Acetylcholinesterase (AChE) is a vital serine hydrolase found throughout the body and it is responsible for the catalytic hydrolysis of the neurotransmitter acetylcholine. Organophosphorus (OP) compounds are capable of inhibiting AChE by phosphylation of a serine residue at the catalytic site of AChE, resulting in an accumulation of acetylcholine. Therefore, exposure to OP compounds can often be fatal and lead to death. OP compounds were initially synthesized to be used as pesticides and are still utilized for crop protection today. However, these OP pesticides would go on to be developed into lethal chemical nerve agents and used in wars and acts of terrorism. To date, a limited number of oxime-based drugs have shown the ability to reactivate OP-inhibited AChE. However, reactivation of AChE can be complicated by a second phase of OP poisoning, and this second step is known as aging. For the OP-aged form, oxime therapeutics have been shown to be ineffective, and to date, no FDA-approved clinical treatment has been developed in order to bring OP-aged AChE back to its native form. To address this limitation of current therapeutics, the Hadad lab reported the development of novel small molecule therapeutics, quinone methide precursors (QMPs), to resurrect OP-aged AChE. Previous work in the group showed that the 4-aminomethyl-3-hydroxyquinoline Mannich-based framework with the appropriate amine can restore AChE activity. Intrigued by this result, we sought to 1) further expand the library of quinoline based QMPs and 2) explore other heteroarenes that are common in drugs, such as indoles and benzimidazoles, to evaluate new possible drug candidate scaffolds. This presentation will highlight the current efforts made in synthesizing these novel QMPs from various biologically active bicyclic heteroarenes.

Exploring bicyclic heteroarenes as quinone methide precursors to combat organophosphorus poisoning

ACS Spring 2022

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