2. Academic Validation
  3. Multi-target Triazole-Benzopyrone hybrids modulating cholinergic dysfunction, oxidative stress, and neuroinflammation through GFAP/NF-κB/APOE/NLRP3 axis in Alzheimer's disease

Multi-target Triazole-Benzopyrone hybrids modulating cholinergic dysfunction, oxidative stress, and neuroinflammation through GFAP/NF-κB/APOE/NLRP3 axis in Alzheimer's disease

  • Eur J Med Chem. 2026 Oct 5:315:118949. doi: 10.1016/j.ejmech.2026.118949.
Omar K El-Mokaddem 1,  Ghada F Elmasry 2,  Abeer Salama 3,  Heba M Mansour 4,  Walaa R Mahmoud 5,  Lina M A Abdel Ghany 6
Affiliations

Affiliations

  • 1 Postgraduate program in Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt; Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October city, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt. Electronic address: [email protected].
  • 3 Pharmacology Department, National Research Centre, Dokki, Cairo, 12622, Egypt.
  • 4 Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6 of October, Giza, Egypt.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, Egypt.
  • 6 Department of Pharmaceutical Chemistry, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October city, Egypt. Electronic address: [email protected].
PMID: 42150247 DOI: 10.1016/j.ejmech.2026.118949
Abstract

Alzheimer's disease (AD) is a degenerative neurological disorder characterized by a deterioration in cognitive abilities, especially memory and learning. The main aim of this study is to evaluate the effects of our agents on oxidative stress, neuroinflammation, cognitive function, and behavioral performance in an LPS-induced AD animal model and comprehensive in vitro and in vivo assays. The synthesized compounds, namely 4b, 5b, 6, 8a-d, and 11a-c, revealed acetylcholinesterase inhibitory activity (3.50-5.91 nM) superior to that of the reference drug donepezil (6.33 nM). The IC50 value of 11a the most active candidate was 3.50 nM against hAChE, with a significant reduction in Amyloid-β accumulation by 70% compared to LPS-treated groups, it also reduced neuronal damage, as evidenced by histopathological analysis. Compared to LPS treated groups, 11a decreased brain GFAP, NLRP3, NF-κB, apoE and MDA by 76%, 65%, 48%, 75%, and 59% respectively while increasing GSH by 81%. Molecular docking simulation, along with 100 ns molecular dynamics (MD) simulations conducted on the AChE-ligand complexes, demonstrated favorable conformations of ligand-protein complex throughout the simulations, predicting a dual binding to the CAS and PAS regions of the enzyme which is consistent with kinetic studies against hAChE. Moreover, the chemical stability and reactivity of the drug-target complex were evaluated using global and local reactive descriptors. These findings suggested that compound 11a possessed promising potential as a multi-target lead compound for the development of anti-Alzheimer treatments based on cholinergic, amyloidogenic, and neuroinflammation, through GFAP/NF-κB/apoE/NLRP3 signaling axis.

Keywords

AChE; Alzheimer's diseases; BACE-1; BChE; Benzopyrone; Coumarin; HOMO/LUMO analysis; PAMPA-BBB.

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