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 moieties was designed and synthesized and their biological activities were evaluated. Compounds , and exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungal with minimum inhibitory concentration (MIC) values ranged from 0.95 ± 0.22 to 3.25 ± 1.00 μg/mL. Furthermore, cytotoxicity studies against MCF-7 cells revealed that compounds and were the most potent with IC values of 10.17 ± 0.65 and 11.59 ± 0.59 μM, 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 of displayed excellent inhibitory activity against DNA B gyrase and moderate one against Topoisomerase IV (IC = 0.33 ± 1.25 and 19.72 ± 1.00 µM, respectively) in comparison with novobiocin (IC values 0.28 ± 1.45 and 10.65 ± 1.02 µM, respectively). Finally, the molecular docking was done to position compound into the DNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound may serve as a potential dual DNA B and Topoisomerase IV inhibitor.