Journal
DRUG DEVELOPMENT RESEARCH
Volume 84, Issue 3, Pages 470-483Publisher
WILEY
DOI: 10.1002/ddr.22039
Keywords
antimycobacterial activity; docking studies; isoniazid; pyridinium salts; tuberculosis
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Novel isoniazid-based pyridinium salts were designed, synthesized, and tested for their antimycobacterial activities, and 4k, 4l, and 7d showed exceptional activities. In vitro and in silico studies suggested that 4k is a potentially promising lead compound for the development of antitubercular candidates.
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 MIC90 at 1 mu g/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 mu g/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.
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