Donepezil-derived multi-target-directed ligands: design, synthesis, and anti-Alzheimer's evaluation

  • Bioorg Chem. 2026 Aug 15:178:109924. doi: 10.1016/j.bioorg.2026.109924.
Marwa S K Bassiouny  1 ,  Mai I Shahin  2 ,  Maiy Y Jaballah  2 ,  Tarek E Ahmed  3 ,  Maged Henary  4 ,  Nermin Samir  5
Affiliations
  • 1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassaia, Cairo 11566, Egypt. Electronic address: [email protected].
  • 2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassaia, Cairo 11566, Egypt.
  • 3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassaia, Cairo 11566, Egypt; Department of Chemistry and Center of Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue SE, Atlanta, GA 30303, USA.
  • 4. Department of Chemistry and Center of Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue SE, Atlanta, GA 30303, USA.
  • 5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassaia, Cairo 11566, Egypt. Electronic address: [email protected].
PMID: 42090829 DOI: 10.1016/j.bioorg.2026.109924
Abstract

Alzheimer's disease (AD), a leading cause of dementia with high mortality and disability, has prompted the emergence of multi-target drug development as a key therapeutic strategy due to its complex and not yet fully understood pathogenesis. Herein, we present new multi-target-directed ligands combining pharmacophore fragments capable of simultaneously inhibiting key Enzymes implicated in AD pathology. These compounds exhibit inhibitory activities against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and β-secretase (BACE-1), while also demonstrating anti-aggregation effects on β-amyloid (Aβ) and hyperphosphorylated tau (p-tau), both of which contribute to neurodegeneration. Among the synthesized series, compound 13f illustrated a well-balanced inhibitory profile, with IC₅₀ values of 0.387 μM for AChE, 0.430 μM for BuChE, and 0.531 μM for BACE-1. Furthermore, In vivo studies revealed that compound 13f effectively reduced AChE concentrations in the brain by 30%, alongside a more substantial suppression of BuChE and BACE-1, with reductions of 60% and 62%, respectively. Additionally, 13f reduced Aβ and p-tau brain aggregates concentrations by over 30%, highlighting its potential as a promising lead for further optimization. These findings offer a compelling foundation for the development of effective multi-target directed ligands (MTDLs) for AD intervention.

Keywords
AChE; Alzheimer's disease; BACE-1; BuChE; Indazole; MTDLs.
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