Development of Novel Sulfonamide-Based Pyrazole-Clubbed Pyrazoline Derivatives: Synthesis, Biological Evaluation, and Molecular Docking Study

Abstract

To overcome the multidrug-resistant tuberculosis (MDR-TB) problem, we reported the synthesis of novel sulfonamide-based pyrazole-clubbed pyrazoline derivatives (9a-p) by reaction of 1-(7-chloroquinolin-4-yl)-3-(thiophene/furan-2-yl)-1H-pyrazole-4-carbaldehyde chalcone derivatives (8a-p) and 4-hydrazinylbenzenesulfonamide (2) in the presence of a catalytic amount of Conc. HCl and ethanol are used as a solvent. Newly synthesized compounds were tested against the Mycobacterium tuberculosis H37Rv strain, wherein compounds 9g, 9h, 9i, 9j, 9m, and 9n were found to be the most potent. The structures of the newly synthesized analogues were determined by different spectroscopic techniques like ESI-MS, FT-IR, NMR, and UV methods. Additionally, molecular docking studies of the active site of mycobacterial InhA resulted in well-aggregated elucidations for these compounds with a binding strength in the range of -9.714 to -8.647. Compound 4-(1′-(7-chloroquinolin-4-yl)-5-(4-fluorophenyl)-3′-(thiophen-2-yl)-3,4-dihydro-1′H,2H-[3,4′-bipyrazol]-2-yl)benzenesulfonamide (9g) shows excellent antitubercular activity against M. tuberculosis H37Rv, achieving an MIC of 10.2 μg/mL and 99% inhibition with a docking score of -9.714 and a Glide energy of -64.183 kcal/mol. In silico ADMET predictions indicated the drug-likeness of synthesized novel molecules.