A Comprehensive İnvestigation of Schiff Bases and Bis-Α-Aminophosphonates As Potent Agents Against Alzheimer's Disease By Computer-Aided Drug Discovery Techniques and in Vitro Examinations

Abstract

In this study, we designed and synthesized new Schiff bases (7–11) and bis-α-aminophosphonate derivatives (13–16) to examine their inhibitory properties against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes which are associated with Alzheimer's disease (AD). All newly synthesized compounds were characterized by FT-IR, 1H, and 13C NMR and were tested were appraised for their inhibitory potential opposite to AChE and BChE enzymes, by determining their IC50 and Ki values. Bis-α-aminophosphonate derivatives showed significantly strong inhibitory affinity against AChE, whereas they had weak inhibitory activities against BChE. Schiff bases exhibited low inhibitory activity against both AChE and BChE. Among bis-α-aminophosphonates, compounds 14, 15, and 16 showed excellent inhibitory properties against AChE with an IC50 value of 6.48, 9.00, and 10.88 μM, respectively, with respect to positive control pyridostigmine bromide (IC50= 26.2 μM). Kinetic studies showed that the inhibition mechanism of 14, 15, and 16 against AChE is non-competitive. The physicochemical properties of compounds and their affinities towards the protein were investigated by quantum chemical calculations, molecular docking, and molecular dynamics simulation techniques. So, among the investigated compounds, compound 15 has been found as significantly higher binding affinity against AChE. This observation hints at the capacity of these compounds to potentially influence enzyme activity, indicating their potential relevance in the realm of treatment of Alzheimer's disease.