Synthesis, investigation of the cholinesterase inhibitory activities and in silico studies of some novel N-substituted phthalimide derivatives

Abstract

Novel N-substituted phthalimide derivatives (4a-c) were synthesized using a three-step procedure in high yields. The inhibitory effects of these compounds against Electric eel acetylcholinesterase (eeAChE) and Equine serum butyrylcholinesterase (eqBChE) were examined in comparison with galantamine used as a standard drug. All compounds displayed quite good inhibition against both eeAChE and eqBChE. Compound 4b, carrying a 4-methyl piperidine moiety, showed the best activity against the both enzymes (IC50 = 0.052, Ki = 0.022 mu M for eeAChE, and IC50 = 0.307, Ki = 0.112 mu M for eqBChE) in noncompetitive inhibition type. In silico molecular docking studies detected that phthalimide ring, N-alkyl, and 4-methyl piperidine moieties of compound 4b were effective in the binding to the cholinesterase enzymes. The docking studies also showed that 4b has the best interaction energy value in agreement with our experimental data, and interacts with both catalytic active site (CAS) and peripheral anionic site (PAS) residues of eeAChE, while it interacts the CAS residues of homo sapiens BChE. In silico ADMET studies of all compounds suggested acceptable drug-likeness scores for these compounds. Consequently, the compounds, especially 4b, can be considered as new promising inhibitors for the cholinesterase enzymes.