Synthesis, antimicrobial activity and molecular simulation of thiourea derivatives containing 6-carboalkoxybenzo[d]thiazole and <sc>d</sc>-glucose moieties

Several substituted thiourea derivatives containing 6-carboalkoxybenzothiazole and D-glucose moieties 4a-i have been synthesized from the reaction of corresponding alkyl 2-aminobenzothiazole-6-carboxyl 2a-i with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate. Their antimicrobial activity against bacteria (including Gram-positive and Gram-negative) and fungi were screened. The obtained results showed that several compounds exhibited significant inhibition abilities, including 4a, 4b, 4d, 4f, 4i (anti-Gram-positive bacterial), 4a, 4b, 4c, 4d, 4f (anti-Gram-negative bacterial), and 4b, 4d (anti-fungal) with MICs of 0.78-3.125 mu g mL(-1). Thioureas 4b, 4d, and 4i exhibited excellent inhibitory activity against S. aureus, in the order of 4d > 4b > 4i, with MICs of 0.78-1.56 mu g mL(-1). These inhibitors also expressed good inhibitory activity against S. aureus DNA gyrase and topoisomerase IV enzymes, especially compound 4d, which had IC50 values of 0.573 and 0.283 mu M, respectively, against these tested enzymes. Molecular docking simulations and MM-GBSA calculations indicated that compound 4d interacted effectively with residues, including ALA1068, VAL1071, GLY1072, ASP1073, MET1075, GLY1076, ALA1120, MET1121 (chain B), ASP1088, MET1121, ARG1122 (chain D), DG10, and DC11 (chain E); DG10 and DC11 (chain F), just as the co-crystal interacted at the active site of S. aureus DNA gyrase (2XCS).