. A.; Simeonov, A.; Thomas, C. J.; Inglese, J.; Austin, C. P.; Williams, D. L. Nat. Med. 2008, 14, 407. (83) Rai, G.; Sayed, A. A.; Lea, W. A.; Luecke, H. F.; Chakrapani, H.; Prast-Nielsen, S.; Jadhav, A.; Leister, W.; Shen, M.; Inglese, J.; Austin, C. P.; Keefer, L.; Arnér, E. S. J.; Simeonov, A.; Maloney, D. J.; Williams, D. L.; Thomas, C. J. J. Med. Chem. 2009, 52, 6474. (84) Flannery, E. L.; Fidock, D. A.; Winzeler, E. J. Med. Chem. 2013, 56, 7761. (85) Kato, N.; Sakata, T.; Breton, G.; Le Roch, K. G.; Nagle, A.; Andersen, C.; Bursulaya, B.; Henson, K.; Johnson, J.; Kumar, K. A.; Marr, F.; Mason, D.; McNamara, C.; Plouffe, D.; Ramachandran, V.; Spooner, M.; Tuntland, T.; Zhou, Y.; Peters, E. C.; Chatterjee, A. K.; Schultz, P. G.; Ward, G. E.; Gray, N.; Harper, J.; Winzeler, E. Nat. Chem. Biol. 2008, 4, 347. (86) McNamara, C. W.; Lee, M. C. S.; Lim, C. S.; Lim, S. H.; Roland, J.; Nagle, A.; Simon, O.; Yeung, B. K. S.; Chatterjee, A. K.; McCormack, S. L.; Manary, M. J.; Zeeman, A.-M.; Dechering, K. J.; Kumar, T. R. S.; Henrich, P. P.; Gagaring, K.; Ibanez, M.; Kato, N.; Kuhen, K. L.; Fischli, C.; Rottmann, M.; Plouffe, D. M.; Bursulaya, B.; Meister, S.; Rameh, L.; Trappe, J.; Haasen, D.; Timmerman, M.; Sauerwein, R. W.; Suwanarusk, R.; Russell, B.; Renia, L.; Nosten, F.; Tully, D. C.; Kocken, C. H. M.; Glynne, R. J.; Bodenreider, C.; Fidock, D. A.; Diagana, T. T.; Winzeler, E. Nature 2013, 504, 248. (87) Spillman, N. J.; Allen, R. J. W.; McNamara, C. W.; Yeung, B. K. S.; Winzeler, E.; Diagana, T. T.; Kirk, K. Cell Host Microbe 2013, 13, 227. (88) Kissinger, J. C. Trends Parasitol. 2006, 22, 240. (89) Phillips, M. A. Mol. Microbiol. 2012, 86, 10. (90) Lancelot, J.; Caby, S.; Dubois-Abdesselem, F.; Vanderstraete, M.; Trolet, J.; Oliveira, G.; Bracher, F.; Jung, M.; Pierce, R. J. PLoS Neglected Trop. Dis. 2013, 7, e2428. (91) Abdulla, M.-H.; Lim, K.-C.; Sajid, M.; McKerrow, J. H.; Caffrey, C. R. PLoS Med. 2007, 4, e14. (92) Patel, G.; Karver, C. E.; Behera, R.; Guyett, P. J.; Sullenberger, C.; Edwards, P.; Roncal, N. E.; Mensa-Wilmot, K.; Pollastri, M. P. J. Med. Chem. 2013, 56, 3820. (93) Aubé, J. ACS Med. Chem. Lett. 2012, 3, 442. (94) Ashburn, T. T.; Thor, K. B. Nat. Rev. Drug Discovery 2004, 3, 673. (95) Nzila, A.; Ma, Z.; Chibale, K. Future Med. Chem. 2011, 3, 1413. (96) Keiser, J.; Utzinger, J. Curr. Pharm. Des. 2012, 18, 3531. (97) Le, W. J.; You, J. Q.; Mei, J. Y. Yao Xue Xue Bao 1983, 18, 619. (98) Le, W. J.; You, J. Q.; Yang, Y. Q.; Mei, J. Y.; Guo, H. F.; Yang, H. Z.; Zhang, C. W. Yao Xue Xue Bao 1982, 17, 187. (99) Hua, H.-Y.; Liang, Y.-S.; Zhang, Y.; Wei, J.-F.; Guo, H.-X. Parasitol. Res. 2010, 107, 873. (100) Utzinger, J.; Xiao, S.