Yan, Yu-Hang published the artcileStructure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors, Category: chlorides-buliding-blocks, the publication is European Journal of Medicinal Chemistry (2022), 113965, database is CAplus and MEDLINE.
X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives, I [R1 = cyclopropyl, 4-pyridylmethyl, 2-(1-methyltetrazol-5-yl)sulfanylethyl, etc.; R2 = R3 = Me, cyclopropyl, Ph, etc.] was reported by considering how to engage with the active-site flexible loops and improve penetration into Gram-neg. 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 crystallog. analyses. Of the tested ICA inhibitors, I [R1 = 4-pyridylmethyl, R2 = R3 = H] displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clin. isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphol. and internal structural changes of bacterial cells after treatment further demonstrated that I [R1 = 4-pyridylmethyl, R2 = R3 = H] crossed the outer membrane and reversed the activity of meropenem. Moreover, I [R1 = 4-pyridylmethyl, R2 = R3 = H] showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-neg. carbapenem resistance.
European Journal of Medicinal Chemistry published new progress about 939-99-1. 939-99-1 belongs to chlorides-buliding-blocks, auxiliary class Fluoride,Chloride,Benzyl chloride,Benzene, name is 1-(Chloromethyl)-4-(trifluoromethyl)benzene, and the molecular formula is C3H6O2, Category: chlorides-buliding-blocks.
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