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.
N-(Substituted sulfonyl)benzamide derivative and preparation method and pharmaceutical application thereof
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, (2019/04/17)
The invention relates to an N-(substituted sulfonyl)benzamide derivative and preparation method and pharmaceutical application thereof, in particular to an N-(substituted sulfonyl)benzamide derivativeshown as general formula (I), preparation method thereof, medicinal salts of the derivative, and their application as therapeutics, especially as Nav1.7 inhibitors, wherein substituents in the general formula (I) shown in the description are defined the same as in the description.
NOVEL DXR INHIBITORS FOR ANTIMICROBIAL THERAPY
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, (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.
Synthesis and antiparasitic and antitumor activity of 2,4-diamino-6- (arylmethyl)-5,6,7,8-tetrahydroquinazoline analogues of piritrexim
Rosowsky, Andre,Papoulis, Andrew T.,Forsch, Ronald A.,Queener, Sherry F.
, p. 1007 - 1017 (2007/10/03)
Nineteen previously undescribed 2,4-diamino-6-(arylmethyl)-5,6,7,8- tetrahydroquinazolines (5a-m, 10-12) were synthesized as part of a larger effort to assess the therapeutic potential of lipophilic dihydrofolate reductase (DHFR) inhibitors against opportunistic infections of AIDS. Condensation of appropriately substituted (arylmethyl)triphenylphosphoranes with 4,4-ethylenedioxycyclohexanone, followed by hydrogenation (H2/Pd-C) and acidolysis, yielded the corresponding 4-(arylmethyl)cyclohexanones, which were then condensed with cyanoguanidine to form the tetrahydroquinazolines. Three simple 2,4-diamino-6-alkyl-5,6,7,8-tetrahydroquinazoline model compounds (9a-c) were also prepared in one step from commercially available 4-alkylcyclohexanones by this method. Enzyme inhibition assays against rat liver DHFR, Pneumocystis carinii DHFR, and the bifunctional DHFR-TS enzyme from Toxoplasma gondii were carried out, and the selectivity ratios IC50(rat)/IC50(P. carinii) and IC50(rat)/IC50(T. gondii) were compared. The three most potent inhibitors of P. carinii DHFR were the 2,5- dimethoxybenzyl (5j), 3,4-dimethoxybenzyl (5k), and 3,4,5-trimethoxybenzyl (51) analogues, with IC50 values of 0.057, 0.10, and 0.091 μM, respectively. The remaining compounds generally had IC50 values in the 0.1- 1.0 μM range. However all the compounds were more potent against the rat liver enzyme than the P. carinii enzyme and thus were nonselective. The T. gondii enzyme was always more sensitive than the P. carinii enzyme, with most of the analogues giving IC50 values of 0.01-0.1 μM. Moderate 5-10-fold selectivity for T. gondii versus rat liver DHFR was observed with five compounds, the best combination of potency and selectivity being achieved with the 2-methoxybenzyl analogue 5d, which had an IC50 of 0.014 μM and a selectivity ratio of 8.6. One compound (51) was tested for antiproliferative activity against P. carinii trophozoites in culture at a concentration of 10 μg/mL and was found to completely suppress growth over 7 days. The suppressive effect of 51 was the same as that of trimethoprim (10 μg/mL) + sulfamethoxazole (250 μg/mL), a standard clinical combination for the treatment of P. carinii pneumonia in AIDS patients. Four compounds (5a,h,k,l) were tested against T. gondii tachyzoites in culture and were found to have a potency (IC50 = 0.1-0.5 μM) similar to that of pyrimethamine (IC50 = 0.69 μM), a standard clinical agent for the treatment of cerebral toxoplasmosis in AIDS patients. Compound 5h was also active against T. gondii infection in mice when given qdx8 by peritoneal injection at doses ranging from 62.5 (initial dose) to 25 mg/kg. Survival was prolonged to the same degree as with 25 mg/kg clindamycin, another widely used drug against toxoplasmosis. Three compounds (5j-l) were tested for antiproliferative activity against human tumor cells in culture. Among the 25 cell lines in the National Cancer Institute panel for which data were confirmed in two independent experiments, the IC50 for at least two of these compounds was 50 of 50 was 0.01 μM.
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.
