2-Arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropanoic acids as selective and effective carboxylesterase inhibitors with powerful antioxidant potential

Article

作者: Borisevich, Sophia S ; Charushin, Valery N ; Rudakova, Elena V. ; Richardson, Rudy J. ; Khudina, Olga G ; Kovaleva, Nadezhda V. ; Krasnykh, Olga P. ; Malysheva, Ksenia O ; Malysheva, Ksenia O. ; Makhaeva, Galina F. ; Burgart, Yanina V. ; Elkina, Natalia A. ; Triandafilova, Galina A ; Shchegolkov, Evgeny V ; Triandafilova, Galina A. ; Zhilina, Ekaterina F. ; Makhaeva, Galina F ; Ilyina, Margarita G ; Rudakova, Elena V ; Krasnykh, Olga P ; Saloutin, Victor I. ; Boltneva, Natalia P. ; Serebryakova, Olga G. ; Boltneva, Natalia P ; Richardson, Rudy J ; Khudina, Olga G. ; Burgart, Yanina V ; Ilyina, Margarita G. ; Zhilina, Ekaterina F ; Shchegolkov, Evgeny V. ; Serebryakova, Olga G ; Borisevich, Sophia S. ; Kovaleva, Nadezhda V ; Saloutin, Victor I ; Lushchekina, Sofya V. ; Lushchekina, Sofya V ; Elkina, Natalia A ; Charushin, Valery N.

A series of 2-arylhydrazinylidene-3-oxo acids (AHOAs) was prepared by dealkylation of alkyl-2-arylhydrazinylidene-3-oxo-3-alkanoates with AlBr₃. Using X-Ray, NMR spectroscopy, and quantum mechanical calculations (QM), the existence of AHOAs in a thermodynamically favorable Z-form stabilized by two intramolecular H-bonds was established. All AHOAs had acceptable ADME parameters. The esterase profile study showed that polyfluoroalkyl-AHOAs were effective and selective carboxylesterase (CES) inhibitors, while they were inactive against acetyl- and butyrylcholinesterase. In agreement with molecular docking, the most effective CES inhibitors (IC₅₀ as low as 42 nM) were compounds bearing long polyfluoroalkyl substituents. The acids were also active against hCES1 and hCES2, and CF₃-containing acids possessed selectivity against hCES2. Non-fluorinated acids did not inhibit CES, but they exhibited potent antioxidant capability. AHOAs having unsubstituted phenyl or electron-donating groups in the arylhydrazinylidene moiety displayed high primary antioxidant activity in the ABTS, FRAP, and ORAC tests, which did not depend on the substituent in the acyl fragment in the ABTS and ORAC assays. The radical-scavenging mechanism of AHOAs was investigated using QM calculations, showing a preference for cleavage of NH rather than OH bonds. For the lead antioxidants, 4-methoxysubstituted AHOAs, protective effects on erythrocyte membranes in AAPH-induced oxidative stress conditions were shown, including membrane stabilizing activity, inhibition of AAPH-induced lipid peroxidation of erythrocyte membranes, and Fe(II)-chelating ability. Thus, a new class of potent and selective CES inhibitors with powerful antioxidant potential has been developed as promising co-drugs capable of regulating the metabolism of esterified drugs and scavenging reactive radicals that form during Phase I biotransformation.

2021-06-01·European Journal of Medicinal Chemistry1区 · 医学

Novel potent bifunctional carboxylesterase inhibitors based on a polyfluoroalkyl-2-imino-1,3-dione scaffold

1区 · 医学

Article

作者: Shchegolkov, Evgeny V ; Boltneva, Natalia P ; Stupina, Tatyana S ; Palyulin, Vladimir A ; Terentiev, Alexey A ; Radchenko, Eugene V ; Burgart, Yanina V ; Saloutin, Victor I ; Rudakova, Elena V ; Elkina, Natalia A ; Bachurin, Sergey O ; Richardson, Rudy J ; Makhaeva, Galina F ; Serebryakova, Olga G ; Kovaleva, Nadezhda V ; Lushchekina, Sofya V

An expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc)₂-catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase (CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, bind to the CES active site suggesting subsequent reactions: formation of a tetrahedral adduct, and a slow hydrolysis reaction. The results of molecular modeling allowed us to explain some structure-activity relationships of CES inhibition by HOPs 3: their selectivity toward CES in comparison with cholinesterases and the high selectivity of pentafluoroethyl-substituted HOP 3p to hCES1 compared to hCES2. All compounds were predicted to have good intestinal absorption and blood-brain barrier permeability, low cardiac toxicity, good lipophilicity and aqueous solubility, and reasonable overall drug-likeness. HOPs with a TFK group and electron-donor substituents in the arylhydrazone moiety were potent antioxidants. All compounds possessed low cytotoxicity and low acute toxicity. Overall, a new promising type of bifunctional CES inhibitors has been found that are able to interact with the active site of the enzyme with the participation of two functional groups. The results indicate that HOPs have the potential to be good candidates as human CES inhibitors for biomedicinal applications.

2014-10-01·Journal of Chromatography B3区 · 医学

Use of a carboxylesterase inhibitor of phenylmethanesulfonyl fluoride to stabilize epothilone D in rat plasma for a validated UHPLC–MS/MS assay

3区 · 医学

Article

作者: Zhang, Duxi ; Yuan, Long ; Arnold, Mark E ; Aubry, Anne-Françoise ; Peng, Qianping ; Fu, Yunlin ; Xia, Yuan-Qing

A sensitive, accurate and rugged UHPLC-MS/MS method was developed and validated for the quantitation of Epothilone D (EpoD), a microtubule stabilizer in development for treatment of Alzeimer's disease, in rat plasma. The ester group in EpoD can be hydrolyzed by esterases in blood or plasma, which creates a stability concern for the bioanalysis of EpoD. Species differences in the stability of EpoD in plasma were observed. Carboxylesterases were identified as the likely esterases responsible for the hydrolysis of EpoD in plasma ex vivo, and the cause of the species different stability. Phenylmethanesulfonyl fluoride, a carboxylesterase inhibitor, was used to stabilize EpoD in rat blood during sample collection, processing, and storage. A systematic method screening and optimization strategy was used to improve the assay sensitivity and minimize potential bioanalytical risks. The stabilized plasma samples were extracted by liquid-liquid extraction. Chromatographic separation was achieved on an Acquity UPLC BEH Phenyl column with a gradient elution. EpoD and its stable isotope labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The standard curve, which ranged from 0.100 to 100ng/mL was fitted to a 1/x(2) weighted linear regression model. The intra-assay precision was within ±3.6% CV and inter-assay precision was within ±4.2% CV. The assay accuracy was within ±8.3% of the nominal values. Assay recovery of EpoD was high (∼90%) and matrix effect was minimal (1.02-1.05). EpoD was stable in stabilized rat plasma for at least 30h at room temperature, 180 days at -20°C, and following three freeze-thaw cycles. The validated method was successfully applied to sample analysis in toxicology studies.

100 项与 Carboxylesterase Inhibitors(Takeda Oncology) 相关的药物交易

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