Novel bis(benzylidene)-6-methyl-2-thiouracil derivatives: design, synthesis, and molecular docking as potential...

Pyrimidine-based heterocycles are crucial scaffolds in medicinal chemistry due to their extensive biological activity. This study involved the condensation of 6-methyl-2-thiouracil with various aromatic aldehydes under reflux in acetic and hydrochloric acid, resulting in the synthesis of a novel series of bis(benzylidene)-6-methyl-2-thiouracil derivatives (2a-e). IR, ¹H, ¹³C-NMR, mass spectrometry, and elemental analysis were employed to elucidate the products. The antimicrobial activity was evaluated against the pathogenic fungus Candida albicans and multidrug-resistant (MDR) Gram-positive (Bacillus cereus, Staphylococcus aureus) and Gram-negative (Escherichia coli, Helicobacter pylori) bacteria using the agar well diffusion and microdilution methods. Compound 2e exhibited the most potent antibacterial activity among all derivatives, surpassing gentamicin against several tested pathogens. Molecular docking and molecular dynamics (MD) simulations, bolstered by favorable van der Waals and electrostatic interactions, confirmed the robust and stable binding of compound 2e inside the catalytic region of β-ketoacyl-ACP synthase III. The synthesized compounds exhibited favorable drug-likeness, satisfactory solubility, and minimal anticipated toxicity, as per an in silico ADMET study. These results indicate that compound 2e and other bis(benzylidene)-thiouracil derivatives are viable candidates for the development of new antimicrobial drugs targeting resistant diseases.