Design, synthesis, molecular docking, and antibacterial activity of novel amide-linked tetrahydrobenzothienopyrimidinone derivatives as potential DNA gyrase and topoisomerase IV inhibitors

A series of tetrahydrobenzo [4, 5] thieno [2, 3-d] pyrimidinone derivatives 3a–j and 4–6 was synthesized, and tested for their inhibitory activity against E. coli DNA gyrase in a supercoiling assay. The results showed that the five most promising compounds, 3d, 3g, 3h, 3i and 3j were the most potent, therefore, they were selected for investigating their inhibitory activity against E. coli topoisomerase IV, S. aureus DNA gyrase, and S. aureus topoisomerase IV. The results revealed that compound 3j was a more effective inhibitor of E. coli topoisomerase IV, S. aureus DNA gyrase and S. aureus topoisomerase IV, respectively. The molecular docking study of compound 3j has revealed that it binds effectively in the active sites of E. coli DNA gyrase B and E. coli DNA topoisomerase. The hybrid 3j particularly showed promise as a scaffold for designing and developing novel therapeutic antibacterial candidates.