170737-96-9Relevant academic research and scientific papers
Development of methionyl-trna synthetase inhibitors as antibiotics for gram-positive bacterial infections
Faghih, Omeed,Zhang, Zhongsheng,Ranade, Ranae M.,Gillespie, J. Robert,Creason, Sharon A.,Huang, Wenlin,Shibata, Sayaka,Barros-álvarez, Ximena,Verlinde, Christophe L. M. J.,Hol, Wim G. J.,Fan, Erkang,Buckner, Frederick S.
, (2017)
Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Both previously published and new selective inhibitors were shown to be highly active against Gram-positive bacteria with MICs of 1.3 g/ml against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated that the mechanism of activity was due to the inhibition of protein synthesis. Little activity against Gram-negative bacteria was observed, consistent with the fact that Gram-negative bacterial species contain a different type of MetRS enzyme. The ratio of the MIC to the minimum bactericidal concentration (MBC) was consistent with a bacteriostatic mechanism. The level of protein binding of the compounds was high (95%), and this translated to a substantial increase in MICs when the compounds were tested in the presence of serum. Despite this, the compounds were very active when they were tested in a Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144, given by oral gavage, resulted in 3- to 4-log decreases in the bacterial load compared to that in vehicle-treated mice, which was comparable to the results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development.
Optimization of methionyl tRNA-synthetase inhibitors for treatment of Cryptosporidium infection
Buckner, Frederick S.,Ranade, Ranae M.,Robert Gillespie,Shibata, Sayaka,Hulverson, Matthew A.,Zhang, Zhongsheng,Huang, Wenlin,Choi, Ryan,Verlinde, Christophe L.M.J.,Hol, Wim G.J.,Ochida, Atsuko,Akao, Yuichiro,Choy, Robert K.M.,Van Voorhis, Wesley C.,Arnold, Sam L.M.,Jumani, Rajiv S.,Huston, Christopher D.,Fan, Erkang
, (2019)
Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most need
2,3-DIARYL- OR HETEROARYL-SUBSTITUTED 1,1,1-TRIFLUORO-2-HYDROXYPROPYL COMPOUNDS
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Page/Page column 43, (2010/10/19)
The present invention relates to compounds of formula I wherein R1a to R1c, R2, R3 and R5 are as defined in the description and claims and R4 signifies a bicyclic heteroaryl group or a cyanophenyl group, as well as pharmaceutically acceptable salts thereof. The compounds are glucocorticoid receptor antagonists useful for the treatment and/or prevention of diseases such as diabetes, dyslipidemia, obesity, hypertension, cardiovascular diseases, adrenal imbalance or depression.
1-H-3-aryl-pyrrolidine-2, 4-dione derivatives as pest-control agents
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, (2008/06/13)
The present invention relates to new 1-H-3-aryl-pyrrolidine-2,4-dione derivatives of the formula (I) in which A, B, G, X, Y and Z have the meanings given in the description, to processes for their preparation, and to intermediates therefor. The compounds
