School of Science, Anhui Agricultural University, 230036, Hefei, People's Republic of China.
School of Science, Anhui Agricultural University, 230036, Hefei, People's Republic of China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210093, Nanjing, People's Republic of China.
Eur J Med Chem. 2018 Sep 5;157:81-87. doi: 10.1016/j.ejmech.2018.07.059. Epub 2018 Jul 26.
The identification of novel Topoisomerase II (Topo II) inhibitors is one of the most attractive directions in the field of bactericide research and development. In our ongoing efforts to pursue the class of inhibitors, six series of 70 novel coumarin-pyrazole carboxamide derivatives were designed and synthesized. As a result of the evaluation against four destructive bacteria, including Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8III-k (MIC = 0.25 mg/L) showed considerable inhibitory activity than ciprofloxacin (MIC = 0.5 mg/L) against Escherichia coli and 8V-c (MIC = 0.05 mg/L) exhibited excellent antibacterial activity than ciprofloxacin (MIC = 0.25 mg/L) against Salmonella. The selected compounds (8III-k, 8V-c and 8V-k) exhibit potent inhibition against Topo II and Topo IV with IC values (9.4-25 mg/L). Molecular docking model showed that the compounds 8V-c and 8V-k can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial Topo II inhibiting bactericides.
新型拓扑异构酶 II（Topo II）抑制剂的鉴定是杀菌剂研发领域最具吸引力的方向之一。在我们追求这一类抑制剂的持续努力中，设计并合成了 70 种新型香豆素-吡唑甲酰胺衍生物的 6 个系列。通过对包括金黄色葡萄球菌、单核细胞增生李斯特菌、大肠杆菌和沙门氏菌在内的四种破坏细菌的评估，化合物 8III-k（MIC = 0.25 mg/L）对大肠杆菌的抑制活性明显优于环丙沙星（MIC = 0.5 mg/L），化合物 8V-c（MIC = 0.05 mg/L）对沙门氏菌的抗菌活性优于环丙沙星（MIC = 0.25 mg/L）。所选化合物（8III-k、8V-c 和 8V-k）对拓扑异构酶 II 和拓扑异构酶 IV 具有很强的抑制作用，IC 值（9.4-25 mg/L）。分子对接模型表明，化合物 8V-c 和 8V-k 可以通过与氨基酸残基相互作用很好地与靶标结合。这将为商业拓扑异构酶 II 抑制性杀菌剂提供一些有价值的信息。
