41128-19-2Relevant academic research and scientific papers
Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-β-lactamases
Zhang, Dong,Markoulides, Marios S.,Stepanovs, Dmitrijs,Rydzik, Anna M.,El-Hussein, Ahmed,Bon, Corentin,Kamps, Jos J.A.G.,Umland, Klaus-Daniel,Collins, Patrick M.,Cahill, Samuel T.,Wang, David Y.,von Delft, Frank,Brem, Jürgen,McDonough, Michael A.,Schofield, Christopher J.
supporting information, p. 2928 - 2936 (2018/04/19)
Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging ‘hydrolytic’ water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.
AMIDO-ISOTHIAZOLE COMPOUNDS AND THEIR USE AS INHIBITORS OF 11BETA-HSD1 FOR THE TREATMENT OF METABOLIC SYNDROME AND RELATED DISORDERS
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Page/Page column 77, (2010/12/31)
The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain amido-isothiazole compounds that, inter alia, inhibit 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 11β-hydroxysteroid dehydrogenase type 1; to treat disorders that are ameliorated by the inhibition of 11β-hydroxysteroid dehydrogenase type 1; to treat the metabolic syndrome, which includes disorders such as type 2 diabetes and obesity, and associated disorders including insulin resistance, hypertension, lipid disorders and cardiovascular disorders such as ischaemic (coronary) heart disease; to treat CNS disorders such as mild cognitive impairment and early dementia, including Alzheimer's disease; etc.
4-Aryl-1,3,2-oxathiazolylium-5-olates as pH-controlled NO-donors: The next generation of S-nitrosothiols
Lu, Dongning,Nadas, Janos,Zhang, Guisheng,Johnson, Wesley,Zweier, Jay L.,Cardounel, Arturo J.,Villamena, Frederick A.,Wang, Peng George
, p. 5503 - 5514 (2008/02/07)
S-Nitrosothiols (RSNOs) are important exogenous and endogenous sources of nitric oxide (NO) in biological systems. A series of 4-aryl-1,3,2- oxathiazolylium-5-olates derivatives with varying aryl para-substituents (-CF3, -H, -Cl, and -OCH3) were synthesized. These compounds were found to release NO under acidic condition (pH = 5). The decomposition pathway of the aryloxathiazolyliumolates proceeded via an acid-catalyzed ring-opening mechanism after which NO was released and an S-centered radical was generated. Electron paramagnetic resonance (EPR) spin trapping studies were performed to detect NO and the S-centered radical using the spin traps of iron(II) N-methyl-D-glucamine dithiocarbamate [(MGD) 2-FeII] and 5,5-dimethyl-1-pyrroline N-oxide (DMPO). Also, EPR spin trapping and UV-vis spectrophotometry were used to analyze the effect of aryl para substitution on the NO-releasing property of aryloxathiazolyliumolates. The results showed that the presence of an electron-withdrawing substituent such as -CF3 enhanced the NO-releasing capability of the aryloxathiazolyliumolates, whereas an electron-donating substituent like methoxy (-OCH3) diminished it. Computational studies using density functional theory (DFT) at the PCM/B3LYP/6-31+G*7/B3LYP/6-31G* level were used to rationalize the experimental observations. The aryloxathiazolyliumolates diminished susceptibility to reduction by ascorbate or gluthathione, and their capacity to cause vasodilation as compared to other S-nitrosothiols suggests potential application in biological systems.
