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

Novel 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 mu M, 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 mu M compared with tacrine and donepezil as reference drugs (0.005 and 0.95 mu M, 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.