Development of Bis-cyclic Imidazolidine-4-one Derivatives as Potent Antibacterial Agents.,Journal of Medicinal Chemistry

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Development of Bis-cyclic Imidazolidine-4-one Derivatives as Potent Antibacterial Agents.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-11 , DOI: 10.1021/acs.jmedchem.0c00171
Minghui Wang ₁ , Ruixuan Gao ₁ , Mengmeng Zheng ₁ , Peng Sang ₁ , Chunpu Li _{1,

2} , En Zhang _{1,

3} , Qi Li ₂ , Jianfeng Cai ₁

Affiliation

Antibiotic resistance has emerged as one of the biggest public health concerns all over the world. In an effort to combat bacterial infections, a series of imidazolidine-4-one derivatives with potent and broad-spectrum antibacterial activity and low rates of drug resistance were developed by mimicking the salient physiochemical features of host defense peptides. These small molecules displayed potent activity against both Gram-negative and Gram-positive bacteria including several multidrug-resistant bacteria strains. Meanwhile, time–kill kinetics and drug resistance studies suggested that the most potent compound 3 could not only eliminate the bacteria rapidly but also exhibit a low probability of drug resistance in MRSA over many passages. Further mechanistic studies suggested that 3 eradicated bacterial pathogens by disintegrating membranes of both Gram-negative and Gram-positive bacteria. Together with their small molecular weight and low production cost compared with HDPs, these imidazolidine-4-one compounds may be developed into a new generation of antibiotic therapeutics combating emergent drug resistance.

中文翻译：

双环咪唑烷-4-酮衍生物作为强效抗菌剂的开发。

抗生素耐药性已成为全世界最大的公共卫生问题之一。为了对抗细菌感染，通过模仿宿主防御肽的显着理化特征，开发了一系列具有强效广谱抗菌活性和低耐药率的咪唑烷-4-酮衍生物。这些小分子对革兰氏阴性和革兰氏阳性细菌（包括几种耐多药细菌菌株）均表现出有效的活性。同时，时间-杀灭动力学和耐药性研究表明，最有效的化合物3不仅可以快速消除细菌，而且在 MRSA 中表现出较低的耐药概率。进一步的机理研究表明，3通过分解革兰氏阴性和革兰氏阳性细菌的膜来根除细菌病原体。与 HDPs 相比，它们的分子量小、生产成本低，这些咪唑烷-4-酮化合物可能被开发成新一代的抗生素治疗药物，以对抗新出现的耐药性。

更新日期：2020-09-11

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