Discovery of New Isoniazid Derivatives As Anti-tubercular Agents: In silico Studies, Synthesis, and In vitro Activity Evaluation

Abstract

This research aimed to discover novel isoniazid (INH) derivatives as anti-tubercular (anti-TB) agents. The chemical structures of isoniazid-based pyridazinone (IBP) derivatives were designed, and their toxicity and pharmacokinetic properties were predicted using the ProTox II and Swiss-ADME databases. The molecular docking of non-toxic IBPs was also performed concerning INH, pyrazinamide (PYZ), ethionamide (ETH), macozinone (MCZ), and BTZ043 utilizing DprE1 enzyme’s proteins (PDB IDs: 4F4Q, 4NCR and 6HEZ). Based on the in silico study results, IBP19, IBP21, IBP22, and IBP29 were selected for their synthesis, and the spectral analysis confirmed their chemical structures. In vitro, anti-TB activity against Mtb H37Rv strain and MTT assay (against HepG2 and Vero cell lines) of IBP19, IBP21, IBP22, and IBP29 were also carried out. A total of eleven non-toxic IBPs were identified with promising pharmacokinetic parameters. The docking score (DS in kcal/mol against 6HEZ protein) of IBP19 (-9.52), IBP21 (-8.78), IBP22 (-9.07), and IBP29 (-9.99) was better than MCZ (-8.76) and BTZ043 (-8.56) revealing their DprE1 enzyme inhibitory action. The in vitro anti-TB activity evaluation (MIC values) confirmed that IBP19 (1.562 µg/ml), IBP21 (1.562 µg/ml), IBP22 (1.562 µg/ml), and IBP29 (1.562 µg/ml) had almost double potency than INH (3.125 µg/ml), and PYZ (3.125 µg/ml). IBP19, IBP21, IBP22, and IBP29 also displayed a CC50 value of > 300 µg/ml against HCL and VCL cell lines. This effect was better than INH (> 200 µg/ml), ETH (> 150 µg/ml), and PYZ (> 200 µg/ml). Accordingly, IBP19, IBP21, IBP22, and IBP29 provide a new template for developing safe and effective novel DprE1 inhibitors.