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

Abstract

A series of new quinazolin-2,4-dione derivatives incorporating amide/eight-membered nitrogen-heterocycles <b>2a</b>-<b>c</b>, in addition, acylthiourea/amide/dithiolan-4-one and/or phenylthiazolidin-4-one <b>3a</b>-<b>d</b> and <b>4a</b>-<b>d</b>. The starting compound <b>1</b> was prepared by reaction of 4-(2,4-dioxo-1,4-dihydro-2<i>H</i>-quinazolin-3-yl)-benzoyl chloride with ammonium thiocyanate and cyanoacetic acid hydrazide. The reaction of <b>1</b> with strong electrophiles, namely, <i>o</i>-aminophenol, <i>o</i>-amino thiophenol, and/or <i>o</i>-phenylene diamine, resulted in corresponding quinazolin-2,4-dione derivatives incorporating eight-membered nitrogen-heterocycles <b>2a</b>-<b>d</b>. Compounds <b>3a</b>-<b>d</b> and <b>4a</b>-<b>d</b> were synthesized in good-to-excellent yield through a one-pot multi-component reaction (MCR) of <b>1</b> 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, ¹H-NMR, ¹³C-NMR, and MS. The antibacterial efficacy of the obtained eleven molecules was examined in vitro against two Gram-positive bacterial strains (<i>Staphylococcus aureus</i> and <i>Staphylococcus haemolyticus</i>). 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 (<i>S. aureus</i> and <i>S. haemolyticus</i>) to explain their binding mode of actions. Notably, our findings highlight compounds <b>2b</b> and <b>2c</b> as showing both the best antibacterial activity and docking scores against the targets. Finally, according to ADMET predictions, compounds <b>2b</b> and <b>2c</b> possessed acceptable pharmacokinetics properties and drug-likeness properties.