Exploring novel thiazolo[5,4-f]quinoline-based scaffolds as promising antimicrobial agents through synthesis and molecular insights

Abstract

Abstract In pursuit of novel antimicrobial agents, a series of thiazolo[5,4-f]quinoline derivatives incorporating pyridine and thiophene moieties were synthesized and structurally characterized using IR and 1H-NMR spectroscopy. The synthetic strategy employed diverse condensation and cyclization reactions involving cyanoacetamide intermediates, aryl isothiocyanates, and α-halocarbonyl compounds. The resulting compounds were evaluated for their antimicrobial efficacy against Staphylococcus aureus, Escherichia coli, and Candida albicans. Notably, compounds 18, 19, and 23 exhibited potent broad-spectrum activity, surpassing standard drugs such as chloramphenicol and cephalothin in several assays (MIC = 3.125–6.25 µg/mL). Structure-activity relationship (SAR) analysis revealed that the incorporation of bulky, lipophilic aromatic systems and electron-withdrawing substituents significantly enhanced antimicrobial potency. Molecular docking studies further supported these findings, with compound 19 demonstrating the strongest binding affinity (-6.6951 kcal/mol) to bacterial DNA gyrase (PDB: 6F86) via a synergistic network of hydrogen bonds and π-interactions. These results highlight the thiazoloquinoline framework, particularly derivatives bearing thiophene and naphthoyl functionalities, as a promising scaffold for future antimicrobial drug development.