Novel Insights into the Thioesterolytic Activity of N-Substituted Pyridinium-4-oximes.

Blaženka Foretić,Igor Picek,Vladimir Damjanović,Robert Vianello

doi:10.3390/molecules25102385

Blaženka Foretić, Igor Picek + Show 2 more

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https://doi.org/10.3390/molecules25102385

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Abstract

The pyridinium oximes are known esterolytic agents, usually classified in the literature as catalysts, which mimic the catalytic mode of hydrolases. Herein, we combined kinetic and computational studies of the pyridinium-4-oxime-mediated acetylthiocholine (AcSCh+) hydrolysis to provide novel insights into their potential catalytic activity. The N-methyl- and N-benzylpyridinium-4-oximes have been tested as oximolytic agents toward the AcSCh+, while the newly synthesized O-acetyl-N-methylpyridinium-4-oxime iodide was employed for studying the consecutive hydrolytic reaction. The relevance of the AcSCh+ hydrolysis as a competitive reaction to AcSCh+ oximolysis was also investigated. The reactions were independently studied spectrophotometrically and rate constants, koxime, kw and kOH, were evaluated over a convenient pH-range at I = 0.1 M and 25 °C. The catalytic action of pyridinium-4-oximes comprises two successive stages, acetylation (oximolysis) and deacetylation stage (pyridinium-4-oxime-ester hydrolysis), the latter being crucial for understanding the whole catalytic cycle. The complete mechanism is presented by the free energy reaction profiles obtained with (CPCM)/M06–2X/6–311++G(2df,2pd)//(CPCM)/M06–2X/6–31+G(d) computational model. The comparison of the observed rates of AcSCh+ oximolytic cleavage and both competitive AcSCh+ and consecutive pyridinium-4-oxime-ester hydrolytic cleavage revealed that the pyridinium-4-oximes cannot be classified as non-enzyme catalyst of the AcSCh+ hydrolysis but as the very effective esterolytic agents.

Highlights

The mono- and bis-pyridinium oximes, as quaternized derivatives of pyridyl oximes, are known as pharmacologically important agents [1]
Even though the antidotal potency of pyridinium oximes is primarily attributed to their ability to displace the phosphoryl moiety from the enzyme active site by virtue of their powerful nucleophilicity, they can bind to AcChE
The question which still remains is can the pyridinium-4-oxime be classified as a non-enzyme catalyst toward the AcSCh+ hydrolysis? To answer it, as precisely as possible, the following facts should be taken into account

Summary

Introduction

The mono- and bis-pyridinium oximes, as quaternized derivatives of pyridyl oximes, are known as pharmacologically important agents [1]. The ability of oximes to act as esterolytic agents had already been recognized in the late 1950s and various terms like oximolysis, esterolysis, thiocholine ester hydrolysis and cholinesterase pseudo-activity have been adopted to describe the phenomenon [2,3,4,5,6,7,8,9,10] This reflects their biological role, making them especially effective reagents involved in the reactivation of acetylcholinesterase (AcChE) initially inhibited by organophosphorus poisons (pesticides, nerve gases) [1] or catalysts, which mimic the catalytic mode of hydrolases, as well as Molecules 2020, 25, 2385; doi:10.3390/molecules25102385 www.mdpi.com/journal/molecules. A particular focus is placed on electron and charge transfer processes where pyridinium-4-oxime cations are recognized as new electron acceptors for the formation of colored, supramolecular, inter-ionic charge-transfer complexes with hexacyanoferrate(II)

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