Structure elaboration of isoniazid: synthesis, in silico molecular docking and antimycobacterial activity of isoniazid–pyrimidine conjugates

Designing small molecule-based new drug candidates through structure modulation of the existing drugs has drawn considerable attention in view of inevitable emergence of resistance. A new series of isoniazid–pyrimidine conjugates were synthesized in good yields and evaluated for antitubercular activity against the H37Rv strain of Mycobacterium tuberculosis using the microplate Alamar Blue assay. Structure–anti-TB relationship profile revealed that conjugates 8a and 8c bearing a phenyl group at C-6 of pyrimidine scaffold were most active (MIC 99 10 µM) and least cytotoxic members of the series. In silico docking of 8a in the active site of bovine lactoperoxidase as well as a cytochrome C peroxidase mutant N184R Y36A revealed favorable interactions similar to the heme enzyme catalase peroxidase (KatG) that activates isoniazid. This investigation suggests a rationale for further work on this promising series of antitubercular agents. Graphic abstract