Design, Synthesis, Molecular Docking, ADME/Tox Predictions and DFT Study of Quinazolinone-1,2,4-Triazole Analogues as Promising Antimicrobial Agents

Two significant worldwide health issues that call for the creation of new therapeutic medicines are oxidative stress and antibiotic resistance. Quinazolinone-1,2,4-triazole derivatives, which have a variety of pharmacological characteristics, may be able to help with these problems. As possible antibacterial and anticancer targets, this study sought to synthesized novel quinazoline-4(3H)-one derivatives containing an NH group at position 3 with 1,2,4-triazoles (7a–7k). The chemical structures of all compounds were characterized by NMR (1H/13C), IR and mass spectroscopy. Notably, derivatives 7d and 7e exhibited the greatest MIC values against S. epidermidis, while 7f was the best against S. aureus with MIC of 3.5 μg mL−1, two-fold efficacy more than that was recorded with moxifloxacin. All of the synthesized compounds showed promising anti-proliferative activity, with one compounds 7e having potent cytotoxic activity against MDA-MB-231 cell line (IC50 = 11.80 ± 1.2 μM) and active against MCF-7 (IC50 = 11.80 ± 1.2 μM respectively) in comparison to the reference DXN (IC50 = 9.48 ± 0.6 and 7.12 ± 2.0 μM, respectively). Molecular docking was performed using the protein structure of E. coli Topoisomerase IV, with the interacting effectively with key residues IleA:116, SerA:117, ArgA:93, GluA:46, ThrA:163, and GlyA:71, consistent with their antimicrobial activity. The chemical nature of these compounds was revealed by performing the density functional theory (DFT) calculation using hybrid B3LYP functional with 6-31 g(d) basis set. Additionally, these compounds exhibited promising physicochemical properties, paving the way for discovering new antimicrobial drugs.