RSC Symposium on Medicinal Chemistry for Global Health: A

Editorial Cite This: ACS Infect. Dis. 2018, 4, 424−428

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2nd SCI/RSC Symposium on Medicinal Chemistry for Global Health: A Unique Opportunity for the Field

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break, Dr. Julian Rayner from the Wellcome Trust Sanger Institute described the platform built at the Sanger Institute to systematically explore the essentiality of the Plasmodium genome. The goal is to identify and prioritize targets to get new therapies by using large-scale reverse genetic screens. Dr. Rayner illustrated the potential uses of this technology for pooled phenotyping (mosquito stages, invasion adhesion, spleen clearance) and new types of screens.6 Finally, after a brief description of the DNDi portfolio and mission, Dr. Benjamin Perry from DNDi introduced the NTD Drug Discovery Booster program directed at visceral leishmaniasis (VL) and Chagas disease. The goals include the expansion of HTS hits, reduction of redundancy by pooling of structures and information, acceleration of discovery while reducing costs, and experiments with a new open innovation approach to drug discovery. To achieve these goals, DNDi has established a consortium of several pharmaceutical companies including Eisai, Shionogi, Takeda, Cellgene, AstraZeneca, Merck and Abbvie. In the consortium, each company runs an in silico screen on the same DNDi hit; then, the closest structures from their database are shared with DNDi. After in vitro confirmation, the best analog is shared among the consortium and the process starts again or moves to lead optimization. More than 26 booster interactions have been run so far.7 The program next shifted to tuberculosis and featured talks on both target and phenotypic-based drug discovery approaches. Chris Abell of the University of Cambridge highlighted his lab’s efforts to apply fragment-based drug discovery to tuberculosis (TB) and showed examples in the coenzyme A (CoA) biosynthetic pathway and several optimized fragments that inhibit P450 enzymes. As observed in many target-based approaches for TB, conversion to wholecell active compounds proved challenging. In the case of TB, the in vitro−in vivo disconnect is particularly pronounced due to the inability to properly model in vitro the complex in vivo physiology, metabolic adaptations, and interplay of Mycobacterium tuberculosis (Mtb) with the host immune system. Carl Nathan at Weill Cornell Medical College, whose lab focuses on phenotypic tolerance of Mtb to antibiotics, presented intriguing data on a novel class of β-lactam antibiotics, which lack the conserved carboxylic acid, are active against nonreplicating Mtb, and do not involve inhibition of penicillin-binding proteins.8 While the mechanism of action remains elusive, activity-based protein profiling has helped refine a list of potential targets. Prof. Nathan has now screened over six thousand β-lactams from Sanofi and GSK and identified many new candidates possessing this unique activity profile as part of the Tuberculosis Drug Accelerator (TBDA) program. Carlos Alemparte rounded out the TB session with an inspiring story on the

n 2009, the Lancet published an article by Koplan et al. defining global health as an interdisciplinary and multidisciplinary supra-discipline focusing on issues that affect health, including both prevention and clinical care, across national boundaries. Under this definition falls a large group of infectious and parasite driven diseases as well as noncommunicable diseases.1 Traditionally, the term global health has been associated with developing countries as the burden of preventable diseases is devastating in low-income countries. However, antimicrobial resistance to tuberculosis and antiparasitic drugs are now affecting middle- and high-income countries. The key element that differentiates global health from terms such as public or international health is the emphasis on collaboration among countries, nongovernmental organizations (NGOs) and funding agencies. Therefore, although the disciplines involved in the development of new drugs are the same as that for any other disease area, global health drug discovery is distinctive in terms of funding models, scientific knowledge and the number of research scientists involved. These unique features motivated the Society for Chemistry and Industry (SCI) and Royal Society of Chemistry (RSC) to organize a scientific meeting focused on drug discovery for global health (SCI/RSC Symposium on Medicinal Chemistry for Global Health).2 Like the inaugural meeting in 2014,3 the second was convened at GlaxoSmithKline (GSK) in Tres Cantos, Spain during the 18th−20th of June 2017. The threeday meeting brought together scientists from more than 15 countries working on malaria, Chagas disease, leishmaniasis, African trypanosomiasis, tuberculosis, diarrheal diseases, viral diseases (Dengue, Zika, hepatitis), schistosomiasis, filariasis and other neglected tropical diseases. The forum was also an opportunity to understand operating models and portfolios from funding agencies like the Wellcome Trust (WT), Medicines from Malaria Venture (MMV), the Bill and Melinda Gates Foundation (BMGF), and Drugs for Neglected Disease Initiative (DNDi). The meeting was divided in six sessions centered on a particular topic, disease or group of related diseases, except the last one, which was a mixture. After the welcome introduction from the GSK malaria unit head, John Haselden, and SCI member, Caroline Low, the meeting started with a keynote lecture from Dr. Ann MillsDuggan (Innovations Division Strategic Partnership Group at the Wellcome Trust), who gave an overview of the key elements of the Wellcome Trust (WT) strategy and the new areas the trust is supporting. She showed some of the outputs of their strategy along with the new Innovator awards, which aim to help researchers develop healthcare innovations that could make an impact on human health.4 The following talk was presented by Prof. Matthew Todd from the University of Sidney, who has pioneered an innovative open source program wherein groups around the world collaborate in a completely open manner. He described the Six Laws of Open Science and current achievements from his antimalarial program.5 After the © 2018 American Chemical Society

