102-47-6Relevant articles and documents
Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
Yan, Yu-Hang,Li, Wenfang,Chen, Wei,Li, Chao,Zhu, Kai-Rong,Deng, Ji,Dai, Qing-Qing,Yang, Ling-Ling,Wang, Zhenling,Li, Guo-Bo
, (2021/11/17)
Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the ‘last-resort’ carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
NOVEL DXR INHIBITORS FOR ANTIMICROBIAL THERAPY
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Page/Page column 89-90, (2011/05/05)
The present invention generally concerns particular methods and compositions for antimicrobial therapy. In particuarl embodiments, the compositions target DXR. In specific embodiments, the compositions are electron-deficient heterocyclic rings.
1-[2-(1-Adamantyl)-2-(R-thio)ethyl]imidazoles and 1-[2-(1-adamantyl)-2-(R-oxy)ethyl]imidazoles
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, (2008/06/13)
Compounds of the formula STR1 wherein R is alkyl, cycloalkyl, cycloalkyl lower alkyl, phenyl or phenyl lower alkyl, said phenyl and phenyl lower alkyl optionally substituted on the phenyl ring with one or more substituents independently selected from the group consisting of halo, lower alkyl and trifluoromethyl; and X is oxygen or sulfur with the proviso that X is not oxygen when R is phenyl or substituted phenyl; and the antimicrobial acid addition salts thereof are useful as antifungal, antibacterial and antiprotozoal agents.
