Synthesis and In Vitro/In Silico α‑Glucosidase Inhibitory Study of Novel Ethanones Containing Naphthalene-Linked 1,2,4-Triazole

  • ACS Med Chem Lett. 2025 Jul 31;16(8):1676-1681. doi: 10.1021/acsmedchemlett.5c00387.
Cong T Nguyen  1 ,  Dung T K Hoang  2 ,  Vu A Truong  3 ,  Loan T K Nguyen  1 ,  Phi C Dinh  4 ,  Dung H A Mai  5 ,  Duc T Le  2  6 ,  Nam N Pham  3
Affiliations
  • 1. Faculty of Chemistry, Ho Chi Minh City University of Education, Ho Chi Minh City, 700000, Vietnam.
  • 2. Institute of Advanced Technology, Vietnam Academy of Science and Technology, Ho Chi Minh City, 700000, Vietnam.
  • 3. Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 300044, Taiwan.
  • 4. Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, 700000, Vietnam.
  • 5. Department of Chemical Engineering, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, South Korea.
  • 6. Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Hanoi, 100000, Vietnam.
PMID: 40832538 DOI: 10.1021/acsmedchemlett.5c00387
Abstract

Type 2 Diabetes mellitus is a chronic-metabolic disorder characterized by Insulin Resistance, resulting in persistent hyperglycemia and severe complications. α-Glucosidase inhibitors (AGIs) effectively control postprandial blood glucose level by delaying carbohydrate digestion. This study reports the synthesis of novel naphthalene-linked 1,2,4-triazole-bearing ethanones (5a-e and 7a-f) as potential AGIs. Enzymatic assay demonstrated significantly superior α-glucosidase inhibitory potency of aryl-substituted derivatives (7a-f) compared to ethyl-substituted analogs (5a-e), highlighting the advance of aromatic substituents. Compounds 7b and 7c exhibited exceptional inhibitory activity (IC50 = 9.23-9.61 μM), conferring 37-fold more potency than voglibose. Molecular docking and dynamics simulations indicated predominant π-π stacking and hydrophobic interactions contributing to their stable enzyme binding. MM/GBSA binding-affinity calculation further supported their enhanced binding affinity, providing mechanistic insights into their potent activity. Collectively, these findings highlight the promise of naphthalene- and 1,2,4-triazole-bearing ethanones for the development of effective antidiabetic therapies.

Keywords
1,2,4-Triazole; Ethanones; Molecular Docking; Molecular Dynamics; Naphthalene; α-Glucosidase inhibition.
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