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Design, synthesis and biological evaluation of light-driven on-off multitarget AChE and MAO-B inhibitors

Marco Paolino1, Mariagrazia Rullo2, Samuele Maramai1

  • 1Dipartimento di Biotecnologie, Chimica e Farmacia (Dipartimento di Eccellenza 2018-2022), Università degli Studi di Siena Via A. Moro 2 53100 Siena Italy paolino3@unisi.it.

RSC Medicinal Chemistry
|August 4, 2022
PubMed

Insights

Researchers developed novel light-modulated cinnamic acid compounds that inhibit key enzymes linked to Alzheimer's disease (AD). These multitarget drugs offer a promising new avenue for treating neurodegenerative disorders.

Area of Science:

  • Medicinal Chemistry
  • Neuroscience
  • Drug Discovery

Background:

  • Neurodegenerative diseases involve protein misfolding, oxidative stress, and neuroinflammation, leading to neuronal loss and cognitive decline.
  • Current treatments for neurodegenerative diseases can be improved by multitarget-directed molecules offering synergistic effects.
  • Light-modulated bioactive compounds present an innovative approach for personalized therapies.

Purpose of the Study:

  • To design and synthesize cinnamic acid-inspired isomeric compounds with light-modulated activity.
  • To investigate the inhibitory potential of these compounds against enzymes relevant to Alzheimer's disease (AD), specifically acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B).
  • To achieve selective inhibition over butyrylcholinesterase (BChE) and monoamine oxidase A (MAO-A).

Main Methods:

  • Synthesis of a library of cinnamic acid-inspired isomeric compounds.
  • Evaluation of inhibitory activities of pure E-diastereomers and E/Z-diastereomer mixtures.
  • UV irradiation to induce isomerization and assess light-modulated activity.
  • Molecular docking studies to elucidate structure-activity relationships for potent analogues.

Main Results:

  • The synthesized compounds demonstrated potent and selective inhibition of AChE and MAO-B.
  • Light modulation influenced the inhibitory activity of the compounds.
  • Molecular docking provided insights into the binding interactions of E and Z diastereomers.

Conclusions:

  • The developed multitarget compounds exhibit promising photo-switchable properties for inhibiting key AD-related enzymes.
  • These findings pave the way for innovative photodynamic therapies against neurodegenerative diseases.
  • Further development could lead to novel drugs for personalized treatment of Alzheimer's disease.

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