Synthesis, Antimicrobial Activity and Molecular Docking of Novel Thiourea Derivatives Tagged with Thiadiazole, Imidazole and Triazine Moieties as Potential DNA Gyrase and Topoisomerase IV Inhibitors

To develop new antimicrobial agents, a series of novel thiourea derivatives incorporated with different moieties2-13was designed and synthesized and their biological activities were evaluated. Compounds7a,7band8exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungalAspergillus flavuswith minimum inhibitory concentration (MIC) values ranged from 0.95 +/- 0.22 to 3.25 +/- 1.00 mu g/mL. Furthermore, cytotoxicity studies against MCF-7 cells revealed that compounds7aand7bwere the most potent with IC(50)values of 10.17 +/- 0.65 and 11.59 +/- 0.59 mu M, respectively. On the other hand, the tested compounds were less toxic against normal kidney epithelial cell lines (Vero cells). The in vitro enzyme inhibition assay of8displayed excellent inhibitory activity againstEscherichia coliDNA B gyrase and moderate one againstE. coliTopoisomerase IV (IC50= 0.33 +/- 1.25 and 19.72 +/- 1.00 mu M, respectively) in comparison with novobiocin (IC(50)values 0.28 +/- 1.45 and 10.65 +/- 1.02 mu M, respectively). Finally, the molecular docking was done to position compound8into theE. coliDNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound8may serve as a potential dualE. coliDNA B and Topoisomerase IV inhibitor.