Design and Synthesis of Novel 1,2,3-Triazole Conjugates Featuring Hydroxamic Acid and Sulfonamide Moieties: Exploring Dual Pharmacophores for Enhanced Biological Activity.

A new series of N-hydroxy-1-(4-(aryl sulfonamido)phenyl)-1H-1,2,3-triazole-4-carboxamide derivatives (8a-j) were synthesized through a concise multistep route integrating three key pharmacophores: the 1,2,3-triazole core, an aryl sulfonamide moiety, and an N-hydroxycarboxamide group. Biological evaluation demonstrated promising antimicrobial potential for several derivatives. Compounds 8f, 8g, and 8i exhibited notable antibacterial activity against both Gram-positive and Gram-negative bacteria, whereas most analogues showed weak antifungal activity. In the antimalarial assay, compound 8d emerged as the most potent derivative (IC50 = 0.84 μg/mL), while compounds 8b, 8e, 8g, and 8h also displayed appreciable activity. Antitubercular evaluation identified compounds 8g and 8i as the most active derivatives against Mycobacterium tuberculosis H37Rv, with MIC values of 62.5 and 50 μg/mL, respectively. The molecular docking study against DNA gyrase (PDB ID: 7FVT) and lanosterol 14α-demethylase (PDB ID: 5V5Z) as relevant antibacterial and antifungal targets, respectively, showed a similar trend of activity. Computational studies, including molecular docking, MM/GBSA, molecular dynamics simulations, and ADME prediction, supported the structural and pharmacokinetic characteristics of the synthesized compounds, with selected derivatives exhibiting favorable interactions with the c-KIT kinase active site and generally acceptable drug-like properties. Overall, these triazole-sulfonamide-N-hydroxycarboxamide hybrids represent promising lead molecules for further structural optimization and biological investigation.