Drug Design & Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Allahabad, India.
Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India.
Chem Biol Drug Des. 2020 Aug;96(2):861-869. doi: 10.1111/cbdd.13695. Epub 2020 May 5.
The compounds were tested against panel of three Gram-positive, viz. Staphylococcus aureus, Bacillus subtilis, Bacillus cereus and three Gram-negative bacterial strains viz. Pseudomonas aeruginosa, Escherichia coli, and Proteus vulgaris where they showed significant to moderate antibacterial activity. The compound also showed considerable antibiofilm activity against S. aureus and B. subtilis. The most potent compounds 7l and 7m found bacteriostatic in time-kill assay via inhibition of DNA gyrase enzyme and interacting with Glu58, Val130, Ile175 and Ile186 via numerous H-bonds as revealed by docking. In S. aureus-induced murine infection model, compound 7m showed dose-dependent reduction of viability of bacteria with maximum activity in 25 mg/kg treated group. The antifungal activity against human fungal pathogens was also estimated, where these compounds showed considerable inhibitory activity as compared to standard. The metabolic liability of compound 7m was determined using RS-Predictor and MetaPrint 2D React. The molecules were proved as effective antibacterial agent via inhibition of DNA gyrase as a mechanism together with significant antifungal activity.
这些化合物在针对三个革兰氏阳性菌（金黄色葡萄球菌、枯草芽孢杆菌、蜡样芽孢杆菌）和三个革兰氏阴性菌（铜绿假单胞菌、大肠杆菌、普通变形杆菌）的药敏试验中表现出显著到中度的抗菌活性。该化合物对金黄色葡萄球菌和枯草芽孢杆菌的生物膜也表现出相当大的抑制活性。通过抑制 DNA 回旋酶酶和与 Glu58、Val130、Ile175 和 Ile186 形成氢键相互作用，发现最有效的化合物 7l 和 7m 具有抑菌作用，这一点通过对接得到了证实。在金黄色葡萄球菌诱导的小鼠感染模型中，化合物 7m 表现出剂量依赖性的细菌活力降低，在 25mg/kg 治疗组中表现出最大活性。这些化合物对人体真菌病原体的抗真菌活性也进行了评估，与标准相比，这些化合物表现出相当大的抑制活性。使用 RS-Predictor 和 MetaPrint 2D React 确定了化合物 7m 的代谢不稳定性。这些分子通过抑制 DNA 回旋酶作为一种机制，以及显著的抗真菌活性，被证明是有效的抗菌剂。
