52726-21-3Relevant 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.
4-alkyl-imidazole-2-carboxylic acid synthesizing method
-
Paragraph 0028; 0030-0032, (2017/01/26)
The invention provides a method for synthesizing 4-alkylimidazole-2-carboxylic acid I. The method comprises the steps of firstly, reacting 2-alkyl-imidazole II as a raw material with BnX in the presence of a base to generate a mixture of a pair of position isomers IIIa and IIIb; secondly, on the premise that the mixture is not separated, reacting the mixture with halogenated formate (i.e., XCOOR2) in the presence of a base to generate a pair of corresponding isomers IVa and IVb; thirdly, hydrogenating to remove a benzyl group V in the presence of a hydrogenation catalyst; and fourthly, in the presence of a base, hydrolyzing to obtain the desired product 4-alkylimidazole-2-carboxylic acid I. The reaction route is shown in the specification, wherein R1 is selected from hydrogen atom and lower alkyl groups such as methyl and ethyl and R2 is selected from C1-C6 alkyl, C1-C6 alkoxy substituted group, a phenyl group or a benzyl group. The method disclosed by the invention has ingenious concept, since an inexpensive reagent is used in the respective step, and the yield of each step is high, the final target product 4-alkylimidazole-2-carboxylic acid I can be obtained in efficiency, convenience and low cost.
Catalysis and regioselectivity in the Michael addition of azoles. Kinetic vs. thermodynamic control
Horvath, Andras
, p. 4423 - 4426 (2007/10/03)
Bicyclic guanidine bases, TBD and MTBD were found to be high]y efficient catalysts in the Michael addition of azoles with α,β-unsaturated nitriles and esters. The factors influencing regioselectivity have been elucidated, and some new azole-Michael adduct
