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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

Citation

Ferrins, L and Rahmani, R and Sykes, ML and Jones, AJ and Avery, VM and Teston, E and Almohaywi, B and Yin, JX and Smith, J and Hyland, C and White, KL and Ryan, E and Campbell, M and Charman, SA and Kaiser, M and Baell, JB, 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, 66 pp. 450-465. ISSN 0223-5234 (2013) [Refereed Article]

Copyright Statement

Copyright 2013 Elsevier Masson

DOI: doi:10.1016/j.ejmech.2013.05.007

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 structureeactivity 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.

Item Details

Item Type:Refereed Article
Keywords:3-(Oxazolo[4,5-b]pyridin-2-yl)anilides, human African trypanosomiasis, sleeping sickness, trypanosomacidal agent, trypanosoma brucei
Research Division:Chemical Sciences
Research Group:Medicinal and Biomolecular Chemistry
Research Field:Biologically Active Molecules
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Chemical Sciences
Author:Almohaywi, B (Ms Basmah Almohaywi)
Author:Yin, JX (Mr JieXiang Yin)
Author:Smith, J (Associate Professor Jason Smith)
Author:Hyland, C (Dr Chris Hyland)
ID Code:88741
Year Published:2013
Web of Science® Times Cited:16
Deposited By:Chemistry
Deposited On:2014-02-13
Last Modified:2016-11-07
Downloads:0

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