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  3. Boosting caffeic acid performance as antioxidant and monoamine oxidase B/catechol-O-methyltransferase inhibitor

Boosting caffeic acid performance as antioxidant and monoamine oxidase B/catechol-O-methyltransferase inhibitor

  • Eur J Med Chem. 2022 Sep 8;243:114740. doi: 10.1016/j.ejmech.2022.114740.
Daniel Chavarria 1,  Sofia Benfeito 1,  Pedro Soares 1,  Carla Lima 1,  Jorge Garrido 2,  Paula Serrão 3,  Patrício Soares-da-Silva 3,  Fernando Remião 4,  Paulo J Oliveira 5,  Fernanda Borges 6
Affiliations

Affiliations

  • 1 CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal.
  • 2 CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal; Department of Chemical Engineering, School of Engineering (ISEP), Polytechnic of Porto, 4200-072, Porto, Portugal.
  • 3 Department of Biomedicine - Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, 4200-319, Porto, Portugal.
  • 4 UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.
  • 5 CNC - Center for Neuroscience and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology. University of Coimbra, UC Biotech Building, Cantanhede, Portugal.
  • 6 CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007, Porto, Portugal. Electronic address: fborges@fc.up.pt.
PMID: 36116233 DOI: 10.1016/j.ejmech.2022.114740
Abstract

Increased oxidative stress (OS) and depletion of nigrostriatal dopamine (DA) are closely linked to the neurodegeneration observed in Parkinson's Disease (PD). Caffeic acid (CA)-based Antioxidants were developed, and their inhibitory activities towards monoamine oxidases (MAOs) and catechol O-methyltransferases (COMT) were screened. The results showed that the incorporation of an extra double bond maintained or even boosted the antioxidant properties of CA. α-CN derivatives displayed redox potentials (Ep) similar to CA (1) and inhibited hMAO-B with low μM IC50 values. Moreover, catechol amides acted as MB-COMT inhibitors, showing IC50 values within the low μM range. In general, CA derivatives presented safe cytotoxicity profiles at concentrations up to 10 μM. The formation of Reactive Oxygen Species (ROS) induced by CA derivatives may be underlying the cytotoxic effects observed at higher concentrations. Catechol amides 3-6, 8-11 at 10 μM protected cells against oxidative damage. Compounds 3 and 8 were predicted to cross the blood-brain barrier (BBB) by passive diffusion. In summary, we report for the first time BBB-permeant CA-based multitarget lead compounds that may restore DAergic neurotransmission (dual hMAO-B/MB-COMT inhibition) and prevent oxidative damage. The data represents a groundbreaking advancement towards the discovery of the next generation of new drugs for PD.

Keywords

Antioxidants; Caffeic acid; Catechol-O-Methyltransferase; Monoamine oxidase; Neuroprotection; Parkinson's disease.

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