Special Issue: Drug Discovery for Global Health Received: January 23, 2018 Published: April 13, 2018 424

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radical cure of Plasmodium vivax, which causes a milder recurring form of malaria. The ability for the organism to go dormant in the liver as a hypnozoite for long periods of time leads to relapse after successful treatment of the blood stage of infection. The major barrier in the field has been an inability to continuously culture P. vivax in blood and lack of a liver stage P. vivax assay. Dr. Campo thus enthusiastically reported the preliminary evaluation of several of the most promising MMV compounds against three new liver stage assays. Improvements of these assays over the next couple of years should expand the screening capacity enabling identification of suitable candidates to affect the proclaimed radical cure of P. vivax. Leishmaniasis is a parasitic infection caused by leishmania species transmitted by the sandfly and can lead to three forms of infection ranging from the milder cutaneous leishmaniasis to the lethal visceral leishmaniasis (VL). Current treatments for VL are extremely toxic with efficacies ranging from 35% to 95% depending on the drug and local resistance patterns, thus motivating the search for an effective, safe, and convenient treatment. Dr. Tim Miles at GSK Tres Cantos and Dr. Gavin Whitlock at Sandexis and DNDi presented their independent and complementary research programs that yielded two promising preclinical series effective against VL. Notably both studies employed the more physiologically relevant macrophage infection assay. Dr. Miles’ team at GSK in collaboration with the University of Dundee explored a promising pyrazolopyrimidine hit and lead optimization centered on balancing potency and solubility, which was critical to obtain oral bioavailability. Their efforts were rewarded with the identification of a promising lead endorsed by both GSK and DNDi as a preclinical candidate for VL. Dr. Whitlock’s group pursued an aminopyrazole hit that exhibited weak activity in axenic culture and no activity in the macrophage infection assay.17 Medicinal chemistry optimization provided DNDI-2491047 with impressive activity against all leishmania strains evaluated, an excellent safety profile, and greater than 99% effectiveness in a murine VL infection model. Hopefully we can expect new treatments for visceral leishmaniasis, a truly devastating NTD in the near future. Adi Nagle of the Genomic Institute of the Novartis Research Foundation (GNF) described efforts to develop a pankinetoplastid inhibitor for treatment of leishmaniasis, Chagas disease, and trypanosomiasis. Given the limited resources for these NTDs, the concept of a pan-kinetoplastid inhibitor is fiscally prudent, yet a scientifically challenging proposition. GNF deployed its considerable resources and screened all pathogens in live cell assays and identified a promising oxazolopyridine pan-kinetoplastid hit. This initial compound was marred by poor solubility, no oral bioavailability, low metabolic stability, and modest micromolar activity against Leishmania donovani in the mouse macrophage assay. Through an elegant medicinal chemistry optimization, the investigators addressed all of the aforementioned liabilities while further improving the potency against each kinetoplastid. The final compound GNF-3408 was active in animal infection models of VL, Chagas disease, and Human African Trypanosomiasis (HAT) achieving cure with no relapse. Mechanism of action studies indicated GNF-3408 targets the kinetoplastid proteosomes binding in a unique position between the β4 and β5 subunits and attains a high level of biochemical selectivity against the human proteasome and immunoproteasome. GNF3408 is now undergoing preclinical safety assessment.

