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 occurs. Organophosphorus (OP) intoxication has been shown to irreversibly inhibit the enzyme, preventing hydrolysis of acetylcholine (ACh). This causes a buildup of ACh at neurosynaptic junctions, subsequently leading to respiratory failure. FDA-approved nucleophilic oximes, such as the reactivator pralidoxime (2-PAM), exist to treat this inhibition. However, these compounds 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 are capable of resurrecting aged AChE showing moderate resurrection activity after 24 hours of incubation. A series of 3- hydroxypyridine compounds have been computationally 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 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. It has also been hypothesized that amide functional groups at the 4-position of the phenolic ring orient well with the gorge of AChE, taking advantage of residues lining the gorge of AChE, enhancing binding affinity. Installing these proposed amide substituents to the 4-position while experimenting with the secondary amine leaving groups has been studied. The synthesis and experimental validation of such QMP derivatives will be presented.

Aromatic and substituent effects for the therapeutic treatment of exposure to organophosphorus intoxication

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