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6-Arylpyrazine-2-carboxamides : a new core for Trypanosoma brucei inhibitors

Rahmani, Raphaël and Ban, Kung and Jones, Amy J. and Ferrins, Lori and Ganame, Danny and Sykes, Melissa L. and Avery, Vicky M. and White, Karen L. and Ryan, Eileen and Kaiser, Marcel and Charman, Susan A. and Baell, Jonathan B.. (2015) 6-Arylpyrazine-2-carboxamides : a new core for Trypanosoma brucei inhibitors. Journal of medicinal chemistry, 58 (17). pp. 6753-6765.

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Official URL: http://edoc.unibas.ch/42085/

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Abstract

From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure-activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol(-1)) of our starting hit (9) and its potency (0.49 μM), the SAR around the core was explored, leading to compounds having an EC50 as low as 25 nM against T. b. brucei and being more than 1500 times less toxic against mammalian L6 and HEK293 cell lines. The most potent compounds in the series were exquisitely selective for T. brucei over a panel of other protozoan parasites, showing an excellent correlation with the human infective parasite Trypanosoma brucei rhodesiense, the most potent compound (65) having an EC50 of 24 nM. The compounds are highly drug-like and are able to penetrate the CNS, their only limitation currently being their rate of microsomal metabolism. To that effect, efforts to identify potential metabolites of selected compounds are also reported.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:05 Dec 2017 10:50
Deposited On:21 Apr 2016 11:54

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