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To develop new antimicrobial agents, a series of novel thiourea derivatives incorporated with different moieties <b>2–13</b> was designed and synthesized and their biological activities were evaluated. Compounds <b>7a</b>, <b>7b</b> and <b>8</b> exhibited excellent antimicrobial activity against all Gram-positive and Gram-negative bacteria, and the fungal <i>Aspergillus flavus</i> 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 <b>7a</b> and <b>7b</b> were the most potent with IC₅₀ 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 <b>8</b> displayed excellent inhibitory activity against <i>Escherichia coli</i> DNA B gyrase and moderate one against <i>E. coli</i> Topoisomerase IV (IC₅₀ = 0.33 ± 1.25 and 19.72 ± 1.00 µM, respectively) in comparison with novobiocin (IC₅₀ values 0.28 ± 1.45 and 10.65 ± 1.02 µM, respectively). Finally, the molecular docking was done to position compound <b>8</b> into the <i>E. coli</i> DNA B and Topoisomerase IV active pockets to explore the probable binding conformation. In summary, compound <b>8</b> may serve as a potential dual <i>E. coli</i> DNA B and Topoisomerase IV inhibitor.