Thiourea derivatives containing 4-arylthiazoles and d-glucose moiety: design, synthesis, antimicrobial activity evaluation, and molecular docking/dynamics simulations.

ABSTRACT

Some substituted glucose-conjugated thioureas containing 1,3-thiazole ring, 4a-h, were synthesized by the reaction of the corresponding substituted 2-amino-4-phenyl-1,3-thiazoles 2a-h with 2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isocyanate. The antibacterial and antifungal activities of these thiazole-containing thioureas were estimated using a minimum inhibitory concentration protocol. Among these compounds, 4c, 4g, and 4h were better inhibitors with MIC = 0.78-3.125 µg mL-1. These three compounds were also tested for their ability to inhibit S. aureus enzymes, including DNA gyrase, DNA topoisomerase IV (Topo IV), and dihydrofolate reductase, and compound 4h was found to be a strong inhibitor with IC50 = 1.25 ± 0.12, 67.28 ± 1.21, and 0.13 ± 0.05 µM, respectively. Induced-fit docking and MM-GBSA calculations were performed to observe the binding efficiencies and steric interactions of these compounds. The obtained results showed that compound 4h is compatible with the active site of S. aureus DNA gyrase 2XCS with four H-bond interactions with residues Ala1118, Met1121, and FDC11 and also three interactions with FDG10 (two interactions) and FDC11 (one interaction). Molecular dynamics simulation in a water solvent system showed that ligand 4h had active interactions with enzyme 2XCS through residues Ala1083, Glu1088, Ala1118, Gly1117, and Met1121.