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Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei

Ferrins, Lori and Gazdik, Michelle and Rahmani, Raphaël and Varghese, Swapna and Sykes, Melissa L. and Jones, Amy J. and Avery, Vicky M. and White, Karen L. and Ryan, Eileen and Charman, Susan A. and Kaiser, Marcel and Bergström, Christel A. S. and Baell, Jonathan B.. (2014) Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei. Journal of medicinal chemistry, 57 (15). pp. 6393-6402.

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Official URL: http://edoc.unibas.ch/dok/A6298862

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Abstract

A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
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
Bibsysno:Link to catalogue
Publisher:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Dec 2017 10:38
Deposited On:10 Oct 2014 09:19

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