1621-91-6Relevant articles and documents
Mass Spectrometry of Nitroazoles. 3-Ortho Effects: The loss of OH. and H2O from Methyl Substituted Nitrodiazoles
Luijten, W. C. M. M.,Thuijl, J. van
, p. 299 - 303 (1982)
Methyl substituted nitrodiazoles which have the substituents at adjacent positions in the ring are subject to several ortho effects.Deuterium labelling of the methyl group and the mobile N-bonded hydrogen show that the loss of OH. originates from the substituents.In some cases the N-bonded hydrogen atom participates also in the loss of OH. and of H2O.
Synthesis and evaluation of original bioisosteres of bacterial type IIA topoisomerases inhibitors
Petrella, Stéphanie,Aubry, Alexandra,Janvier, Geneviève,Coutant, Eloi P.,Cartier, Alex,Dao, Thuy-Ha,Bonhomme, Frédéric J.,Motreff, Laurence,Pissis, Cédric,Bizet, Chantal,Clermont, Dominique,Begaud, Evelyne,Retailleau, Pascal,Munier-Lehmann, Hélène,Capton, Estelle,Mayer, Claudine,Janin, Yves L.
, p. 240 - 250 (2015)
A recently discovered series of inhibitors of the ATPase function of bacterial type IIA topoisomerases featuring a carboxypyrrole component led us to attempt to replace this group with a potentially bioisosteric carboxypyrazole. Accordingly, synthetic pathways to 2-(4-(1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids or 2-(4-(N-methyl-1H-pyrazole-5-carboxamido)piperidin-1-yl)thiazole-5-carboxylic acids featuring an array of substituents on the pyrazole ring were explored. Unfortunately, none of the analogues made were effective on the ATPase function of Mycobacterium tuberculosis gyrase as well on the DNA supercoiling activity of the whole gyrase of M. tuberculosis and Escherichia coli. However, this work is still providing original insights in chemistry as well as in the structure-activity relationships of this series of inhibitors.
Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors
Janssen, Antonius P.A.,Van Hengst, Jacob M.A.,Béquignon, Olivier J.M.,Deng, Hui,Van Westen, Gerard J.P.,Van Der Stelt, Mario
, p. 7910 - 7922 (2019/10/11)
Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis-Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase inhibitors is expected to aid in the discovery and development of more selective covalent inhibitors.
Optimization and biological evaluation of 2-aminobenzothiazole derivatives as Aurora B kinase inhibitors
Lee, Eun,An, Ying,Kwon, Junhee,Kim, Keun Il,Jeon, Raok
, p. 3614 - 3622 (2017/06/13)
A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G2/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics.
