期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 21, 页码 9686-9720出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00442
关键词
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资金
- National Health and Medical Research Council of Australia (NHMRC), IRIISS grant [361646]
- NHMRC [1020411, 1025581, 1079351]
- Victorian State Government OIS grant
- Tres Cantos Open Lab Foundation [TC150]
- Wellcome Trust [100476]
- University of Western Australia
- Australian Government
- National Health and Medical Research Council of Australia [1079351] Funding Source: NHMRC
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.
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