Design and Synthesis of 2-(4-Bromophenyl)Quinoline-4-Carbohydrazide Derivatives <i>via</i> Molecular Hybridization as Novel Microbial DNA-Gyrase Inhibitors

Abstract

Microbial DNA gyrase is regarded as an outstanding microbial target. Hence, 15 new quinoline derivatives (<b>5</b>-<b>14</b>) were designed and synthesized. The antimicrobial activity of the afforded compounds was pursued via <i>in vitro</i> approaches. The investigated compounds displayed eligible MIC values, particularly against G-positive <i>Staphylococcus aureus</i> species. Consequently, an <i>S. aureus</i> DNA gyrase supercoiling assay was performed, using ciprofloxacin as a reference control. Obviously, compounds <b>6b</b> and <b>10</b> unveiled IC₅₀ values of 33.64 and 8.45 μM, respectively. Alongside, ciprofloxacin exhibited an IC₅₀ value of 3.80 μM. Furthermore, a significant docking binding score was encountered by compound <b>6b</b> (-7.73 kcal/mol), surpassing ciprofloxacin (-7.29 kcal/mol). Additionally, both compounds <b>6b</b> and <b>10</b> revealed high GIT absorption without passing the blood brain barrier. Finally, the conducted structure-activity relationship study assured the usefulness of the hydrazine moiety as a molecular hybrid for activity either in cyclic or opened form.