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Potent antibacterial activity of dihydydropyrimidine-1,3,5-triazines via inhibition of DNA gyrase and antifungal activity with favourable metabolic profile.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-04-25 , DOI: 10.1111/cbdd.13695 Anup Masih 1 , Jitendra Kumar Shrivastava 1 , Hans Raj Bhat 2 , Udaya Pratap Singh 1
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-04-25 , DOI: 10.1111/cbdd.13695 Anup Masih 1 , Jitendra Kumar Shrivastava 1 , Hans Raj Bhat 2 , Udaya Pratap Singh 1
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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.
中文翻译：
Dihydydropyrimidine-1,3,5-triazines通过抑制DNA促旋酶的有效抗菌活性和具有良好代谢特性的抗真菌活性。
这些化合物针对三个革兰氏阳性的检测，即。金黄色葡萄球菌，枯草芽孢杆菌，蜡状芽孢杆菌和三种革兰氏阴性细菌菌株。铜绿假单胞菌，大肠埃希氏菌和寻常变形杆菌在其中显示出显着至中等的抗菌活性。该化合物还对金黄色葡萄球菌和枯草芽孢杆菌具有相当大的抗生物膜活性。最有效的化合物7l和7m通过对DNA促旋酶的抑制，并在时间杀灭试验中发现抑菌作用，并通过对接揭示了通过许多H键与Glu58，Val130，Ile175和Ile186相互作用。在金黄色葡萄球菌诱导的鼠感染模型中，化合物7米显示在25mg / kg的治疗组具有最大活性的细菌的存活力的剂量依赖性降低。还估计了对人真菌病原体的抗真菌活性，与标准化合物相比，这些化合物表现出相当大的抑制活性。使用RS‐Predictor和MetaPrint 2D React测定化合物7m的代谢能力。通过抑制DNA促旋酶作为一种机制以及显着的抗真菌活性，证明了该分子是有效的抗菌剂。
更新日期：2020-04-25
中文翻译：
Dihydydropyrimidine-1,3,5-triazines通过抑制DNA促旋酶的有效抗菌活性和具有良好代谢特性的抗真菌活性。
这些化合物针对三个革兰氏阳性的检测，即。金黄色葡萄球菌，枯草芽孢杆菌，蜡状芽孢杆菌和三种革兰氏阴性细菌菌株。铜绿假单胞菌，大肠埃希氏菌和寻常变形杆菌在其中显示出显着至中等的抗菌活性。该化合物还对金黄色葡萄球菌和枯草芽孢杆菌具有相当大的抗生物膜活性。最有效的化合物7l和7m通过对DNA促旋酶的抑制，并在时间杀灭试验中发现抑菌作用，并通过对接揭示了通过许多H键与Glu58，Val130，Ile175和Ile186相互作用。在金黄色葡萄球菌诱导的鼠感染模型中，化合物7米显示在25mg / kg的治疗组具有最大活性的细菌的存活力的剂量依赖性降低。还估计了对人真菌病原体的抗真菌活性，与标准化合物相比，这些化合物表现出相当大的抑制活性。使用RS‐Predictor和MetaPrint 2D React测定化合物7m的代谢能力。通过抑制DNA促旋酶作为一种机制以及显着的抗真菌活性，证明了该分子是有效的抗菌剂。
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