-H.; Tanner, M.; Keiser, J. Curr. Opin. Invest. Drugs 2007, 8, 105. (101) Xiao, S.; Keiser, J.; Chollet, J.; Utzinger, J.; Dong, Y.; Endriss, Y.; Vennerstrom, J. L.; Tanner, M. Antimicrob. Agents Chemother. 2007, 51, 1440. (102) Keiser, J.; Ingram-Sieber, K.; Vargas, M.; Chollet, J.; Wang, X.; Dong, Y.; Vennerstrom, J. L. Antimicrob. Agents Chemother. 2012, 56, 1090. (103) Ingram-Sieber, K.; Schiaffo, C. E.; Sittiwong, W.; Benner, E.; Dussault, P. H.; Keiser, J. J. Antimicrob. Chemother. 2012, 67, 1979. (104) Ingram-Sieber, K.; Yaremenko, I. A.; Krylov, I. B.; Hofer, L.; Terent’ev, A. O.; Keiser, J. J. Med. Chem. 2012, 55, 8700. 11161

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Chemical Reviews

Review

(105) Portela, J.; Boissier, J.; Gourbal, B.; Pradines, V.; Collière, V.; Coslédan, F.; Meunier, B.; Robert, A. PLoS Neglected Trop. Dis. 2012, 6, e1474. (106) Portela, J.; Boissier, J.; Gourbal, B.; Pradines, V.; Collière, V.; Coslédan, F.; Meunier, B.; Robert, A. PLoS Neglected Trop. Dis. 2012, 6, e1474. (107) Brooker, S.; Akhwale, W.; Pullan, R.; Estambale, B.; Clarke, S. E.; Snow, R. W.; Hotez, P. J. Am. J. Trop. Med. Hyg. 2007, 77, 88. (108) Booth, M.; Vennervald, B. J.; Kenty, L.; Butterworth, A. E.; Kariuki, H. C.; Kadzo, H.; Ireri, E.; Amaganga, C.; Kimani, G.; Mwatha, J. K.; Otedo, A.; Ouma, J. H.; Muchiri, E.; Dunne, D. W. BMC Infect. Dis. 2004, 4, 13. (109) Keiser, J.; N’Guessan, N. A.; Adoubryn, K. D.; Silué, K. D.; Vounatsou, P.; Hatz, C.; Utzinger, J.; N’Goran, E. K. Clin. Infect. Dis. 2010, 50, 1205. (110) Basra, A.; Mombo-Ngoma, G.; Melser, M. C.; Diop, D. A.; Würbel, H.; Mackanga, J.-R.; Fürstenau, M.; Zoleko, R. M.; Adegnika, A. A.; Gonzalez, R.; Menendez, C.; Kremsner, P. G.; Ramharter, M. Clin. Infect. Dis. 2013, 56, e68. (111) Ingram-Sieber, K.; Cowan, N.; Panic, G.; Vargas, M.; Mansour, N. R.; Bickle, Q. D.; Wells, T. N. C.; Spangenberg, T.; Keiser, J. PLoS Neglected Trop. Dis. 2014, 8, e2610. (112) Pollastri, M. P.; Campbell, R. K. Future Med. Chem. 2011, 3, 1307. (113) Weinmann, H.; Metternich, R. ChemBioChem 2005, 6, 455. (114) Katiyar, S.; Kufareva, I.; Behera, R.; Thomas, S. M.; Ogata, Y.; Pollastri, M.; Abagyan, R.; Mensa-Wilmot, K. PLoS One 2013, 8, e56150. (115) Ojo, K. K.; Gillespie, J. R.; Riechers, A. J.; Napuli, A. J.; Verlinde, C. L. M. J.; Buckner, F. S.; Gelb, M. H.; Domostoj, M. M.; Wells, S. J.; Scheer, A.; Wells, T. N. C.; Van Voorhis, W. C. Antimicrob. Agents Chemother. 2008, 52, 3710. (116) Oduor, R. O.; Ojo, K. K.; Williams, G. P.; Bertelli, F.; Mills, J.; Maes, L.; Pryde, D. C.; Parkinson, T.; Van Voorhis, W. C.; Holler, T. P. PLoS Negl. Trop. Dis. 2011, 5, e1017. (117) Woodland, A.; Grimaldi, R.; Luksch, T.; Cleghorn, L. A. T.; Ojo, K. K.; Van Voorhis, W. C.; Brenk, R.; Frearson, J. A.; Gilbert, I. H.; Wyatt, P. G. ChemMedChem 2013, 8, 1127. (118) Fugel, W.; Oberholzer, A. E.; Gschloessl, B.; Dzikowski, R.; Pressburger, N.; Preu, L.; Pearl, L. H.; Baratte, B.; Ratin, M.; Okun, I.; Doerig, C.; Kruggel, S.; Lemcke, T.; Meijer, L.; Kunick, C. J. Med. Chem. 2013, 56, 264. (119) Li, Z.; Umeyama, T.; Wang, C. C. PLoS Pathog. 