41128-19-2Relevant articles and documents
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.
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.
