Synthesis, In vitro and In silico Evaluation of a Series of Pyrazolines as New Anticholinesterase Agents

Author(s): Mehlika Dilek Altıntop*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 5 , 2020

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Abstract:

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 anticholinesterase effects.

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 modeling package.

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.

Keywords: Acetylcholinesterase, molecular docking, piperidine, pyrazoline, anticholinesterase agents, ADME.

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Article Details

VOLUME: 17
ISSUE: 5
Year: 2020
Page: [574 - 584]
Pages: 11
DOI: 10.2174/1570180816666190618111023
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