2009, 5, e1000575. (120) Jetton, N.; Rothberg, K. G.; Hubbard, J. G.; Wise, J.; Li, Y.; Ball, H. L.; Ruben, L. Mol. Microbiol. 2009, 72, 442. (121) Ochiana, S. O.; Pandarinath, V.; Wang, Z.; Kapoor, R.; Ondrechen, M. J.; Ruben, L.; Pollastri, M. P. Eur. J. Med. Chem. 2013, 62, 777. (122) Diaz-Gonzalez, R.; Kuhlmann, F. M.; Galan-Rodriguez, C.; Madeira da Silva, L.; Saldivia, M.; Karver, C. E.; Rodriguez, A.; Beverley, S. M.; Navarro, M.; Pollastri, M. P. PLoS Neglected Trop. Dis. 2011, 5, e1297. (123) Crabbe, T.; Welham, M. J.; Ward, S. G. Trends Biochem. Sci. 2007, 32, 450. (124) Engelman, J. A. Nat. Rev. Cancer 2009, 9, 550. (125) Seebeck, T.; Sterk, G. J.; Ke, H. Future Med. Chem. 2011, 3, 1289. (126) Bland, N. D.; Wang, C.; Tallman, C.; Gustafson, A. E.; Wang, Z.; Ashton, T. D.; Ochiana, S. O.; McAllister, G.; Cotter, K.; Fang, A. P.; Gechijian, L.; Garceau, N.; Gangurde, R.; Ortenberg, R.; Ondrechen, M. J.; Campbell, R. K.; Pollastri, M. P. J. Med. Chem. 2011, 54, 8188. (127) Orrling, K. M.; Jansen, C.; Vu, X. L.; Balmer, V.; Bregy, P.; Shanmugham, A.; England, P.; Bailey, D.; Cos, P.; Maes, L.; Adams, E.; van den Bogaart, E.; Chatelain, E.; Ioset, J.-R.; van de Stolpe, A.; Zorg, S.; Veerman, J.; Seebeck, T.; Sterk, G. J.; de Esch, I. J. P.; Leurs, R. J. Med. Chem. 2012, 55, 8745.

(128) Ochiana, S. O.; Gustafson, A.; Bland, N. D.; Wang, C.; Russo, M. J.; Campbell, R. K.; Pollastri, M. P. Bioorg. Med. Chem. Lett. 2012, 22, 2582. (129) Wang, C.; Ashton, T. D.; Gustafson, A.; Bland, N. D.; Ochiana, S. O.; Campbell, R. K.; Pollastri, M. P. Bioorg. Med. Chem. Lett. 2012, 22, 2579. (130) Beghyn, T. B.; Charton, J.; Leroux, F.; Laconde, G.; Bourin, A.; Cos, P.; Maes, L.; Deprez, B. J. Med. Chem. 2011, 54, 3222. (131) Beghyn, T. B.; Charton, J.; Leroux, F.; Henninot, A.; Reboule, I.; Cos, P.; Maes, L.; Deprez, B. J. Med. Chem. 2012, 55, 1274. (132) Wu, T.; Nagle, A.; Chatterjee, A. K. Curr. Med. Chem. 2011, 18, 853. (133) Painter, H. J.; Morrisey, J. M.; Mather, M. W.; Vaidya, A. B. Nature 2007, 446, 88. (134) Baldwin, J.; Michnoff, C. H.; Malmquist, N. A.; White, J.; Roth, M. G.; Rathod, P. K.; Phillips, M. A. J. Biol. Chem. 2005, 280, 21847. (135) Heikkilä, T.; Thirumalairajan, S.; Davies, M.; Parsons, M. R.; McConkey, A. G.; Fishwick, C. W. G.; Johnson, A. P. Bioorg. Med. Chem. Lett. 2006, 16, 88. (136) Heikkilä, T.; Ramsey, C.; Davies, M.; Galtier, C.; Stead, A. M. W.; Johnson, A. P.; Fishwick, C. W. G.; Boa, A. N.; McConkey, G. A. J. Med. Chem. 