Evaluation of Quinazolin-2,4-Dione Derivatives as Promising Antibacterial Agents: Synthesis, In Vitro, In Silico ADMET and Molecular Docking Approaches.

A series of new quinazolin-2,4-dione derivatives incorporating amide/eight-membered nitrogen-heterocycles -, in addition, acylthiourea/amide/dithiolan-4-one and/or phenylthiazolidin-4-one - and -. The starting compound was prepared by reaction of 4-(2,4-dioxo-1,4-dihydro-2-quinazolin-3-yl)-benzoyl chloride with ammonium thiocyanate and cyanoacetic acid hydrazide. The reaction of with strong electrophiles, namely, -aminophenol, -amino thiophenol, and/or -phenylene diamine, resulted in corresponding quinazolin-2,4-dione derivatives incorporating eight-membered nitrogen-heterocycles -. Compounds - and - were synthesized in good-to-excellent yield through a one-pot multi-component reaction (MCR) of with carbon disulfide and/or phenyl isocyanate under mild alkaline conditions, followed by ethyl chloroacetate, ethyl iodide, methyl iodide, and/or concentrated HCl, respectively. The obtained products were physicochemically characterized by melting points, elemental analysis, and spectroscopic techniques, such as FT-IR, H-NMR, C-NMR, and MS. The antibacterial efficacy of the obtained eleven molecules was examined in vitro against two Gram-positive bacterial strains ( and ). Furthermore, Computer-Aided Drug Design (CADD) was performed on the synthesized derivatives, standard drug (Methotrexate), and reported antibacterial drug with the target enzymes of bacterial strains ( and ) to explain their binding mode of actions. Notably, our findings highlight compounds and as showing both the best antibacterial activity and docking scores against the targets. Finally, according to ADMET predictions, compounds and possessed acceptable pharmacokinetics properties and drug-likeness properties.