COMBATTING ORGANOPHOSPHORUS INTOXICATION: A STUDY OF THE AROMATIC AND SUBSTITUENT EFFECTS ON NOVEL SMALL MOLECULE THERAPEUTICS
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Date
2023-05
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The Ohio State University
Abstract
Acetylcholinesterase (AChE) is an enzyme in the body found primarily in erythrocytes, brain synapses and neuromuscular junctions. Located in the active site of the enzyme, the triad of serine, histidine and glutamate is where selective hydrolysis of the neurotransmitter acetylcholine takes place. Organophosphorus (OP) intoxication has been shown to irreversibly inhibit the enzyme, preventing hydrolysis of acetylcholine. This causes a buildup of acetylcholine at neurosynaptic junctions, subsequently leading to respiratory failure.
There exists select FDA-approved nucleophilic oximes to treat the inhibition by organophosphorus compounds. However, such oximes are rendered ineffective once the inhibited enzyme ages, a spontaneous process in which the dealkylation of the phosphylated serine residue occurs. Through the effort of computational research, our team reported that a class of quinone methide precursors (QMPs) can treat the OP-aged AChE via a posited realkylation of the phosphylated oxyanion. Our team was the first to demonstrate a family of QMPs that were able to resurrect aged AChE showing moderate resurrection activity after 24 hours of incubation.
A series of 3-hydroxypyridine compounds have been proposed to have a higher binding affinity to the active site of AChE with the most effective compounds bearing pyrrolidine and (R)-2-methylpyrrolidine as the leaving group bonded to the benzylic carbon at the 2-position. It has been hypothesized that attaching various substituents to the 6-position may alter the effects of reactivation and resurrection. However, it is unknown as to which substituent and amine leaving group combination may produce the best results. Promising results have been shown by methylation of the 6-position of the pyridine ring. As a result, adding an ethyl or propyl group may lead to higher reactivation and resurrection activities.
Our team has also exhibited success with various groups at the 4-position of a phenol framework. Previous experimentation with different electron-withdrawing and electron- donating groups have suggested installation of the amide functionality on the ring. It has been hypothesized that amide functional groups at the 4-position of the phenolic ring will orient well with the gorge of AChE, which can take advantage of various residues that line the gorge of AChE for enhanced binding affinity. Various amide substituents and their steric effects can provide insight to reactivation and potential resurrection capabilities that have yet to be studied. Installing these proposed amide substituents to the 4-position while experimenting with the secondary amine leaving groups have been studied. The synthesis and experimental validation of such QMP derivatives are presented.