- Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
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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.
- 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
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- Synthesis of 4-Methylimidazole-2-Carboxylic Acid
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4-Methylimidazole-2-carboxylic acid was synthesized from 4-methylimidazole with a total yield of 65% over four steps including an N-benzyl protection, acylation, debenzylation, and ester hydrolysis. The solvent, base, temperature, and reaction time are op
- Wang, Xianheng,Zhao, Changkuo,Gao, Lei,Zhou, Yiqi,Xu, Lang
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p. 2619 - 2622
(2018/09/25)
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- 4-alkyl-imidazole-2-carboxylic acid synthesizing method
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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.
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Paragraph 0028; 0030-0032
(2017/01/26)
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- Development of a regioselective N-methylation of (benz)imidazoles providing the more sterically hindered isomer
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An efficient and highly regioselective N-methylation of (NH)-(benz)imidazoles furnishing the sterically more hindered, less stable, and usually minor regioisomer has been developed. The methodology involves very mild reaction conditions and tolerates a wide range of functional groups.
- Van Den Berge, Emilie,Robiette, Raphael
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p. 12220 - 12223
(2014/01/06)
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- Catalysis and regioselectivity in the Michael addition of azoles. Kinetic vs. thermodynamic control
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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
- Horvath, Andras
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p. 4423 - 4426
(2007/10/03)
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- PREPARATION OF STERICALLY MORE CROWDED 1,5-DISUBSTITUTED IMIDAZOLES BY THE REGIOSELECTIVE N-ALKYLATION
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4-Substituted 1-acetylimidazoles (6), which were derived from 4(5)-substituted imidazole (1), were N-alkylated by treatment with alkyl halides.During the work-up, the resulting N-alkylated products were easily hydrolyzed into 1,5-disubstituted imidazoles (3).These reactions were regarded to be the general method for the preparation of sterically more crowded 1,5-disubstituted imidazoles (3).
- Kashima, Choji,Harada, Yukari,Hosomi, Akira
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p. 433 - 440
(2007/10/02)
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- THE CHEMICAL SIMULATION OF THE "ATP-IMIDAZOLE" CYCLE
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The synthetic strategy inherent in the "ATP-Imidazole" cycle and centred around the vicinal disposition of -NH2 and -CONH2 functions, has been demonstrated with anthranilamide (2) and 1-benzyl-5-aminoimidazole-4-carboxamide (1) as regeneratable carriers involving specifically N-alkylated quinazolin-4-ones, hypoxantines and adenines, as key intermediates.The isolation and characterization of the enamine (22) coupled with other observations has made it possible to rationalize the pathways involved in these cyclic operations.The practical utility of the synthetic strategy using regeneratable carriers has beem illustrated with the synthesis of a range of 1,5-disubstituted imidazoles.Whilst pathways leading to specific N-alkylation in the Natural cycle and in simulation studies are comparable, the subsequent events take place in a reverse order, primarily because of the divergence in the hydrolitic profile of the alkylated substrates.The action of dilute alkali on 3-alkylated quinazolin-4-ones leads to 2-3 rather than 3-4 bond rupture.Endeavours to promote the latter path, by blocking the 2 position gave unexpected results. 2-Methyl-3-phenacyl quinazolin-4-one gave with dilute alkali the novel aromatic tricyclic system (32) from trans-annular cyclization.On the other hand the 2-blocked 3-benzamido quinazolin-4-ones (33) and (34) gave triazoles (35) and (36) arising from the desired 3-4 rupture followed by cyclization initiated by the resulting amidine unit. 2-Phenil-3-benzamidoquinazolin-4-one (34) with distilled water at 200 deg C gave a number of products whicc have been identified and their formation explained.
- Ranganathan, Darshan,Farooqui, Firdous,Bhattacharyya, Diphti,Mehrotra, Sanjiv,Kesavan, K.
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p. 4481 - 4492
(2007/10/02)
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- SYNTHESIS ON TEMPLATES: REGIOSPECIFIC SYNTHESIS OF IMIDAZOLES
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A new, biomimetic template operated strategy has been developed leading to regiospecific synthesis of imidazoles.
- Ranganathan, Darshan,Farooqui, Firdous
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p. 5701 - 5704
(2007/10/02)
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