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

Abstract In 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 H 37 Rv strain of Mycobacterium tuberculosis using rifampicin as a standard. The pyridinium salts 4k, 4l , and 7d showed exceptional antimycobacterial activities with MIC 90 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 LC 50 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.