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Sains Malaysiana 54(11)(2025): 2697-2705
http://doi.org/10.17576/jsm-2025-5411-10
Synthesis, Acetylcholinesterase and Molecular Modelling Analysis of (3E,5E)-3,5-Diarylidene-1-Phenylethylpiperidine-4-One
Derivatives as a Therapeutic Agent for Alzheimer’s Disease
MOHD KHAIRUL NIZAM MAZLAN1,2,3,4, MOHAMAD
NURUL AZMI4, AGUSTONO WIBOWO1,5,
MOHD SALLEH ROFIEE2,6, MUNTAZ ABU BAKAR7, MUHAMMAD
SOLEHIN ABD GHANI4, MOHAMMED TASYRIQ CHE OMAR8,
THAIGARAJAN PARUMASIVAM9 & MOHD FAZLI MOHAMMAT1,2,*
1Organic Synthesis Research
Laboratory, Institute of Science (I.O.S), Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor, Malaysia 8Biological Section, School of
Distance Education, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
Received: 20 June 2025/Accepted: 23 October 2025
Abstract
New diarylidiene-1-phenylethylpiperidine-4-one
derivatives 2a-h were successfully synthesised with yields ranging from 57%
to 96% and characterised with various spectroscopic methods. The compounds were
evaluated for their in vitro acetylcholinesterase inhibition activity
with galantamine as positive control. Among the synthesised compounds, compounds 2g and 2h were found to be most potent against
acetylcholinesterase enzyme with half-maximal inhibitory concentration (IC50) of 46.3 ± 0.53 µM
and IC50 = 29.7 ± 0.41 µM, respectively. The binding energy and interaction of
compounds 2g and 2h with acetylcholinesterase protein were
further studied through molecular docking studies. Compound 2h (-12.1 ± 0.0 kcal mol-1) showed a
strong binding affinity than compound 2g (-10.6 ± 0.0 kcal mol-1) and both compounds
exhibit several binding interactions with amino acids in acetylcholinesterase
protein. The molecular docking studies of these compounds supports the in
vitro acetylcholinesterase inhibition activity, suggesting that diarylidene
phenylethyl-1-piperidone scaffold might be a promising drug candidate for a new
acetylcholinesterase inhibitor drug development.
Keywords: Acetylcholinesterase inhibitor; Alzheimer's
disease; diarylidene; molecular docking; piperidone
Abstrak
Sebatian terbitan baharu diarilidena-1-fenetilpiperidina-4-one 2a–h telah berjaya disintesis dengan peratusan hasil antara 57% hingga 96% dan dicirikan menggunakan pelbagai kaedah spektroskopi. Penilaian terhadap aktiviti perencatan enzim asetilkolinesterase secara in
vitro telah dijalankan dengan galantamina sebagai kawalan positif. Dalam kalangan sebatian yang disintesis, sebatian 2g dan 2h didapati menunjukkan keupayaan paling kuat dalam perencatan enzim asetilkolinesterase dengan nilai kepekatan perencatan (IC50) masing-masing 46.3 ± 0.53 µM dan 29.7 ± 0.41 µM. Tenaga pengikatan dan interaksi antara sebatian 2g dan 2h dengan protein asetilkolinesterase telah dikaji dengan lebih lanjut melalui analisis pengedokan molekul. Sebatian 2h(-12.1 ± 0.0 kcal/mol) menunjukkan tenaga pengikatan yang lebih tinggi berbanding sebatian 2g(-10.6 ± 0.0 kcal/mol) dan kedua-dua sebatian membentuk beberapa interaksi dengan asid amino dalam protein asetilkolinesterase. Kajian pemadanan dok molekul ini menyokong keputusan aktiviti perencatan secara in vitro, sekali gus mencadangkan bahawa sebatian diarilidena piperidona berpotensi sebagai calon drug untuk pembangunan perencat asetilkolinesterase yang baharu.
Kata kunci: Diarilidene; pengedokan molekul; penyakit Alzheimer; perencat asetilkolinesterase; piperidona
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*Corresponding author; email:
mnazmi@usm.my
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