Integrated approach to design 5-indolyl-pyrazoles as anti-TB agent

This study reports a structure-guided design, synthesis, and biological evaluation of a novel class of hybrid molecules combining indole and pyrazole scaffolds-both known for their broad pharmacological profiles. A series of 5-indolyl-pyrazole derivatives (n = z1-z44) were synthesized and characterized through ¹H/¹³C NMR and HR-MS analysis. The synthesized compounds were screened against H37Rv and two multidrug-resistant clinically isolated strains M.tb* and M.tb**. Several derivatives (notably z1 and z8) showed potent inhibition at concentrations as low as 25 μg/mL may be even more potent at lower concentrations and a comparative analysis could be possible. Complementary molecular docking studies were conducted using the InhA enzyme (PDB ID: 4TZK), a validated target in mycolic acid biosynthesis. Lead compounds demonstrated favorable binding energies (e.g., -6.35 kcal/mol for z1), engaging key active-site residues (PHE97, MET103, PHE149, TYR158) through hydrophobic, π-stacking, and van der Waals interactions, alongside critical contact with the NAD⁺ cofactor. Interaction fingerprint analysis correlated ligand-residue contacts with biological activity, underscoring the importance of aromatic planarity and substituent modulation for effective InhA inhibition. This integrated synthetic-biological-computational workflow lays a promising foundation for the development of next-generation anti-TB agents with improved efficacy against resistant strains.