Abstract:
Here, new phenoxide derivatives of diisopropyl flourophosphate for reaction with Lewis basic sites on acetyl cholinesterase (AChE) were designed. Such binding interaction or reaction inhibits the hydrolysis of the acetylcholine (ACh) neurotransmitter thus enhancing its concentration. This increased neurotransmitter concentration can enhance memory and cognition thus improving symptoms of neurodegenerative diseases such as Alzheimer disease and down syndrome. For docking analysis, we particularly targeted those reception sites on AChE that interacts with the ACh. This led to structural design of derivatives of diisopropyl phenoxyphosphate with controlled reactivity stemming from para substituted phenoxide leaving group. Impact of electron donating (CH3, OCH3) and withdrawing substituents (COCH3) on para position of phenol group on rate of acyl addition elimination reaction was modeled using QM DFT technique. Difference in activation energy between electron donating and withdrawing substituents on phenoxide was noted hence making the derivatives of diisopropyl phenoxyphosphate less reactive and more selective. Docking also confirmed binding of designed derivatives with AChE. Hence novel derivatives with high binding energy and controlled reactivity were designed for retrosynthesis.
