Cyclization of Chalcone Derivatives: Design, Synthesis, In Silico Docking Study, and Biological Evaluation of New Quinazolin-2,4-diones Incorporating Five-, Six-, and Seven-Membered Ring Moieties as Potent Antibacterial Inhibitors.

ABSTRACT

Four novel series of quinazolin-2,4-diones bearing five-, six-, and seven-membered heterocyclic moieties 2-14 (such as pyrazole, oxazole, pyrimidine, and azepines) through the 1,4-phenyl linkage were designed, synthesized, and evaluated in terms of their antibacterial activities. Analytical and spectral techniques (FT-IR, 1H NMR, 13C NMR, and Mass) were utilized for the structural elucidation of all of the synthesized compounds 2-14. Furthermore, the potential antibacterial activity of the thirteen compounds was further evaluated in vitro against two different Gram-negative G-ve bacterial strains (named Escherichia coli ATCC 25955, Pseudomonas aeruginosa ATCC 10145) and two Gram-positive G+ve bacterial strains (named Bacillus subtilis ATCC 6633 and Staphylococcus aureus NRRL B-767). Investigation of the antibacterial potential indicated that the newly synthesized compounds, especially 13, exhibited remarkable antibacterial activity against pathogens, comparable to the standard drug ciprofloxacin (a known potent antibacterial agent). Additionally, compounds 2-14 and ciprofloxacin were assessed in silico using molecular docking studies against the target thymidine phosphorylase enzyme (PDB ID 4EAD). Moreover, the structure activity relationship (SAR) for these compounds was also described to give guidance about the effective molecules that could play an important role in identifying potential antibacterial agents. Finally, the drug-likeness and physicochemical parameters of the newly synthesized molecules 2-14 were in silico investigated. Among them, we found that the compound 3-[4-(6-phenyl-6,7-dihydro-5-oxa-9-aza-benzocyclohepten-8-yl)-phenyl]-1H-quinazolin-2,4-dione 13 with the highest binding affinity showed a strong fit to the active site of the tested enzyme, indicating 13 as a promising drug candidate for designing and developing novel classes of antibiotics.