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Pyrazolopyridine-Containing Compounds as Multitargeted Anti-Alzheimer Agents: Synthesis, Biological Evaluation, and

Omnia M Waly1,2, Selwan M El-Sayed1,3, Mariam A Ghaly1

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New pyrazolopyridine-based multitargeted directed ligands (MTDLs) show promise for Alzheimer's disease (AD) treatment by inhibiting key pathological pathways. Compounds 15 and 23 demonstrated significant activity and safety, suggesting potential therapeutic applications.

Keywords:
Aβ1‐42 aggregation inhibitionhAChE inhibitionhBuChE inhibitionhGSK3β inhibitionpyrazolopyridine synthesistau aggregation inhibition

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Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Drug Design

Background:

  • Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple contributing factors.
  • Current treatments offer limited efficacy, necessitating novel therapeutic strategies like multitargeted directed ligands (MTDLs).

Purpose of the Study:

  • To design and synthesize novel pyrazolopyridine-based MTDLs for Alzheimer's disease.
  • To evaluate the potential of these compounds to inhibit key AD pathological hallmarks, including cholinesterase enzymes, amyloid-beta aggregation, tau hyperphosphorylation, and metal-induced oxidative damage.

Main Methods:

  • Design and synthesis of three series of pyrazolopyridine derivatives.
  • In vitro evaluation of enzyme inhibition (cholinesterases, GSK3β).
  • Assessment of amyloid-beta aggregation inhibition.
  • Biometal chelation studies.
  • Metabolic stability assessment (compound 31 as metabolite of 23).
  • Cytotoxicity testing (WI-38 cell line).
  • In silico blood-brain barrier penetration prediction.

Main Results:

  • Compounds 15 and 23 effectively inhibited cholinesterases, prevented Aβ aggregation, and targeted GSK3β.
  • The pyrazolopyridine core facilitated binding to target sites.
  • Compound 31, a metabolite of 23, also exhibited MTDL properties, suggesting prolonged action.
  • Compounds 15 and 23 showed a good safety profile and favorable pharmacokinetic properties (Lipinski's rule, BBB penetration).

Conclusions:

  • The designed pyrazolopyridine-based MTDLs are promising candidates for Alzheimer's disease therapy.
  • Compounds 15 and 23 represent lead compounds with multi-target inhibitory potential and a favorable safety profile.
  • Further investigation is warranted to explore their therapeutic efficacy in preclinical AD models.