Background: Pyrazolines, electron-rich nitrogen carriers, are of great importance due to
their potential applications for the treatment of many diseases including inflammation, infectious
diseases and neurodegenerative disorders.
Objectives: The purpose of this work was to synthesize new pyrazoline derivatives and evaluate their
Methods: 1-Aryl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (1-7)
were synthesized via the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(piperidin-1-yl)phenyl]prop-2-
en-1-one with arylhydrazine hydrochloride derivatives in acetic acid, whereas 1-aryl-5-[4-
(morpholin-4-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (8-14) were obtained
by the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one with
arylhydrazine hydrochloride derivatives in acetic acid. Their inhibitory effects on
acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were determined using a
modification of Ellman’s spectrophotometric method. In silico docking and Absorption, Distribution,
Metabolism and Excretion (ADME) studies were performed using Schrödinger’s Maestro molecular
Results: In general, piperidine derivatives were found to be more effective than morpholine
derivatives on cholinesterases (ChEs). 1-Phenyl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)-
4,5-dihydro-1H-pyrazole (1) and 1-(4-cyanophenyl)-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-
dimethoxyphenyl)-4,5-dihydro-1H-pyrazole (7) were identified as the most effective AChE
inhibitors in this series with 40.92% and 38.98%, respectively. Compounds 1 and 7 were docked into
the active site of human AChE (PDB code: 4EY7). Both the compounds were found to be capable of
forming π-π stacking interactions with Trp286. Based on in silico ADME studies, these compounds
are expected to have reasonable oral bioavailability.
Conclusion: In the view of this work, the structural modification of the identified agents is going on
for the generation of new anticholinesterase agents with enhanced efficacy.