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Tacrine-Based Hybrids: Past, Present, and Future.

Anna Bubley1, Alexaner Erofeev2, Peter Gorelkin2

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International Journal of Molecular Sciences
|January 21, 2023
PubMed
Summary

Tacrine-based hybrids offer a promising "one drug-multiple targets" strategy for Alzheimer's disease (AD) drug development. Research shows these hybrids can improve cognition while reducing the hepatotoxicity associated with early treatments.

Keywords:
Alzheimeracetylcholinesteraseamyloid-βbutyrylcholinesterasetacrine

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Drug Discovery

Background:

  • Alzheimer's disease (AD) is a neurodegenerative disorder marked by beta-amyloid aggregation, tau hyperphosphorylation, and neuronal loss.
  • Key AD hallmarks include oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation.
  • The "one drug-multiple targets" approach is gaining traction for AD therapeutics.

Purpose of the Study:

  • To review Tacrine (THA)-based hybrid compounds developed between 2006 and 2022.
  • To provide an overview of drug design strategies for multi-target AD agents.
  • To highlight approaches yielding cognitive improvements and reduced hepatotoxicity.

Main Methods:

  • Literature review of THA-based hybrids from 2006-2022.
  • Analysis of drug design strategies and therapeutic outcomes.
  • Evaluation of cognitive effects and hepatotoxicity profiles.

Main Results:

  • Tacrine (THA), an early cholinesterase inhibitor, serves as a valuable scaffold despite prior hepatotoxicity.
  • THA-based hybrids have been designed to target multiple AD hallmarks simultaneously.
  • Studies indicate successful cognitive enhancement and mitigation of hepatotoxicity in THA-based hybrid designs.

Conclusions:

  • THA-based hybrids represent a viable strategy for developing multi-target drugs against Alzheimer's disease.
  • Optimized THA derivatives show potential for improved efficacy and safety profiles.
  • Further research into these hybrids could lead to novel AD therapeutics.