Synthesis, antitubercular evaluation, and molecular docking studies of hybrid pyridinium salts derived from isoniazid

Abstract

AbstractIn the quest to develop potent inhibitors for Mycobacterium tuberculosis, novel isoniazid‐based pyridinium salts were designed, synthesized, and tested for their antimycobacterial activities against the H37Rv strain of Mycobacterium tuberculosis using rifampicin as a standard. The pyridinium salts 4k, 4l, and 7d showed exceptional antimycobacterial activities with MIC90 at 1 µg/mL. The in vitro cytotoxicity and pharmacokinetics profiles of these compounds were established for the identification of a lead molecule using in vivo efficacy proof‐of‐concept studies and found that the lead compound 4k possesses LC50 value at 25 µg/mL. The in vitro antimycobacterial activity results were further supported by in silico studies with good binding affinities ranging from −9.8 to −11.6 kcal/mol for 4k, 4l, and 7d with the target oxidoreductase DprE1 enzyme. These results demonstrate that pyridinium salts derived from isoniazid can be a potentially promising pharmacophore for the development of novel antitubercular candidates.