development of the benzoxaborole clinical candidate GSK-070, which is a potent nanomolar inhibitor of Leucyl-tRNA synthetase (LeuRS). Beginning from an initial screening hit, scientists at GSK were able to optimize the potency by more than two orders of magnitude resulting in a compound with outstanding pharmacokinetic (PK) properties, no observable mammalian toxicity, in vivo efficacy in a chronic murine mouse model, and excellent synergy in TB drug combinations.9 The success marks another triumph for the benzoxaborole class of compounds and represents one of the few examples of a targetbased drug discovery approach in anti-infectives. Fungal diseases have risen dramatically over the last 20 years and now cause as many deaths as malaria and TB. Although not formerly a NTD, fungal diseases remain neglected relative to other therapeutic areas and have similar challenges as observed in other parasitic eukaryotic pathogens. The organizers thus invited Dr. Stephane Jeanmart, who gave a wonderful perspective of the field of antifungal research with several vignettes from his research at Syngenta, a global leader in antifungal drug discovery. Dr. Jeanmart disclosed 35 high quality hit compounds from phenotypic screening and emphasized the importance of carefully scrutinizing hits for potential assay interference,10 which he noted might be even more problematic for phenotypic screening, where information on the molecular mechanism of action is typically unknown. The success in malaria drug development over the last decade is undisputable and the four talks on malaria captured the excitement in the field. Prof. Ed Tate of the Imperial College London and the Francis Crick Institute shared his work on a target-based approach to discover inhibitors of Nmyristoyl transferase (NMT) in P. falciparum, an enzyme that controls the activity of dozens of other critical proteins involved in diverse functions in the malaria parasite through their posttranslational modification. The target was submitted to highthroughput screening (HTS)11 and multiple chemotypes were identified. Subsequent medicinal chemistry optimization furnished lead compounds with demonstrated on-target subnanomolar cidal activity for blood and liver stages of disease against all plasmodium strains evaluated.12 NMT has now been genetically validated in several trypanosomal diseases13 and against Leishmania spp.,14 suggesting this approach may be useful for other significant eukaryotic pathogens. Dr. Neil Nocrosse from the Drug Discovery Unit (DDU) at the University of Dundee next spoke about his team’s efforts to develop a multistage preclinical candidate for malaria and highlighted the impressive capabilities of the DDU, which fuses academic and industrial scientists with expertise in chemistry, biology, pharmacology, and drug metabolism into a fully operational and integrated drug discovery group. He described the chemical lead optimization of MMV004 to candidate DDD107498, which displays impressive potency across all stages of the malaria life cycle as well as a novel mechanism of action through inhibition of translation elongation factor 2 (eEF2).15 The following presentation by Dr. Beatriz Diaz at GSK-Tres Cantos reported the first time disclosure of the novel thiotriazole candidate GSK030 that exhibits rapid parasite clearance in vivo by targeting PfATP4 and an excellent safety profile.16 This beautiful medicinal chemistry story highlighted how small changes to molecular structure can have a profound impact on the phyiscochemical and drug disposition properties. In the last talk on malaria, Dr. Brice Campo of the Medicines for Malaria Venture (MMV) discussed his organization’s strategy and recent advances for a 425