2007, 50, 186. (137) Phillips, M. A.; Gujjar, R.; Malmquist, N. A.; White, J.; El Mazouni, F.; Baldwin, J.; Rathod, P. K. J. Med. Chem. 2008, 51, 3649. (138) Davies, M.; Heikkilä, T.; McConkey, G. A.; Fishwick, C. W. G.; Parsons, M. R.; Johnson, A. P. J. Med. Chem. 2009, 52, 2683. (139) Bedingfield, P. T. P.; Cowen, D.; Acklam, P.; Cunningham, F.; Parsons, M. R.; McConkey, G. A.; Fishwick, C. W. G.; Johnson, A. P. J. Med. Chem. 2012, 55, 5841. (140) Coteron, J. M.; Marco, M.; Esquivias, J.; Deng, X.; White, K. L.; White, J.; Koltun, M.; El Mazouni, F.; Kokkonda, S.; Katneni, K.; Bhamidipati, R.; Shackleford, D. M.; Angulo-Barturen, I.; Ferrer, S. B.; Jiménez-Díaz, M. B.; Gamo, F.; Goldsmith, E. J.; Charman, W. N.; Bathurst, I.; Floyd, D.; Matthews, D.; Burrows, J. N.; Rathod, P. K.; Charman, S. A.; Phillips, M. A. J. Med. Chem. 2011, 54, 5540. (141) Gujjar, R.; El Mazouni, F.; White, K. L.; White, J.; Creason, S.; Shackleford, D. M.; Deng, X.; Charman, W. N.; Bathurst, I.; Burrows, J.; Floyd, D. M.; Matthews, D.; Buckner, F. S.; Charman, S. A.; Phillips, M. A.; Rathod, P. K. J. Med. Chem. 2011, 54, 3935. (142) Booker, M.; Bastos, C. M.; Kramer, M. L.; Barker, R. H.; Skerlj, R.; Sidhu, A. B.; Deng, X.; Celatka, C.; Cortese, J. F.; Guerrero Bravo, J. E.; Crespo Llado, K. N.; Serrano, A. E.; Angulo-Barturen, I.; Jiménez-Díaz, M. B.; Viera, S.; Garuti, H.; Wittlin, S.; Papastogiannidis, P.; Lin, J.-W.; Janse, C. J.; Khan, S. M.; Duraisingh, M.; Coleman, B.; Goldsmith, E. J.; Phillips, M. A.; Munoz, B.; Wirth, D. F.; Klinger, J. D.; Wiegand, R.; Sybertz, E. J. Biol. Chem. 2010, 285, 33054. (143) Ross, L. S.; Javier Gamo, F.; Lafuente-Monasterio, M. J. E.; Singh, O. M. P.; Rowland, P.; Wiegand, R. C.; Wirth, D. F. J. Biol. Chem. 2014, 289, 17980. (144) Fisher, N.; Abd Majid, R.; Antoine, T.; Al-Helal, M.; Warman, A. J.; Johnson, D. J.; Lawrenson, A. S.; Ranson, H.; O’Neill, P. M.; Ward, S. A.; Biagini, G. A. J. Biol. Chem. 2012, 287, 9731. (145) Farazi, T. A.; Waksman, G.; Gordon, J. I. J. Biol. Chem. 2001, 276, 39501. (146) Das, U.; Kumar, S.; R. Dimmock, J.; K. Sharma, R. Curr. Cancer Drug Targets 2012, 12, 667. (147) Narayanan, A.; Bailey, C.; Kashanchi, F.; Kehn-Hall, K. Expert Opin. Investig. Drugs 2011, 20, 239. (148) Georgopapadakou, N. H. Expert Opin. Invest. Drugs 2002, 11, 1117. (149) Price, H. P.; Güther, M. L. S.; Ferguson, M. A. J.; Smith, D. F. Mol. Biochem. Parasitol. 2010, 169, 55. (150) Brand, S.; Cleghorn, L. A. T.; McElroy, S. P.; Robinson, D. A.; Smith, V. C.; Hallyburton, I.; Harrison, J. R.; Norcross, N. R.; Spinks, D.; Bayliss, T.; Norval, S.; Stojanovski, L.; Torrie, L. S.; Frearson, J. A.; Brenk, R.; Fairlamb, A. H.; Ferguson, M. A. J.; Read, K. D.; Wyatt, P. G.; Gilbert, I. H. J. Med. Chem. 2012, 55, 140. (151) Frearson, J. A.; Brand, S.; McElroy, S. P.; Cleghorn, L. A. T.; Smid, O.; Stojanovski, L.; Price, H. P.; Guther, M. L. S.; Torrie, L. S.; 11162

