Identification of 1,3‐Substituted Pyrazole‐Based Carboxamide Derivatives as Potent Antitubercular Agents

In recent past, repurposing and subsequent medicinal chemistry efforts on anti‐obesity drug rimonabant has successfully delivered several pyrroles and pyrazole‐based hits active against Mycobacterium tuberculosis (Mtb). Herein, we report the synthesis and biological evaluation of a new series of 1,3‐substituted pyrazole containing carboxamide derivatives as potential antitubercular (anti‐TB) agents. Preliminary screening indicated substantial potency and selectivity towards Mtb H37Rv. Lead compounds when subjected to cell viability test demonstrated low cytotoxicity. Structural optimization of the most active compound (MIC 0.06 μg/mL) led to the identification of 3‐heteroaromatic substituted pyrazole derivatives amongst which the lead compound exhibited equipotent activity (MIC 0.03 μg/mL) against both drug‐susceptible (DS) and drug‐resistant (DR) Mtb besides high selectivity index (SI>333). Further, time‐kill assay found these optimum active compounds endowed with mycobactericidal efficacy. Potent in vitro activity, high selectivity along with mycobactericidal attributes establishes lead compounds of the series as promising antimycobacterial candidates for further development. Scaffold simplification and subsequent optimization of repurposed MmpL3 inhibitor rimonabant led to the identification of 1,3‐substituted pyrazole based carboxamide derivatives active against drug resistant Mycobacterium tuberculosis demonstrating mycobactericidal efficacy quite comparable to first line anti‐TB drug rifampicin.