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Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands.

ABSTRACT: 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 (K_i = 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).

SUBMITTER: Gaso Sokac D

PROVIDER: S-EPMC9655973 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands.

Gašo Sokač Dajana D Zandona Antonio A Roca Sunčica S Vikić-Topić Dražen D Lihtar Gabriela G Maraković Nikola N Bušić Valentina V Kovarik Zrinka Z Katalinić Maja M

International journal of molecular sciences 20221102 21

Seven pyridoxal dioxime quaternary salts (<b>1</b>-<b>7</b>) 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 ...[more]

PMID: 36362178

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Project description:ImportanceThe associations of B vitamin status with metabolic syndrome (MetS) incidence among the US population remain unclear.ObjectiveTo investigate intakes and serum concentrations of folate, vitamin B6, and vitamin B12 in association with MetS risk in a large US cohort.Design, setting, and participantsThis prospective study included Black and White young adults in the US who were enrolled from 1985 to 1986 and studied until 2015 to 2016. Diet was assessed using a validated diet history at examination years 0, 7, and 20. Serum concentrations of folate, vitamin B6, and vitamin B12 were assayed at examination years 0, 7, and 15 in a subset of 1430 participants. MetS was ascertained by clinic and laboratory measurements and self-reported medication use. Data were analyzed between January and July 2021.ExposuresIntakes and serum levels of folate, vitamin B6, and vitamin B12.Main outcomes and measuresMultivariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for the associations of energy-adjusted B vitamin intakes or serum B vitamin levels with incident MetS.ResultsThe study included 4414 participants, with 2225 Black individuals (50.4%) and 2331 women (52.8%). The mean (SD) age at baseline was 24.9 (3.6) years. A total of 1240 incident MetS cases occurred during the 30 years (mean [SD], 22.1 [9.5] years) of follow-up. Compared with the lowest quintile of each energy-adjusted B vitamin intake, the HRs for incident MetS in the highest quintile were 0.39 (95% CI, 0.31-0.49) for folate (P for trend < .001), 0.61 (95% CI, 0.46-0.81) for vitamin B6 (P for trend = .002), and 0.74 (95% CI, 0.58-0.95) for vitamin B12 (P for trend = .008) after adjustment for potential confounders. Similarly, significant inverse associations were observed in the subset with serum data on these B vitamins (folate: HR, 0.23; 95% CI, 0.17-0.33; P for trend < .001; vitamin B6: HR, 0.48; 95% CI, 0.34-0.67; P for trend < .001; and vitamin B12: HR, 0.70; 95% CI, 0.51-0.96; P for trend = .01).Conclusions and relevanceThis prospective cohort study found that intakes and serum concentrations of folate, vitamin B6, and vitamin B12 were inversely associated with incident MetS among Black and White young adults in the US.

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Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands.

Publications

Potential of Vitamin B6 Dioxime Analogues to Act as Cholinesterase Ligands.

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