dx.doi.org/10.1021/cr500098f | Chem. Rev. 2014, 114, 11138−11163

Chemical Reviews

Review

(180) Wyllie, S.; Patterson, S.; Stojanovski, L.; Simeons, F. R. C.; Norval, S.; Kime, R.; Read, K. D.; Fairlamb, A. H. Sci. Transl. Med. 2012, 4, 1. (181) Neftel, K. A.; Woodtly, W.; Schmid, M.; Frick, P. G.; Fehr, J. BMJ (Br. Med. J.) 1986, 292, 721. (182) Olliaro, P.; Nevill, C.; LeBras, J.; Ringwald, P.; Mussano, P.; Garner, P.; Brasseur, P. Lancet 1996, 348, 1196. (183) Harrison, A. C.; Kitteringham, N. R.; Clarke, J. B.; Park, B. K. Biochem. Pharmacol. 1992, 43, 1421. (184) Naisbitt, D. J.; Williams, D. P.; O’Neill, P. M.; Maggs, J. L.; Willock, D. J.; Pirmohamed, M.; Park, B. K. Chem. Res. Toxicol. 1998, 11, 1586. (185) Johansson, T.; Jurva, U.; Grö nberg, G.; Weidolf, L.; Masimirembwa, C. Drug Metab. Dispos. 2009, 37, 571. (186) Shimizu, S.; Atsumi, R.; Itokawa, K.; Iwasaki, M.; Aoki, T.; Ono, C.; Izumi, T.; Sudo, K.; Okazaki, O. Arch. Toxicol. 2009, 83, 701. (187) Bray, P.; Park, B.; Asadollaly, E.; Biagini, G.; Jeyadevan, J.; Berry, N.; Ward, S.; O’ Neill, P. Curr. Top. Med. Chem. 2006, 6, 479. (188) O’Neill, P. M.; Barton, V. E.; Ward, S. A.; Chadwick, J. In Treatment and Prevention of Malaria; Staines, H. M., Krishna, S., Eds.; Springer Basel AG: Basel, 2012; pp 19−44. (189) Årdal, C.; Røttingen, J.-A. PLoS Neglected Trop. Dis. 2012, 6, e1827. (190) Breitstein, J.; Spigelman, M. Clin. Pharmacol. Ther. 2013, 93, 468. (191) Jakobsen, P. H.; Wang, M.; Nwaka, S. PLoS Neglected Trop. Dis. 2011, 5, e1221.

Robinson, D. A.; Hallyburton, I.; Mpamhanga, C. P.; Brannigan, J. A.; Wilkinson, A. J.; Hodgkinson, M.; Hui, R.; Qiu, W.; Raimi, O. G.; van Aalten, D. M. F.; Brenk, R.; Gilbert, I. H.; Read, K. D.; Fairlamb, A. H.; Ferguson, M. A. J.; Smith, D. F.; Wyatt, P. G. Nature 2010, 464, 728. (152) Wright, M. H.; Clough, B.; Rackham, M. D.; Rangachari, K.; Brannigan, J. A.; Grainger, M.; Moss, D. K.; Bottrill, A. R.; Heal, W. P.; Broncel, M.; Serwa, R. A.; Brady, D.; Mann, D. J.; Leatherbarrow, R. J.; Tewari, R.; Wilkinson, A. J.; Holder, A. A.; Tate, E. W. Nat. Chem. 2014, 6, 112. (153) Yu, Z.; Brannigan, J. A.; Moss, D. K.; Brzozowski, A. M.; Wilkinson, A. J.; Holder, A. A.; Tate, E. W.; Leatherbarrow, R. J. J. Med. Chem. 2012, 55, 8879. (154) Rackham, M. D.; Brannigan, J. A.; Moss, D. K.; Yu, Z.; Wilkinson, A. J.; Holder, A. A.; Tate, E. W.; Leatherbarrow, R. J. J. Med. Chem. 2013, 56, 371. (155) Wang, Z.; Englund, P. T. EMBO J. 2001, 20, 4674. (156) Nenortas, E.; Burri, C.; Shapiro, T. A. Antimicrob. Agents Chemother. 