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

• Published in: European journal of medicinal chemistry 2022-12, Vol.243, p.114740-114740, Article 114740
• Main Authors: Chavarria, Daniel, Benfeito, Sofia, Soares, Pedro, Lima, Carla, Garrido, Jorge, Serrão, Paula, Soares-da-Silva, Patrício, Remião, Fernando, Oliveira, Paulo J., Borges, Fernanda
• Format: Article
• Language: English
• Subjects: Antioxidants; Caffeic acid; Catechol-O-Methyltransferase; Monoamine oxidase; Neuroprotection; Parkinson's disease
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114740

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. [Display omitted] •Increased oxidative stress and dopamine depletion are observed in Parkinson's disease.•A series of caffeic acid (CA)-based antioxidants was synthesized.•Four CA-based antioxidants were dual MAO-B/MB-COMT inhibitors.•CA derivatives were safe at 10 μM and protected cells from oxidative damage.•Compounds 3 and 8 were predicted to cross the BBB by passive diffusion.