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Abstract
© 2016 American Chemical Society.
The 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.
The 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.
Original language | English |
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Pages (from-to) | 9686-9720 |
Number of pages | 35 |
Journal | Journal of Medicinal Chemistry |
Volume | 59 |
Issue number | 21 |
Early online date | 22 Aug 2016 |
DOIs | |
Publication status | Published - 10 Nov 2016 |
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Dive into the research topics of 'Hit-to-lead optimization of a novel class of potent, broad-spectrum trypanosomacides'. Together they form a unique fingerprint.Projects
- 1 Finished
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Discovery of Single Agents to Treat Chagas Disease and Human African Trypanosomiasis
Baell, J. (Investigator 01), Avery, V. (Investigator 02), Charman, S. (Investigator 03), Creek, D. (Investigator 04) & Piggott, M. (Investigator 05)
NHMRC National Health and Medical Research Council
1/01/15 → 31/12/17
Project: Research