Schiff bases, azomethine group containing compounds, form a signifi cant 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-fl uorobenzaldehydes

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 diff erent functional groups, the infl uence 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 identifi ed. In the end, our focus

was on evaluating the drug’s potential as an inhibitor against the Alzheimer’s disease, specifi cally 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.