Natural Berberine-derived Azolyl Ethanols as New Structural Antibacterial Agents against Drug-Resistant Escherichia coli

Natural berberine-derived azolyl ethanols as new structural antibacterial agents were designed and synthesized for fighting with dreadful bacterial resistance. Partial target molecules exhibited potent activity against the tested strains, particularly, nitroimidazole derivative 4d and benzothiazole-...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2022-01, Vol.65 (1), p.436-459
Main Authors: Sun, Hang, Huang, Shi-Yu, Jeyakkumar, Ponmani, Cai, Gui-Xin, Fang, Bo, Zhou, Cheng-He
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - pharmacology
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Berberine - chemistry
Berberine - pharmacology
Biofilms - drug effects
DNA, Bacterial - drug effects
Drug Resistance, Multiple, Bacterial - drug effects
Escherichia coli - drug effects
Escherichia coli - metabolism
Hemolysis - drug effects
Humans
Intercalating Agents - chemical synthesis
Intercalating Agents - pharmacology
Microbial Sensitivity Tests
Reactive Oxygen Species
Structure-Activity Relationship
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Summary:Natural berberine-derived azolyl ethanols as new structural antibacterial agents were designed and synthesized for fighting with dreadful bacterial resistance. Partial target molecules exhibited potent activity against the tested strains, particularly, nitroimidazole derivative 4d and benzothiazole-2-thoil compound 18b, with low cytotoxicity both exerted strong antibacterial activities against multidrug-resistant Escherichia coli at low concentrations as 0.007 and 0.006 mM, respectively. Meanwhile, the active compounds 4d and 18b possessed the ability to rapidly kill bacteria and observably eradicate the E. coli biofilm by reducing exopolysaccharide content to prevent bacterial adhesion, which was conducive to alleviating the development of E. coli resistance. Preliminary mechanistic explorations suggested that the excellent antibacterial potential of molecules 4d and 18b might be attributed to their ability to disintegrate membrane, accelerate ROS accumulation, reduce bacterial metabolism, and intercalate into DNA groove. These results provided powerful information for the further exploitation of natural berberine derivatives against bacterial pathogens.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01592