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Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands

Gašo Sokač, Dajana; Zandona, Antonio; Roca, Sunčica; Vikić-Topić, Dražen; Lihtar, Gabriela; Maraković, Nikola; Bušić, Valentina; Kovarik, Zrinka; Katalinić, Maja (2022) Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands. International Journal of Molecular Sciences, 23 (21). ISSN 1422-0067

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Seven pyridoxal dioxime quaternary salts (1–7) were synthesized with the aim of studying their interactions with human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The synthesis was achieved by the quaternization of pyridoxal monooxime with substituted 2-bromoacetophenone oximes (phenacyl bromide oximes). All compounds, prepared in good yields (43–76%) and characterized by 1D and 2D NMR spectroscopy, were evaluated as reversible inhibitors of cholinesterase and/or reactivators of enzymes inhibited by toxic organophosphorus compounds. Their potency was compared with that of their monooxime analogues and medically approved oxime HI-6. The obtained pyridoxal dioximes were relatively weak inhibitors for both enzymes (Ki = 100–400 µM). The second oxime group in the structure did not improve the binding compared to the monooxime analogues. The same was observed for reactivation of VX-, tabun-, and paraoxon-inhibited AChE and BChE, where no significant efficiency burst was noted. In silico analysis and molecular docking studies connected the kinetic data to the structural features of the tested compound, showing that the low binding affinity and reactivation efficacy may be a consequence of a bulk structure hindering important reactive groups. The tested dioximes were non-toxic to human neuroblastoma cells (SH-SY5Y) and human embryonal kidney cells (HEK293).

Item Type: Article
Uncontrolled Keywords: pyridoxal oxime; dioxime; AChE; BChE; reversible inhibition; reactivation; molecular docking; cytotoxicity
Subjects: NATURAL SCIENCES > Chemistry
Divisions: NMR Center
Project titleProject leaderProject codeProject type
Molekularni mehanizmi toksičnosti protuotrova i potencijalnih lijekova-CellToxTargetsMaja KatalinićUIP-2017-05-7260HRZZ
Analiza interakcija butirilkolinesteraze s novim inhibitorima i reaktivatorima-AnalyseBChEZrinka KovarikIP-2018-01-7683HRZZ
Depositing User: Diana Mikoč Radešić
Date Deposited: 25 Jan 2024 12:22
DOI: 10.3390/ijms232113388

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