Fused 1,4‐Dihydropyridines and Their Corresponding Pyridines: Synthesis, Molecular Modeling and Cholinesterase Inhibition

Abstract

AbstractNovel series of fused 1,4‐dihydropyridine derivatives were designed and synthesized. Oxidized to the corresponding pyridines were these dihydropyridines. Both dihydropyridines and pyridines were evaluated as acetyl and butyrylcholinesterase inhibitors. 1,4‐dihydropyridine derivatives outperformed pyridines against the butyrylcholinesterase enzyme, but none had a suitable inhibitory effect against acetylcholinesterase. Among the 1,4‐dihydropyridines, compounds derived from vanillin (4 j–p) inhibited butyrylcholinesterase (BChE) with IC50 values of 2.87–15.61 μM, but compounds derived from 4‐hydroxybenzaldehyde did not show a suitable inhibitory effect against butyrylcholinesterase. Among them, the compound 9‐(4‐((4‐Chlorobenzyl)oxy)‐3‐methoxyphenyl)‐3,4,6,7,9,10‐hexahydroacridine‐1,8(2H,5H)‐dione (4 p) showed appropriate inhibitory activity against BChE with an IC50 value of 2.87 μM compared with tacrine and donepezil as reference drugs (0.005 and 0.95 μM, respectively). The most outstanding results of kinetic and molecular modeling studies is that compound 4 p acts as a mixed and dual binding inhibitor, and binds to CAS and PAS of the BChE enzyme. These results show that with minor changes in the structure of fused 1,4‐dihydropyridines, new anti‐Alzheimer drugs with better performance can be achieved.