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Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2018-03-19 , DOI: 10.1016/j.bmcl.2018.03.046
Ya-Nan Wang , Rammohan R. Yadav Bheemanaboina , Gui-Xin Cai , Cheng-He Zhou

A novel series of purine benzimidazole hybrids were designed and synthesized for the first time with the aim to circumvent the increasing antibiotic resistance. Hexyl appended hybrid 3c gave potent activities against most of the tested bacteria and fungi especially against multidrug-resistant strains Staphylococcus aureus (MIC = 4 µg/mL). Structure-activity relationships revealed that the benzimidazole fragment at the 9-position of purine played an important role in exerting potentially antibacterial activity. Both cell toxicity and ROS generation assays indicated that the purine derivative 3c showed low cytotoxicity and could be used as a safe agent. Molecular modeling suggested that hybrid 3c could bind with the residues of Topo IA through hydrogen bonds and electrostatic interactions. Quantum chemical studies were also performed on the target compound 3c to understand the structural features essential for activity. The active molecule 3c could effectively interact with S. aureus DNA to form 3c–DNA complex through groove binding mode, which might block DNA replication to display their powerful antimicrobial activity.



中文翻译:

新型嘌呤苯并咪唑类药物,可通过调节ROS的产生和靶向临床耐药的金黄色葡萄球菌DNA沟来作为抗菌剂

首次设计并合成了一系列新型嘌呤苯并咪唑杂化物,目的是规避日益增加的抗生素耐药性。加入己基的杂种3c对大多数受试细菌和真菌具有强大的活性,特别是对耐多药金黄色葡萄球菌(MIC = 4 µg / mL)的活性。结构-活性关系表明,苯并咪唑片段在嘌呤的9位上发挥了重要的作用,发挥潜在的抗菌活性。细胞毒性和ROS生成测定均表明嘌呤衍生物3c显示出低细胞毒性,可以用作安全剂。分子建模表明杂交3c可以通过氢键和静电相互作用与Topo IA残基结合。还对目标化合物3c进行了量子化学研究,以了解活性必不可少的结构特征。活性分子3c可通过凹槽结合模式与金黄色葡萄球菌DNA有效相互作用,形成3c –DNA复合物,这可能会阻止DNA复制以显示其强大的抗菌活性。

更新日期:2018-03-19
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