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Influence of structure on nucleophilicity and coordination ability of pharmacologically important N-methylpyridinium aldoximes

Introduction: Pyridinium aldoximes are known as pharmacologically important, strong nucleophilic agents that are effective antidotes against poisoning by organophosphorus compounds (pesticides, chemical warfare nerve agents, drugs used in treatment of cholinergic disorders). Furthermore, the biological function of aldoximes and the mechanism of their metabolism are related to their chelation to metal ions. Nowadays, the aldoxime-induced reactivation of the phosphorylated and thus inhibited acetylcholinesterase (AChE, E.C.3.1.1.7) is the primary therapeutic approach to organophosphorus poisoning. The most commonly pyridinium aldoxime used in routine human therapy is N-methylpyridinium-2-aldoxime chloride (PAM2-Cl) known as Pralidoxime Chloride. Its structural and chemical properties in aqueous media have been correlated with the N-methylpyridinium-3-aldoxime iodide (PAM3-I) and N-methylpyridinium-4-aldoxime iodide (PAM4-I). Subsequently, their coordination ability toward the aquapentacyanoferrate(II) ion, [Fe(CN)5(OH2)]3–, as a model of biologically important macromolecules with the labile sixth coordination site, has been elucidated. Materials and methods: PAM3-I and PAM4-I were synthesized, while PAM2-Cl (Sigma-Aldrich) was reagent-grade and used as purchased. Na3[Fe(CN)5(NH3)]•3H2O (Sigma-Aldrich) was used as a precursor of [Fe(CN)5(OH2)]3–. The pH of the reaction mixtures was adjusted using Britton-Robinson buffers. All kinetic and thermodynamic measurements were carried out on Varian Cary Bio 100 spectrophotometer. The 1H and 13C NMR spectra were recorded at ambient temperature in DMSO-d6 on Bruker Avance 600 spectrometer. FT-IR spectra were recorded on a Perkin Elmer Spectrum GX, Series R spectrometer. Results: Predominant ionic structures of the investigated pyridinum aldoximes in aqueous solution (pH range 4.0–11.5) as well as their ionization ability have been established. The electronic, vibrational and NMR spectral characterization as well as nucleophilic properties of the investigated aldoximes are found to be in agreement with the bond distances and valence angles obtained from the previously performed X-ray structure analysis. The thermodynamic and kinetic properties of their reactive forms toward the iron(II) center in the pentacyanoferrate(II) moiety are evaluated. Conclusion: The nucleophilic strength of the investigated aldoximes at physiological pH is found to be in the following order: PAM2-ClPAM4-IPAM3-I. The pyridinium aldoxime pentacyanoferrate(II) complexes can be classified as thermodynamically instable and kinetically labile.

N-methylpyridinium aldoximes

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