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where Cryptosporidum resides while minimizing potential systemic toxicity. KDU731 was shown to dramatically reduce parasitemia in both murine and neonate calf models and allowed animals to regain normal hydration status within 3 days of treatment. Collectively, the data are very encouraging and provide a promising preclinical candidate while validating PI(4) K is a druggable and vulnerable target in Cryptosporidium. Taken together the BMGF and NITD Cryptosporidium programs illustrate a remarkable level of progress by coordinating efforts and applying state-of-the art technologies. Steven Ward of the Liverpool School of Tropical Medicine gave an update on their long-standing program to develop effective treatments for human filariasis, a disease caused by various species of roundworms such as Brugia malayi and Onchocera volvulus that cause river blindness and the disfiguring elephantitis, respectively. Invermectin only kills the offspring and is unable to kill adult worms, which can live in the host for 10−14 years. The development of a macrofilaricide active against the adult stage has thus been a goal in the field, but has been hampered by close genetic similarity between nematodes and humans. A key breakthrough occurred when the nematode host Wolbachia was discovered, an essential endosymbionic Gram-negative bacteria. The antibiotic tetracycline was shown to deplete Wolbachia and led to death of adult nematodes. Although effective when given for 6 weeks at 200 mg, this broad-spectrum antibiotic disrupts commensal microbiota, is contraindicated in children, and causes drug-induced photosensitivity, certainly not ideal for the sunny tropical regions where filariasis is endemic. The Liverpool team thus set out to discover a short acting (7-day) antibiotic to deplete Wolbachia in adult nematodes. They established a HTS assay and successfully screened over two million compounds. The macrolide antibiotic tylosin emerged from this screen and medicinal chemistry optimization identified a superior analogue exhibiting a two-orders of magnitude increase in potency resulting in 99% kill of Wolbachia when dosed at 10 mg/kg for 14 days. Further exploration of other compound series and medicinal chemistry optimization through scaffold hopping ultimately provided pyridopyrimidine AWZ1066 that fulfilled all of the candidate criteria and led to an impressive 99.8% elimination of Wolbachia when dosed at 50 mg/kg for 7 days. A macrofilaricide candidate thus seems within reach, which could lead to elimination of adult filariasis and another triumph of NTD drug discovery. The last theme of the meeting focused on antivirals and Prof. Johan Neyts of the University of Leuven, Belgium seminar entitled, “Antivirals, a lot has been achieved, yet a long way to go”, beautifully captured the sentiment in the antiviral community. The importance of effective antiviral is underscored by Bill Gates recent TED talk where he proclaimed, “If anything kills over 10 million people in the next few decades, it’s most likely to be a highly infectious virus rather than a war.”22 Prof. Neyts gave a brief overview of the excellent progress from his lab to discover antivirals for Dengue, Zika, Chikungunya, Enteroviruses, Rabies, Hepatitis E, and Noroviruses. He emphasized broad-spectrum RNA virus inhibitors are needed and many excellent molecular targets remain to be further explored including flavivirus NS4B, enterovirus 2C, and alphavirus nsP1. Lastly, he highlighted the potential of drug repurposing for antivirals as sofosbuvir is effective against Hepatitis E virus while HCV nucleoside inhibitors are active toward noro- and rotaviruses.

Drug repurposing represents the most cost efficient means for discovery of new medicines for NTDs and has given us eflornithine for HAT, amphotericin for Leishmania, and Ivermectin for onchoceriasis. However, there are clear limitations as the repurposed drugs are not optimized for the particular infectious disease and many suffer from unacceptable toxicity. Michael Pollastri at Northeastern University described an alternate approach termed “target class repurposing” wherein one matches homologous families of targets between the human and pathogen and screens the human inhibitors against the selected pathogen.18 This strategy has several advantages as it allows one to leverage the tremendous preexisting knowledge for optimization of safety and efficacy and, perhaps more importantly, provides an opportunity to engage pharmaceutical collaborators, who may have considerable experience with the selected target(s) as well as the resources for early stage assessment of drug disposition properties and safety profiling. Dr. Pollastri illustrated the power of his approach by screening the GSK kinase library against Trypanosoma brucei subsp. brucei (Tbb), which identified hundreds of submicromolar hits possessing physicochemical properties predictive of CNS penetration.19 Optimization of the hits is ongoing and data were presenting from a representative pyrazole-azaindole scaffold, which was transformed into a lead compound and is currently under evaluation in a murine HAT infection model. Moreover, analysis of the screening data revealed certain kinase inhibitors were more likely to inhibit Tbb, and Dr. Pollastri presented striking data showing he could use a purely chemocentric approach to select Tbb active kinase inhibitors. The concept of target class repurposing as proposed by Dr. Pollastri is gaining momentum and appears to be ideally suited for eukaryotic pathogens that contain numerous homologous targets to humans. Enteric and diarrheal diseases kill more than 500,000 children less than five years of age annually and those who survive often have lifelong health problems. Cryptosporidium is the leading nonviral cause of diarrhea and nitazoxanide is the only registered agent for treating Cryptosporidium, yet is poorly effective in most at-risk populations. Against this background, Dr. Stephen Ward outlined the Bill & Melinda Gates Foundation (BMGF) efforts using the Grand Challenges Exploration Program to seed new ideas and the Cryptosporidum Drug Accelerator to coordinate discovery activities.20 In less than three years BMGF’s comprehensive Cryptospordinium program has helped create new enabling tools and technologies for culture, gene editing and genome annotation, in vivo testing platforms, and a diverse drug discovery pipeline employing drug repurposing, high throughput screens, and structure-guided design. Dr. Ward noted the future challenges include finding a path to proof-of-concept (POC), meeting regulatory requirements, and identifying patient populations. Next, Dr. Ujjini Manjunatha of the Novartis Institute for Tropical Diseases (NITD) reported the discovery of the first promising Cryptosporidium drug by screening the NITD parasite box in a cytopathic assay employing C. parvum infected HCT-8 colon cells. The assay identified imidazopyrazine and imidazopyridine scaffolds, previously disclosed as inhibitors of P. falciparum phosphatidylinositol-4-OH kinase (PI(4)K).21 The team leveraged their experience with PI(4)K and observed perfect correlation between enzyme inhibition and antiCryptosporidium activity. The primary hit imidazopyridine KDU731 was selected for further evaluation because of its limited oral bioavailability, thus maximizing enteric exposure 426

