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

Autor: Burgart YV; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia., Makhaeva GF; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, Chernogolovka 142432, Russia., Khudina OG; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia., Krasnykh OP; Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990,Russia., Kovaleva NV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, Chernogolovka 142432, Russia., Elkina NA; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia., Boltneva NP; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, Chernogolovka 142432, Russia., Rudakova EV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, Chernogolovka 142432, Russia., Lushchekina SV; Department of Brain Sciences, Weizmann Institute of Science, Rehovot 761001, Israel., Shchegolkov EV; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia., Triandafilova GA; Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990,Russia., Malysheva KO; Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990,Russia., Serebryakova OG; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, Chernogolovka 142432, Russia., Borisevich SS; Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078, Russia., Ilyina MG; Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078, Russia., Zhilina EF; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia., Saloutin VI; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia., Charushin VN; Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia., Richardson RJ; Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Institute for Computational Discovery and Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Institute for Data and AI in Society, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: rjrich@umich.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Oct 03; Vol. 115, pp. 117938. Date of Electronic Publication: 2024 Oct 03.
DOI: 10.1016/j.bmc.2024.117938
Abstrakt: A series of 2-arylhydrazinylidene-3-oxo acids (AHOAs) was prepared by dealkylation of alkyl-2-arylhydrazinylidene-3-oxo-3-alkanoates with AlBr 3 . 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 (IC 50 as low as 42 nM) were compounds bearing long polyfluoroalkyl substituents. The acids were also active against hCES1 and hCES2, and CF 3 -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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Rudy J. Richardson reports a relationship with NeuroX1 that includes: board membership. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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