2. Academic Validation
  3. Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades

Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades

  • J Med Chem. 2022 Mar 24;65(6):4727-4751. doi: 10.1021/acs.jmedchem.1c01883.
Clara Herrera-Arozamena 1 2,  Martín Estrada-Valencia 1,  Patricia López-Caballero 1,  Concepción Pérez 1,  José A Morales-García 3 4 5,  Ana Pérez-Castillo 3 4,  Eric Del Sastre 6,  Cristina Fernández-Mendívil 6,  Pablo Duarte 6,  Patrycja Michalska 6,  José Lombardía 6,  Sergio Senar 7,  Rafael León 1 6,  Manuela G López 6 8,  María Isabel Rodríguez-Franco 1
Affiliations

Affiliations

  • 1 Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, E-28006 Madrid, Spain.
  • 2 Programa de Doctorado en Química Orgánica, Facultad de Química, Universidad Complutense de Madrid, Avda. Complutense s/n, E-28040 Madrid, Spain.
  • 3 Instituto de Investigaciones Biomédicas (CSIC-UAM), C/Arturo Duperier, 4, E-28029 Madrid, Spain.
  • 4 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, E-28031 Madrid, Spain.
  • 5 Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, E-28040 Madrid, Spain.
  • 6 Instituto Teófilo Hernando de I+D del Medicamento, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, E-28029 Madrid, Spain.
  • 7 DrTarget Machine Learning, C/Alejo Carpentier 13, E-28806 Alcalá de Henares, Madrid, Spain.
  • 8 Instituto de Investigación Sanitaria del Hospital Universitario de la Princesa (IIS-IP), C/Diego de León 62, E-28006 Madrid, Spain.
PMID: 35245051 DOI: 10.1021/acs.jmedchem.1c01883
Abstract

By replacing a phenolic ring of (E)-resveratrol with an 1,3,4-oxadiazol-2(3H)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3H)-one (4e) showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.83 μM), selective inhibition of both hMAO-B and QR2 (IC50s = 8.05 and 0.57 μM), and the best ability to promote hippocampal neurogenesis. It showed a good drug-like profile (positive in vitro central nervous system permeability, good physiological solubility, no glutathione conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective and antioxidant actions in both acute and chronic Alzheimer models using hippocampal tissues. Thus, 4e is an interesting MTDL that could stimulate defensive and regenerative pathways and block early events in neurodegenerative cascades.

Figures
Products