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3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis

Ferrins, Lori and Rahmani, Raphaël and Sykes, Melissa L. and Jones, Amy J. and Avery, Vicky M. and Teston, Eliott and Almohaywi, Basmah and Yin, Jiexiang and Smith, Jason and Hyland, Chris and White, Karen L. and Ryan, Eileen and Campbell, Michael and Charman, Susan A. and Kaiser, Marcel and Baell, Jonathan B.. (2013) 3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis. European journal of medicinal chemistry, Vol. 66. S. 450-465.

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Official URL: http://edoc.unibas.ch/dok/A6165196

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Abstract

A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC50 of 91 nM against the human pathogenic strain T.b. rhodesiense and being more than 700 times less toxic towards the L6 mammalian cell line. Physicochemical properties are attractive for many compounds in this series. For the most potent representatives, we show that solubility and metabolic stability are key parameters to target during future optimisation.
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
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0223-5234
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Mar 2014 13:13
Deposited On:27 Mar 2014 13:13

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