1999, 43, 2066. (157) Keiser, J.; Burri, C. Trop. Med. Int. Health 2001, 6, 369. (158) Nenortas, E.; Kulikowicz, T.; Burri, C.; Shapiro, T. A. Antimicrob. Agents Chemother. 2003, 47, 3015. (159) Ma, X.; Zhou, W.; Brun, R. Bioorg. Med. Chem. Lett. 2009, 19, 986. (160) Hiltensperger, G.; Jones, N. G.; Niedermeier, S.; Stich, A.; Kaiser, M.; Jung, J.; Puhl, S.; Damme, A.; Braunschweig, H.; Meinel, L.; Engstler, M.; Holzgrabe, U. J. Med. Chem. 2012, 55, 2538. (161) Ma, D.-L.; Chan, D. S.-H.; Leung, C.-H. Chem. Soc. Rev. 2013, 42, 2130. (162) Hurle, M. R.; Yang, L.; Xie, Q.; Rajpal, D. K.; Sanseau, P.; Agarwal, P. Clin. Pharmacol. Ther. 2013, 93, 335. (163) Liu, Z.; Fang, H.; Reagan, K.; Xu, X.; Mendrick, D. L.; Slikker, W.; Tong, W. Drug Discovery Today 2013, 18, 110. (164) Ekins, S.; Williams, A. J.; Krasowski, M. D.; Freundlich, J. S. Drug Discovery Today 2011, 16, 298. (165) Ponder, E. L.; Freundlich, J. S.; Sarker, M.; Ekins, S. Pharm. Res. 2014, 31, 271. (166) Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer, C.; Hintz, M.; Türbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler, H. K.; Soldati, D.; Beck, E. Science 1999, 285, 1573. (167) Wiesner, J.; Borrmann, S.; Jomaa, H. Parasitol. Res. 2003, 90, S71. (168) Umeda, T.; Tanaka, N.; Kusakabe, Y.; Nakanishi, M.; Kitade, Y.; Nakamura, K. T. Sci. Rep. 2011, 1, 9. (169) Lell, B.; Ruangweerayut, R.; Wiesner, J.; Missinou, M. A.; Schindler, A.; Baranek, T.; Hintz, M.; Hutchinson, D.; Jomaa, H.; Kremsner, P. G. Antimicrob. Agents Chemother. 2003, 47, 735. (170) Jackson, E. R.; Dowd, C. S. Curr. Top. Med. Chem. 2012, 12, 706. (171) Macareo, L.; Lwin, K. M.; Cheah, P. Y.; Yuentrakul, P.; Miller, R. S.; Nosten, F. Malar. J. 2013, 12, 173. (172) Witschel, M.; Rottmann, M.; Kaiser, M.; Brun, R. PLoS Neglected Trop. Dis. 2012, 6, e1805. (173) Chong, C. R.; Chen, X.; Shi, L.; Liu, J. O.; Sullivan, D. J. Nat. Chem. Biol. 2006, 2, 415. (174) Shahinas, D.; Liang, M.; Datti, A.; Pillai, D. R. J. Med. Chem. 2010, 53, 3552. (175) Abdulla, M.; Ruelas, D. S.; Wolff, B.; Snedecor, J.; Lim, K.; Xu, F.; Renslo, A. R.; Williams, J.; McKerrow, J. H.; Caffrey, C. R. PLoS Neglected Trop. Dis. 2009, 3, e478. (176) Gloeckner, C.; Garner, A. L.; Mersha, F.; Oksov, Y.; Tricoche, N.; Eubanks, L. M.; Lustigman, S.; Kaufmann, G. F.; Janda, K. D. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 3424. (177) Miguel, D. C.; Yokoyama-Yasunaka, J. K. U.; Andreoli, W. K.; Mortara, R. A.; Uliana, S. R. B. J. Antimicrob. Chemother. 2007, 60, 526. (178) Torreele, E.; Bourdin Trunz, B.; Tweats, D.; Kaiser, M.; Brun, R.; Mazué, G.; Bray, M. A.; Pécoul, B. PLoS Neglected Trop. Dis. 2010, 4, e923. (179) Raether, W.; Seidenath, H. Ann. Trop. Med. Parasitol. 1983, 77, 13. 11163

dx.doi.org/10.1021/cr500098f | Chem. Rev. 2014, 114, 11138−11163