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Félix Calderón*

Chronic hepatitis B virus (HBV) infection remains an unmet medical need and over 250 million people are infected worldwide with nearly one-third from China. Thus, HBV has attracted considerable attention from the pharmaceutical industry. Dr. Wei Zhu from the Roche Innovation Center in Shanghai shared his company’s efforts to discover a novel antiviral for chronic HBV infection that targets the capsid protein, which is critical for establishing a DNA reservoir in host cells. Dihydropyrimidines based on Bayer’s prototypical Bay 41-4109 compound are promising scaffolds for HBV capsid inhibitor development, but current second-generation inhibitors still exhibit poor metabolic stability and in vitro hERG inhibition. The Roche team eliminated the hERG inhibition while simultaneously improving the metabolic stability by strategic incorporation of a polar carboxy functional group and bioisosteric replacement of the morpholine by a difluoropyrrolidine. Their third-generation lead candidate demonstrated in vivo elimination of HBV DNA in the liver. These early results are extremely promising and could contribute to a curative regimen for chronic HBV.23 An important part of the conference was the poster sessions. Nine were selected to be included in the presentations program in the format of “flash presentations” (3 min). This block covered diseases not presented in the main program, such as the disclosure of several hits for Schistosomiasis treatment with better in vivo efficacy than praziquantel presented by Mark Gardmer (Salvensis) or inhibitors of Trypanosome alternative oxidase for the treatment of human African trypanosomiasis presented by Ryan West (University of Sussex). Three presentations on malaria were included in this block. The first one disclosed efforts to validate methyl transferases as potential targets to treat malaria (Ainoa Rueda Zubiaurre, Imperial colleague). The second malaria presentation was focused on the use of reactive compounds to identify targets following a fragment-based strategy (Jennifer Borthwick, GSK and The Crick Institute). Lastly, Sonia Moliner (GSK) showed the advances in using CRISPR-cas9 to investigate the cellular role of the farnesyltransferase subunit and validation of DHFRTS as the target of the MMV’s malaria box compound MMV027634. Other poster presenters included Adam Hotra (Nanyang Technological University, Singapore), who explained the efforts to obtain Mycobacterium F1F0 ATP synthase inhibitors and Courtney Aldrich (Univesity of Minnesota) who described compounds that break down the wall of the same bacteriuim. Wesley Van Voorhis (University of Washington) explained the profile of BKI-1369. A bumpedkinase inhibitor for Therapy of Cryptosporidium infection and ́ diarrhea. Finally, Mariá Jesús Perez (Instituto de Quimica Médica, CSIC) disclosed triazolopyrimidines against Chukungunya virus discovered by her group. The quality and diversity of the science presented during this three-day meeting offers an interesting reflection on the extensive interest in the scientific community and funding bodies for this field. This meeting, as well as other related ones, are acting as catalysts to promote the work focused on these diseases. We look forward for the third edition scheduled for 2020.

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Tres Cantos, Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain

AUTHOR INFORMATION

ORCID

Courtney C. Aldrich: 0000-0001-9261-594X Félix Calderón: 0000-0003-0486-6883 Notes

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.

