Open AccessDevelopment of Bis-cyclic Imidazolidine-4-one Derivatives as Potent Antibacterial Agents
Author(s) -
Minghui Wang,
Ruixuan Gao,
Mengmeng Zheng,
Peng Sang,
Chunpu Li,
En Zhang,
Qi Li,
Jianfeng Cai
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00171
Subject(s) - imidazolidine , bacteria , antibiotics , chemistry , antibiotic resistance , drug resistance , gram negative bacteria , antimicrobial , multiple drug resistance , drug , drug discovery , microbiology and biotechnology , combinatorial chemistry , pharmacology , biochemistry , biology , stereochemistry , escherichia coli , organic chemistry , gene , genetics
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.