Knowledge Bank

Since their development in the 1930s, organophosphorus nerve agents have been at the forefront of chemical warfare and pesticide usage. Organophosphorus (OP) nerve agents have been tools in chemical warfare in the Iran-Iraq War, the recent Syrian conflict, and have even been deployed by terrorist organizations such as the Aum Shinrikyo cult. OPs have also served as pesticides globally with annual mortality reaching approximately 300,000 people due to pesticide exposure. For these reasons, investigation into organophosphorus compounds has risen greatly in recent decades. OPs act by covalently inhibiting acetylcholinesterase (AChE) via phosphylation of serine203, an amino acid found in the enzyme's active site. AChE is responsible for the hydrolytic breakdown of acetylcholine (ACh), serving to regulate nerve impulses at muscarinic and nicotinic receptors in the central and peripheral nervous system. Given enough time, the phosphylated moiety of AChE can undergo a spontaneous dealkylation reaction known as aging. Aging renders currently approved therapeutics to be ineffective, such as nucleophilic oximes like 2-PAM. The inhibition of AChE by OPs has drastic effects on the well-being of the victim, as continuous neuron impulses results in symptoms including muscle twitching, convulsions, respiratory failure and eventually death if untreated. This has motivated the development of alternative therapeutics capable of resurrecting OP-aged AChE and restoring function of the enzyme in the exposed individual. Our research group focuses on potential routes to resurrect OP-aged AChE through a class of compounds called quinone methides (QMs) sourced from their synthetic precursors (QMPs). Previous literature has shown that QMs are able to serve as realkylators of nucleophiles, applicable to the structure of OP-aged AChE. QMPs are sourced from several organic frameworks but the library synthesized through this research consists mainly of pyridinol, quinolinol, and phenol frameworks with a benzylic amine serving as a leaving group to form the QM. This thesis will highlight the synthesis of a variety of QMPs with modifications including amine identity, aromatic ring identity, as well as varying substituents on the aromatic ring and benzylic carbon. This is with the intention of discovering a potent therapeutic capable of reversing the aging process and reducing the harmful impacts of organophosphorus compounds.