2. Academic Validation
  3. Design, synthesis, and comprehensive evaluation of novel imidazole-chromone hybrids as potent cholinesterase and α-glucosidase inhibitors

Design, synthesis, and comprehensive evaluation of novel imidazole-chromone hybrids as potent cholinesterase and α-glucosidase inhibitors

  • Eur J Med Chem. 2025 Jul 3:297:117927. doi: 10.1016/j.ejmech.2025.117927.
Massaab Khalfaoui 1,  Wahiba Frites 2,  Arif Mermer 3,  Dursun Kisa 4,  Buket Yildirim 5,  Mohamed I Chouiter 6,  Artur M S Silva 7,  Houssem Boulebd 8
Affiliations

Affiliations

  • 1 Laboratory of Polymeric Materials (LPM), Faculty of Chemistry, U.S.T.H.B., BP 32 El-Alia, Algiers, 16111, Algeria.
  • 2 Laboratory of Applied Organic Chemistry (LCOA), Faculty of Chemistry, USTHB, BP 32 EL-Alia, Bab-Ezzouar, Algiers, 16111, Algeria.
  • 3 Faculty of Pharmacy, University of Health Sciences, İstanbul, Turkey; Experimental Medicine Application and Research Center, Validebag Research Park, University of Health Sciences, İstanbul, Turkey; Department of Biotechnology, Hamidiye Institute of Health Sciences, University of Health Sciences, İstanbul, Turkey.
  • 4 Department of Molecular Biology and Genetics, Faculty of Science, Bartin University, Bartin, Turkey.
  • 5 Department of Molecular Biology and Genetics, Graduate School, Bartin University, Bartin, Turkey.
  • 6 Laboratoire des Produits Naturels d'Origine Végétale et de Synthése Organique, Faculté des Sciences Exactes, Campus de Chaabat Ersas, Université des frères Mentouri-Constantine, Consntantine, 25000, Algeria.
  • 7 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, 3810-193, Portugal. Electronic address: artur.silva@ua.pt.
  • 8 Laboratory of Synthesis of Molecules with Biological Interest, University of Constantine 1 Frères Mentouri, Constantine, Algeria. Electronic address: boulebd.houssem@umc.edu.dz.
PMID: 40633337 DOI: 10.1016/j.ejmech.2025.117927
Abstract

A series of new hybrid styrylchromone (3a-3h) molecules incorporating imidazole and chromone nuclei were synthesized and characterized. A Diels-Alder cycloaddition reaction was performed on these compounds, leading to the formation of a new series of tricyclic molecules (4a-4h). The evaluation of their biological activity revealed that the cyclization of the styrylchromones significantly enhances their bioactive potential, in particular their inhibitory capacity towards acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase Enzymes. Among the tested compounds, derivative 4c exhibited the most promising inhibitory activity against both AChE (3.93 μM) and α-glucosidase (9.61 μM), with an efficacy comparable to or even exceeding that of the standard inhibitors tacrine and acarbose. This compound also showed remarkable inhibition of BChE enzyme with an IC50 of 9.41 μM. Furthermore, derivative 4a was identified as the most potent inhibitor of this enzyme, displaying an activity approximately two times greater than that of tacrine (IC50 10.01 vs 22.30 nM). In silico studies, including molecular docking and DFT calculations, were conducted to better understand the interaction modes between the synthesized molecules and their target Enzymes, as well as the reaction mechanism underlying their synthesis. Overall, the results of this study highlight the therapeutic potential of the synthesized compounds, particularly the cyclized derivatives.

Keywords

Cholinesterase; DFT calculations; Diels–Alder reaction; Heterocyclic compounds; Molecular docking; α-Glucosidase.

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