Design, Synthesis, Molecular Docking and Antimicrobial Evaluation of Novel 8-Hydroxyquinoline Schiff Base Hybrids Bearing Heterocyclic Pharmacophores

Abstract

The emergence of antimicrobial resistance has created an urgent need for chemotherapeutic agents with improved efficacy and reduced susceptibility to resistance mechanisms. Among the diverse pharmacologically important scaffolds, 8-hydroxyquinoline and Schiff base motifs have emerged as privileged structural frameworks owing to their diverse pharmacological activities, including antibacterial, antifungal, anticancer, antiviral, anti-inflammatory and antioxidant properties. Hybridization of these privileged pharmacophores with biologically active heterocyclic moieties represents an effective strategy for the development of multifunctional antimicrobial agents. In this study, a series of novel 8-hydroxyquinoline based Schiff base hybrids (SSAJ-01-SSAJ-06) containing different heterocyclic pharmacophores were designed, synthesized and characterized by FT-IR, 1H NMR, 13C NMR and mass spectrometry. Their antimicrobial activities were evaluated against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and fungal strains (Candida albicans and Aspergillus niger) using disc diffusion and broth microdilution methods. Among the newly synthesized compounds SSAJ-06 identifies as the lead molecule, exhibited the highest antibacterial activity with inhibition zones of 22-24 mm and MIC values of 3.25 µg/mL against all tested bacterial strains. SSAJ-05 displayed significant antibacterial and antifungal activities, while SSAJ-03 showed notable antifungal activity against C. albicans. Molecular docking against DNA gyrase (PDB: 3G75) and dihydrofolate reductase (DHFR, PDB: 1M78) demonstrated strong binding affinities, with SSAJ-04 showing the highest affinity for DNA gyrase (-9.6 kcal/mol) and SSAJ-05 for DHFR (-9.3 kcal/mol). These findings identify 8-hydroxyquinoline Schiff base hybrids as promising antimicrobial leads for the development of new quinoline-based therapeutics.