Sains Malaysiana 54(9)(2025): 2201-2210

http://doi.org/10.17576/jsm-2025-5409-08

 

Synthesis and Evaluation of Para-Substituted Bis(Arylidene)Cycloalkanones as Potential

α-Amylase Inhibitor with Molecular Docking and ADMET Profiling

(Sintesis dan Penilaian Para Bis(arilidena)sikloalkanon Tertukar Ganti sebagai Perencat
α-Amilase Berpotensi dengan Dok Molekul dan Pemprofilan ADMET)

 

NUR FARAH ATIQAH AZMI¹, MOHAMAD NURUL AZMI^1,*, MAHDI BABAI¹, MOHAMAD HAFIZI ABU BAKAR², MUNTAZ ABU BAKAR³ & MOHAMMAD TASYRIQ CHE OMAR⁴

 

¹Natural Products and Synthesis Organic Laboratory (NPSO), School of Chemical Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
² Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia
³Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia
⁴ Biological Section, School of Distance Education, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia

 

Received: 15 May 2025/Accepted: 18 July 2025

 

Abstract

Ten para-substituted bis(arylidene)cycloalkanone derivatives were synthesised, characterised and their inhibitory activities against human pancreatic α-amylase were evaluated. Among them, halogen-substituted derivatives 5d (IC₅₀ = 7.6 ± 1.4 µM) and 5e (IC₅₀ = 6.9 ± 1.8 µM) exhibited superior potency compared to the standard drug acarbose (IC₅₀ = 23.5 ± 2.7 µM). Molecular docking studies indicated that these halogenated derivatives (i.e., compound 5d and 5e) showed a good interaction with human pancreatic α-amylase protein (2QV4) with binding energy of -7.4 ± 0.1 kcal/mol and -7.8 ± 0.1 kcal/mol, respectively, compared with acarbose (-3.9 ± 0.1 kcal/mol). Both of them, form crucial π–π stacking and hydrophobic interactions within the enzyme’s active site residues TYR62 and LEU165. In silico ADMET profiling further supported the favourable drug-likeness, synthetic accessibility, and oral bioavailability of these compounds, making them promising candidates for antidiabetic drug development.

 

Keywords: ADMET profiling; antidiabetic agents; α-Amylase inhibitors; bis(arylidene)cycloalkanones; molecular docking

 

Abstrak

Sepuluh terbitan para-bis(arilidena)sikloalkanon yang tertukar ganti telah disintesis, dicirikan dan aktiviti perencatan sebatian ini terhadap enzim α-amilase pankreas manusia telah dinilai. Antaranya sebatian berhalogen, iaitu 5d (IC₅₀ = 7.6 ± 1.4 µM) dan 5e (IC₅₀ = 6.9 ± 1.8 µM), menunjukkan potensi perencatan yang lebih tinggi berbanding ubat piawai akarbosa (IC₅₀ = 23.5 ± 2.7 µM). Kajian pengedokan molekul pula telah menunjukkan bahawa sebatian berhalogen (i.e., sebatian 5d and 5e) menunjukkan interaksi yang baik dengan protein α-amilase pancreas (2QV4) dengan tenaga pengikatan masing-masing -7.4 ± 0.1 kcal/mol dan -7.8 ± 0.1 kcal/mol, berbanding dengan acarbose (-3.9 ± 0.1 kcal/mol). Kedua-dua sebatian ini membentuk interaksi susunan π–π dan interaksi hidrofobik yang signifikan dengan asid amino TYR62 dan LEU165 di tapak aktif enzim tersebut. Analisis ADMET secara in silico turut menyokong ciri keberkesanan ubat yang baik, kebolehcapaian sintetik dan bioketersediaan oral bagi sebatian ini, menjadikannya calon berpotensi untuk pembangunan ubat antidiabetik.

 

Kata kunci: Agen antidiabetik; analisis ADMET; bis(arilidena)sikloalkanon; dok molekul; perencat
α-Amilase

 

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*Corresponding author; email: mnazmi@usm.my