| Summary: | A series of novel thienopyridines and pyridothienoquinolines (<b>3a,b−14</b>) was synthesized, starting with 2-thioxo-1,2-dihydropyridine-3-carbonitriles <b>1a</b> and <b>1b</b>. All compounds were evaluated for their in vitro antimicrobial activity against six bacterial strains. Compounds <b>3a,b, 4a, 5b, 6a,b, 7a, 9b, 12b,</b> and <b>14</b> showed significant growth inhibition activity against both Gram-positive and Gram-negative bacteria compared with the reference drug. The most active compounds (<b>4a, 7a, 9b,</b> and <b>12b</b>) against <i>Staphylococcus aureus</i> were also tested for their in vitro inhibitory action on methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). The tested compounds showed promising inhibition activity, with the performance of <b>12b</b> being equal to gentamicin and that of <b>7a</b> exceeding it. Moreover, the most promising compounds were also screened for their <i>Escherichia coli</i> DNA gyrase inhibitory activity, compared with novobiocin as a reference DNA gyrase inhibitor. The results revealed that compounds (<b>3a, 3b, 4a, 9b,</b> and <b>12b</b>) had the highest inhibitory capacity, with IC<sub>50</sub> values of 2.26−5.87 µM (that of novobiocin is equal to 4.17 µM). Docking studies were performed to identify the mode of binding of the tested compounds to the active site of <i>E. coli</i> DNA gyrase B.
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