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

Abstract

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.

Synthesis and pharmacological evaluation of 1,3-diaryl substituted pyrazole based (thio)urea derivatives as potent antimicrobial agents against multi-drug resistant Staphylococcus aureus and Mycobacterium tuberculosis

“…23 Recently, our group reported 1,3-diaryl substituted pyrazole based carboxamides as inhibitors of Mtb H37Rv where the potent derivative B displayed a MIC of 0.03 μg mL −1 against various drug resistant strains of Mtb with a high SI of >333. 24 Furthermore, 1,3 diaryl pyrazole based imidazole derivatives C have been identified as Mtb CYP121A inhibitors that have also shown promising antimycobacterial activity. 25 The potential of pyrazole derivatives as antimicrobial agents encouraged us to combine it with other pharmacophoric units that may provide an overall improvement in affinity, efficacy and pharmacokinetic parameters.…”