New quinazolinone-based heterocyclic compounds as promising antimicrobial agents: development, DNA gyrase B/topoisomerase IV inhibition activity, and in silico computational studies

Given the growing problem of antibiotic resistance, the development of novel antimicrobial agents is of great importance. This work introduces new compounds based on a hybrid 4-oxo-quinazoline core with pyridine, 1,8-naphthyridine, and pyrimidine ring systems 3-11a, b. Using accurate spectroscopic and analytical data, the molecular structure of each newly produced molecule was described. The antimicrobial effect of the novel substances was assessed versus various types of Gram-positive and Gram-negative bacteria as well as fungal pathogens, employing ampicillin and clotrimazole as reference drugs. 1,8-Naphthyridine and pyridine-based derivatives 9 and 6a-c showed the most promise as broad-spectrum antimicrobials (MIC range 3.30-30.23 mu M). The pyrimidine derivatives 11a and 11b, on the other hand, were very effective against bacteria (MIC range 7.75-24.30 mu M) but showed weak antifungal activity. Promising congeners were also examined as inhibitors of DNA gyrase B/ topoisomerase IV of Escherichia coli compared to novobiocin as a conventional drug. Both enzymes under investigation were greatly suppressed by substance 9, with IC50 measurements of 2.29 f 0.15 and 10.27 f 0.52 mu M, respectively. Although molecules 6b and 6c had equal activity with novobiocin against E. coli DNA gyrase B (IC50 = 4.59 f 0.14 and 3.40 f 0.22 mu M, respectively), they displayed significantly reduced activity to suppress E. coli topoisomerase IV. The strongest analogues, 9, 6b, and bc, were subjected to molecular docking to investigate their ability to attach to the E. coli DNA gyrase B/topoisomerase IV. Furthermore, oral absorption, drug-like features, and molecular dynamics simulations were assessed by computer-based studies.