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System for Efficacy and Cytotoxicity Screening of Inhibitors Targeting Intracellular Mycobacterium tuberculosis
Published on: April 5, 2017
Biarylmethoxy Nicotinamides As Novel and Specific Inhibitors of Mycobacterium tuberculosis
Chaitanya Kumar Kedari1, Nilanjana Roy Choudhury2, Sreevalli Sharma2
1Alkem Laboratories, Ltd. , Peenya Industrial Estate, Bangalore 560058, India.
Abstract:
A whole cell based screening effort on a focused library from corporate collection resulted in the identification of biarylmethoxy nicotinamides as novel inhibitors of M. tuberculosis (Mtu) H37Rv. The series exhibited tangible structure-activity relationships, and during hit to lead exploration, a cellular potency of 100 nM was achieved, which is an improvement of >200-fold from the starting point. The series is very specific to Mtu and noncytotoxic up to 250 μM as measured in the mammalian cell line THP-1 based cytotoxicity assay. This compound class retains its potency on several drug sensitive and single drug resistant clinical isolates, which indicate that the compounds could be acting through a novel mode of action.
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