Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides

by Thompson AM, Marshall AJ, Maes L, Yarlett N, Bacchi CJ, Gaukel E, Wring SA, Launay D, Braillard S, Chatelain E, Mowbray CE, Denny WA. Bioorganic & Medicinal Chemistry Letters 2017, doi 10.1016/j.bmcl.2017.10.067.

Summary: A 900 compound nitroimidazole-based library derived from a pretomanid backup program with TB Alliance was screened against human African trypanosomiasis by DNDi. Potent hits where identified and further studies identified the best lead compound which, with once daily oral dosing, delivered complete cures in an acute murine HAT model and increased survival times in a stage 2 model of disease. Findings from preliminary structure-activity relationship studies provide direction for future studies.

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