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dc.contributor.authorRussell, Stephanie
dc.contributor.authorRahmani, Raphael
dc.contributor.authorJones, Amy J
dc.contributor.authorNewson, Harriet L
dc.contributor.authorNeilde, Kevin
dc.contributor.authorCotillo, Ignacio
dc.contributor.authorKhajouei, Marzieh Rahmani
dc.contributor.authorFerrins, Lori
dc.contributor.authorQureishi, Sana
dc.contributor.authorNghi, Nguyen
dc.contributor.authorMartinez-Martinez, Maria S
dc.contributor.authorWeaver, Donald F
dc.contributor.authorKaiser, Marcel
dc.contributor.authorRiley, Jennifer
dc.contributor.authorThomas, John
dc.contributor.authorDe Rycker, Manu
dc.contributor.authorRead, Kevin D
dc.contributor.authorFlematti, Gavin R
dc.contributor.authorRyan, Eileen
dc.contributor.authorTanghe, Scott
dc.contributor.authorRodriguez, Ana
dc.contributor.authorCharman, Susan A
dc.contributor.authorKessler, Albane
dc.contributor.authorAvery, Vicky M
dc.contributor.authorBaell, Jonathan B
dc.contributor.authorPiggott, Matthew J
dc.description.abstractThe parasitic trypanosomes Trypanosoma brucei and T. cruzi are responsible for significant human suffering in the form of human African trypanosomiasis (HAT) and Chagas disease. Drugs currently available to treat these neglected diseases leave much to be desired. Herein we report optimization of a novel class of N-(2-(2-phenylthiazol-4-yl)ethyl)amides, carbamates, and ureas, which rapidly, selectively, and potently kill both species of trypanosome. The mode of action of these compounds is unknown but does not involve CYP51 inhibition. They do, however, exhibit clear structure–activity relationships, consistent across both trypanosome species. Favorable physicochemical parameters place the best compounds in CNS drug-like chemical space but, as a class, they exhibit poor metabolic stability. One of the best compounds (64a) cleared all signs of T. cruzi infection in mice when CYP metabolism was inhibited, with sterile cure achieved in one mouse. This family of compounds thus shows significant promise for trypanosomiasis drug discovery.
dc.publisherAmerican Chemical Society
dc.relation.ispartofjournalJournal of Medicinal Chemistry
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry not elsewhere classified
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.titleHit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorAvery, Vicky M.
gro.griffith.authorJones, Amy J.

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