Biological and Medicinal Chemistry

Fragment-Based Design of Mycobacterium Tuberculosis InhA Inhibitors

Abstract

Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. InhA, an enoyl ACP-reductase, has been the focus of numerous drug discovery efforts as this is the target of the first line pro-drug isoniazid. However, with resistance to this drug becoming more common the aim has been to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, the screening and validation of a fragment library is described and development of the fragment hits using a fragment growing strategy was employed which led to the development InhA inhibitors with affinities of up to 250 nM.

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Supplementary material

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Supplementary information