39053-78-6Relevant articles and documents
Synthesis and biological evaluation of N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivatives as tubulin polymerization inhibitors
Qi, Jianguo,Dong, Haiyang,Huang, Jing,Zhang, Shufeng,Niu, Linqiang,Zhang, Yahong,Wang, Jianhong
, p. 8 - 20 (2017/11/23)
A series of novel N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxy- lic acid derivatives were synthesized and evaluated for their biological activities. Among all synthesized target compounds, 13d exhibited the most potent antiproliferative ac
Hybrids of coumarin-indole: Design, synthesis and biological evaluation in Triton WR-1339 and high-fat diet induced hyperlipidemic rat models
Sashidhara, Koneni V.,Rao, K. Bhaskara,Sonkar, Ravi,Modukuri, Ram K.,Chhonker, Yashpal S.,Kushwaha, Pragati,Chandasana, Hardik,Khanna,Bhatta, Rabi S.,Bhatia, Gitika,Suthar, Manish Kumar,Saxena, Jitendra Kumar,Kumar, Vikash,Siddiqi, Mohammad Imran
, p. 1858 - 1869 (2016/09/28)
In this study, a series of coumarin-indole hybrids have been synthesized and evaluated for their lipid lowering activity. Preliminary biological screening of the synthesized compounds was undertaken in an in vitro model of the HMG-CoA reductase enzyme, an
Phenyl Esters Are Potent Inhibitors of Caseinolytic Protease P and Reveal a Stereogenic Switch for Deoligomerization
Hackl, Mathias W.,Lakemeyer, Markus,Dahmen, Maria,Glaser, Manuel,Pahl, Axel,Lorenz-Baath, Katrin,Menzel, Thomas,Sievers, Sonja,B?ttcher, Thomas,Antes, Iris,Waldmann, Herbert,Sieber, Stephan A.
supporting information, p. 8475 - 8483 (2015/07/15)
Caseinolytic protease P (ClpP) represents a central bacterial degradation machinery that is involved in cell homeostasis and pathogenicity. The functional role of ClpP has been studied by genetic knockouts and through the use of beta-lactones, which remain the only specific inhibitors of ClpP discovered to date. Beta-lactones have served as chemical tools to manipulate ClpP in several organisms; however, their potency, selectivity and stability is limited. Despite detailed structural insights into the composition and conformational flexibility of the ClpP active site, no rational efforts to design specific non-beta-lactone inhibitors have been reported to date. In this work, an unbiased screen of more than 137000 compounds was used to identify five phenyl ester compounds as highly potent ClpP inhibitors that were selective for bacterial, but not human ClpP. The potency of phenyl esters largely exceeded that of beta-lactones in ClpP peptidase and protease inhibition assays and displayed unique target selectivity in living S. aureus cells. Analytical studies revealed that while phenyl esters are cleaved like native peptide substrates, they remain covalently trapped as acyl-enzyme intermediates in the active site. The synthesis of 36 derivatives and subsequent structure-activity relationship (SAR) studies provided insights into conserved structural elements that are important for inhibition potency and acylation reactivity. Moreover, the stereochemistry of a methyl-substituent at the alpha position to the ester, resembling amino acid side chains in peptide substrates, impacted ClpP complex stability, causing either dissociation into heptamers or retention of the tetradecameric state. Mechanistic insights into this intriguing stereo switch and the phenyl ester binding mode were obtained by molecular docking experiments.
