The long-range objective of this research is to understand how asymmetry present in phosphorothiolates (organophosphorus compounds bearing a P-S-R group) regulates the rate, extent and mechanism of cholinesterase inactivation and reactivation. Isomalathion, a phosphorothiolate impurity found in malathion, bears centers of asymmetry at both carbon and phosphorus and is an excellent starting point for studying interactions with various cholinesterases. A co-objective is to prepare novel chiral phosphorothiolate structures capable of probing cholinesterase function. Although knowledge of the three-dimensional structure of cholinesterase has advanced rapidly in recent years, the needed development of stereochemically precise active site probes and inactivators has lagged behind. The development and demand for these novel compounds could add significantly to our knowledge of solution reactivity, effects of stereoisomerism on mechanism, and cholinesterase structure and function. In this study, two specific aims will be undertaken; (1) to determine the mechanism of cholinesterase inactivation by isomalathion, and (2) to use specific chemical design features inherent to isomalathion in combination with structure-reactivity relationships to design and prepare P-chiral phosphorothiolate-based anticholinesterase agents to test the scope of dual-stage inhibition mechanisms.
A serious chemical problem has remained at the forefront of public concern; "Are organophosphorus (OP) insecticides (e.g., malathion, diazinon, etc.) safe, and if not, what key interactions are responsible or correlate with toxic action and can they be readily identified?" In order to address and answer this question, a basic understanding of the chemical and biochemical mechanisms underlying organophosphate mode of action is required. Although OP mechanism of action is widely understood, very little is known about how "left-" or "right-handedness" or symmetry in OP molecules alters their properties. This research is directed toward pursuing such an understanding.