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REFERENCES

(1) Koplan, J. P., Bond, T. C., Merson, M. H., Reddy, K. S., Rodriguez, M. H., Sewankambo, N. K., and Wasserheit, J. N. (2009) Towards a common definition of global health. Lancet 373, 1993− 1995. (2) https://www.soci.org/news/fine-chems/2nd-symposium-onmedicinal-chemistry-for-global-health-preview. (3) https://www.soci.org/Events/Display-Event.aspx?EventCode= FCHEM138. (4) https://wellcome.ac.uk/funding/innovator-awards. (5) Williamson, A. E, Ylioja, P. M, Robertson, M. N., Antonova-Koch, Y., Avery, V., Baell, J. B., Batchu, H., Batra, S., Burrows, J. N., Bhattacharyya, S., Calderon, F., Charman, S. A., Clark, J., Crespo, B., Dean, M., Debbert, S. L., Delves, M., Dennis, A. S. M., Deroose, F., Duffy, S., Fletcher, S., Giaever, G., Hallyburton, I., Gamo, F.-J., Gebbia, M., Guy, R. K., Hungerford, Z., Kirk, K., Lafuente-Monasterio, M. J., Lee, A., Meister, S., Nislow, C., Overington, J. P., Papadatos, G., Patiny, L., Pham, J., Ralph, S. A., Ruecker, A., Ryan, E., Southan, C., Srivastava, K., Swain, C., Tarnowski, M. J., Thomson, P., Turner, P., Wallace, I. M., Wells, T. N. C., White, K., White, L., Willis, P., Winzeler, E. A., Wittlin, S., and Todd, M. H. (2016) Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles. ACS Cent. Sci. 2, 687−701. (6) Bushell, E., Gomes, A. R., Sanderson, T., Anar, B., Girling, G., Herd, C., Metcalf, T., Modrzynska, K., Schwach, F., Martin, R. E., Mather, M. W., McFadden, G. I., Parts, L., Rutledge, G. G., Vaidya, A. B., Wengelnik, A., Rayner, J. C., and Billker, O. (2017) Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes. Cell 170, 260−272. (7) https://www.dndi.org/2015/open-innovation/openinnovationall-kinetoplastids/drug-discovery-booster. (8) Gold, B., Smith, R., Nguyen, Q., Roberts, J., Ling, Y., Lopez Quezada, L., Somersan, S., Warrier, T., Little, D., Pingle, M., Zhang, D., Ballinger, E., Zimmerman, M., Dartois, V., Hanson, P., Mitscher, L. A., Porubsky, P., Rogers, S., Schoenen, F. J., Nathan, C., and Aubé, J. (2016) Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis. J. Med. Chem. 59, 6027−6044. (9) Li, X., Hernandez, V., Rock, F. L., Choi, W., Mak, Y. S. L., Mohan, M., Mao, W., Zhou, Y., Easom, E. E., Plattner, J. J., Zou, W., PérezHerràn, E., Giordano, I., Mendoza-Losana, A., Alemparte, C., Rullas, J., Angulo-Barturen, I., Crouch, S., Ortega, F., Barros, D., and Alley, M. R. K. (2017) Discovery of a Potent and Specific M. tuberculosis LeucyltRNA Synthetase Inhibitor: (S)−3-(Aminomethyl)-4-chloro-7-(2hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)−ol. J. Med. Chem. 60, 8011−8026. (10) Pouliot, M., and Jeanmart, S. (2016) Pan Assay Interference Compounds (PAINS) and Other Promiscuous Compounds in Antifungal Research. J. Med. Chem. 59 (2), 497−503. (11) Bell, A., Mills, J. E., Williams, G. P., Brannigan, J. A., Wilkinson, A. J., Parkinson, T., Leatherbarrow, R. J., Tate, E. W., Holder, A. A., and Smith, D. F. (2012) PLoS Neglected Trop. Dis. 6 (4), e1625. (12) Yu, Z., Brannigan, J. A., Moss, D. K., Brzozowski, A. M., Wilkinson, A. J., Holder, A. A., Tate, E. W., and Leatherbarrow, R. J. (2012) Design and Synthesis of Inhibitors of Plasmodium falciparum

Courtney C. Aldrich* Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 8-174 Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, Minneosta 55455, United States 427

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