Design, synthesis, biological assessment, and integrated computational analysis of new pyrazole-based antimicrobial candidates

The emergence of antimicrobial resistance needs the development of new chemotherapeutic scaffolds. Pyrazole derivatives are recognized for their broad biological activity; however, further structural innovation is required to enhance antimicrobial efficacy and safety. Thus, new pyrazole-based candidates were designed and synthesized using 3-(4-chlorophenyl)-1-phenylpyrazol-4-yl-2-cyanoacryloyl chloride as a versatile precursor. A series of mono- and bidentate nucleophile-derived compounds was prepared and evaluated for antimicrobial activity against Gram-positive and Gram-negative bacteria and Candida albicans. Several derivatives exhibited potent antibacterial and antifungal activity, particularly against Gram-positive strains, with minimum inhibitory concentrations comparable to standard drugs. Most compounds showed low cytotoxicity toward HepG2 cells, which was further reduced upon antioxidant co-treatment. Notably, vitamin C and N-acetylcysteine showed synergistic enhancement of antimicrobial and antibiofilm effects. Molecular docking studies against dihydropteroate synthase (DHPS, PDB: 5U0V) revealed favorable binding interactions, with the thiophene-based derivative 10 displaying ligand efficiency comparable to the co-crystallized ligand 7VJ. Overall, these findings highlight pyrazole-based scaffolds as promising antimicrobial candidates with favorable biological profiles, providing a strong basis for further structural optimization.