Alzheimer’s Disease Drug Design by Synthesis, Characterization, Enzyme Inhibition, In Silico, SAR Analysis and MM-GBSA Analysis of Schiff Bases Derivatives

Abstract Schiff bases, azomethine group containing compounds, form a significant class in pharmaceutical and medicinal chemistry with biologic applications. In this study, two new Schiff base molecules ( 7 and 9 ) were synthesized from the condensation reaction of 1-amino-5-(4-methylbenzoyl)-4- p -tolylpyrimidin-2(1 H )-one ( Z1 ) with 3-chlorobenzaldehyde and 3-fluorobenzaldehydes in good yields (76–75%). The synthesized Schiff bases were completely characterized by IR, NMR and LC–MS. Moreover, both synthesized compounds were evaluated against acetylcholinesterase and butyrylcholinesterase as two important targets in the treatment of Alzheimer’s disease. Approximately, both new compounds were more potent than positive control tacrine against these studied enzymes. Cholinesterase enzyme inhibition is a widely used treatment approach for a variety of mental illnesses. Through the inhibition of the acetylcholinesterase enzyme, which hydrolyzes acetylcholine, cholinesterase inhibitors directly improve cholinergic transmission. Using the SAR (structure–activity relationship) approach to connect different functional groups, the influence of this synthesized molecule on the activity was examined. The investigated compounds were then structurally characterized at the levels of B3LYP, HF, and M062X/6–31+G(d,p). Using maps of molecular electrostatic potential (MEP), the active sites of the compounds under study were identified. In the end, our focus was on evaluating the drug’s potential as an inhibitor against the Alzheimer’s disease, specifically targeting the Alzheimer’s disease protein, that are Acetylcholinesterase (AChE) (PDB ID: 1OCE, 1QTI, and 4M0E) and Butyrylcholinesterase (BChE) (PDB ID: 6R6V and 2WSL). The binding free energy is computed using MM/GBSA techniques. ADME/T characteristics were investigated to see whether these compounds could be potential drugs.