新型 3-[(1H-pyrazol-3-yl)imino]indolin-2-one 衍生物作为 DNA 促旋酶抑制剂的设计、合成、分子建模和抗菌潜力,Archiv der Pharmazie

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新型 3-[(1H-pyrazol-3-yl)imino]indolin-2-one 衍生物作为 DNA 促旋酶抑制剂的设计、合成、分子建模和抗菌潜力
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2021-11-08 , DOI: 10.1002/ardp.202100266
Abdullah Y Alzahrani ₁ , Yousry A Ammar ₂ , Mohamed A Salem _{1,

2} , Mohammed Abu-Elghait ₃ , Ahmed Ragab ₂

Affiliation

使用分子杂交方法设计了一系列 3-[(1 H -pyrazol-3-yl)imino]indolin-2-one 衍生物，使用不同的光谱技术对其进行了表征，并评估了它们的体外抗菌活性。与环丙沙星和氟康唑相比，大多数目标化合物表现出良好至中等的抗菌活性。四种化合物（8b、9a、9c和10a) 显示出令人鼓舞的结果，最小抑制浓度 (MIC) 值 (53.45–258.32 µM) 可与诺氟沙星 (100.31–200.63 µM) 和环丙沙星 (48.33–96.68 µM) 相媲美。值得注意的是，除了化合物8b和9a分别对大肠杆菌和金黄色葡萄球菌具有抑菌潜力外，这四种衍生物均显示出优异的杀菌和杀真菌活性。针对金黄色葡萄球菌的杀时间动力学研究证实了这些衍生物的功效。此外，四种有希望的衍生物中的两种，9a和10a ，可以防止金黄色葡萄球菌生物膜的形成低浓度不影响细菌生长。一项针对多药耐药细菌铜绿假单胞菌的七种商业抗生素的联合研究表明，抗生素 MIC 值显着降低，主要表现为协同或相加效应。酶促测定表明，最活跃的衍生物对 DNA 促旋酶的抑制效力与环丙沙星相当。进行分子对接和密度泛函理论计算以探索结合模式并研究有前途的化合物的反应性。

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Design, synthesis, molecular modeling, and antimicrobial potential of novel 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives as DNA gyrase inhibitors

A series of 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives were designed using the molecular hybridization method, characterized using different spectroscopic techniques, and evaluated for their in vitro antimicrobial activity. Most of the target compounds demonstrated good to moderate antimicrobial activity compared with ciprofloxacin and fluconazole. Four compounds (8b, 9a, 9c, and 10a) showed encouraging results, with minimal inhibitory concentration (MIC) values (53.45–258.32 µM) comparable to those of norfloxacin (100.31–200.63 µM) and ciprofloxacin (48.33–96.68 µM). Noticeably, the four derivatives revealed excellent bactericidal and fungicidal activities, except for the bacteriostatic potential of compounds 8b and 9a against Escherichia coli and Staphylococcus aureus, respectively. The time-killing kinetic study against S. aureus confirmed the efficacy of these derivatives. Furthermore, two of the four promising derivatives, 9a and 10a, could prevent the formation of biofilms of S. aureus without affecting the bacterial growth at low concentrations. A combination study with seven commercial antibiotics against the multidrug-resistant bacterium P. aeruginosa showed a notable reduction in the antibiotic MIC values, represented mainly through a synergistic or additive effect. The enzymatic assay implied that the most active derivatives had inhibition potency against DNA gyrase comparable to that of ciprofloxacin. Molecular docking and density functional theory calculations were performed to explore the binding mode and study the reactivity of the promising compounds.

更新日期：2022-01-03

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