{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:56:36Z","timestamp":1787637396699,"version":"build-2736575974"},"reference-count":22,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T00:00:00Z","timestamp":1580860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI106850"],"award-info":[{"award-number":["R01AI106850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TropicalMed"],"abstract":"<jats:p>The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis. Eleven scaffolds subsequently underwent hit-to-lead optimization using standard medicinal chemistry approaches. Over a period of six years in an academic setting, 1539 analogs to the 11 scaffolds were synthesized. Eight scaffolds were discontinued either due to insufficient improvement in antiparasitic activity (5), poor pharmacokinetic properties (2), or a slow (static) antiparasitic activity (1). Three scaffolds were optimized to the point of curing the acute and\/or chronic T. brucei infection model in mice. The progress was accomplished without knowledge of the mechanism of action (MOA) for the compounds, although the MOA has been discovered in the interim for one compound series. Studies on the safety and toxicity of the compounds are planned to help select candidates for potential clinical development. This research demonstrates the power of the phenotypic drug discovery approach for neglected tropical diseases.<\/jats:p>","DOI":"10.3390\/tropicalmed5010023","type":"journal-article","created":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T02:59:18Z","timestamp":1580957958000},"page":"23","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach"],"prefix":"10.3390","volume":"5","author":[{"given":"Frederick S.","family":"Buckner","sequence":"first","affiliation":[{"name":"Center for Emerging and Reemerging Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy","family":"Buchynskyy","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pendem","family":"Nagendar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald A.","family":"Patrick","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Robert","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Center for Emerging and Reemerging Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0097-4222","authenticated-orcid":false,"given":"Zackary","family":"Herbst","sequence":"additional","affiliation":[{"name":"Center for Emerging and Reemerging Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R.","family":"Tidwell","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Gelb","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s40265-019-1051-6","article-title":"Fexinidazole: First global approval","volume":"79","author":"Deeks","year":"2019","journal-title":"Drugs"},{"key":"ref_2","first-page":"CD006201","article-title":"Chemotherapy for second-stage Human African trypanosomiasis","volume":"6","author":"Lutje","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_3","unstructured":"(2020, February 04). WHO Interim Guidelines for the Treatment of Gambiense Human African Trypanosomiasis. Available online: https:\/\/apps.who.int\/iris\/handle\/10665\/326178."},{"key":"ref_4","unstructured":"DNDi (2020, February 04). HAT Target Product Profile. Available online: https:\/\/www.dndi.org\/diseases-projects\/hat\/hat-target-product-profile\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1021\/jm401178t","article-title":"Substituted 2-phenylimidazopyridines: A new class of drug leads for human African trypanosomiasis","volume":"57","author":"Tatipaka","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0014-5793(97)01442-7","article-title":"Transport of glutathione prostaglandin A conjugates by the multidrug resistance protein 1","volume":"419","author":"Evers","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3703","DOI":"10.1021\/jm900030h","article-title":"Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease","volume":"52","author":"Suryadevara","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1021\/acs.jmedchem.6b01163","article-title":"Urea derivatives of 2-aryl-benzothiazol-5-amines: A new class of potential drugs for human African trypanosomiasis","volume":"60","author":"Patrick","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_10","unstructured":"Wermuth, C.G. (2003). Chemical mechanisms of toxicity: Basic knowledge for designing safer drugs. The Practice of Medicinal Chemistry, Elsevier Academic Press. [2nd ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1021\/acsmedchemlett.7b00230","article-title":"1-Benzyl-3-aryl-2-thiohydantoin derivatives as anti-Trypanosoma brucei agents: SAR and in-vivo efficacy","volume":"8","author":"Buchynskyy","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_12","unstructured":"Wermuth, C.G. (2003). The Practice of Medicinal Chemistry, Academic Press. [2nd ed.]."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1126\/science.1131943","article-title":"Fluorine in pharmaceuticals: Looking beyond intuition","volume":"317","author":"Muller","year":"2007","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1021\/acsmedchemlett.8b00498","article-title":"Triazolopyrimidines and imidazopyridines as antitrypanosomal agents: Structure-activity relationships and in vivo efficacy","volume":"10","author":"Nagendar","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1016\/j.bmc.2016.04.006","article-title":"Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense","volume":"24","author":"Patrick","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1021\/acsmedchemlett.7b00202","article-title":"New class of antitrypanosomal agents based on imidazopyridines","volume":"8","author":"Silva","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1016\/j.bmc.2016.11.019","article-title":"Discovery of N-(2-aminoethyl)-N-benzyloxyphenyl benzamides: New potent Trypanosoma brucei inhibitors","volume":"25","author":"Buchynskyy","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nature19339","article-title":"Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness","volume":"537","author":"Khare","year":"2016","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nrd2201","article-title":"Drugs for bad bugs: Confronting the challenges of antibacterial discovery","volume":"6","author":"Payne","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1602\/neurorx.2.1.3","article-title":"The blood-brain barrier: Bottleneck in brain drug development","volume":"2","author":"Pardridge","year":"2005","journal-title":"NeuroRx"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3109\/10611869808997889","article-title":"Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors","volume":"6","author":"Camenisch","year":"1998","journal-title":"J. Drug Target."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9318","DOI":"10.1073\/pnas.1820175116","article-title":"Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition","volume":"116","author":"Wyllie","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Tropical Medicine and Infectious Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2414-6366\/5\/1\/23\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:54:56Z","timestamp":1760172896000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2414-6366\/5\/1\/23"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,5]]},"references-count":22,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["tropicalmed5010023"],"URL":"https:\/\/doi.org\/10.3390\/tropicalmed5010023","relation":{},"ISSN":["2414-6366"],"issn-type":[{"value":"2414-6366","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,5]]}}}