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- Boosting caffeic acid performance as antioxidant and monoamine oxidase B/catechol-O-methyltransferase inhibitorPublication . Chavarria, Daniel; Benfeito, Sofia; Soares, Pedro; Lima, Carla; Garrido, Jorge; Serrão, Paula; Soares-da-Silva, Patrício; Remião, Fernando; Oliveira, Paulo J.; Borges, FernandaIncreased 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.
- Synthesis and antioxidant activity of long chain alkyl hydroxycinnamatesPublication . Menezes, Jose C.J.M.D.S; Kamat, Shrivallabh P; Cavaleiro, Jose A.S.; Gaspar, Alexandra; Garrido, Jorge; Borges, FernandaLong chain alkyl hydroxycinnamates (8e21) were synthesized from the corresponding half esters of malonic acid (5e7) and benzaldehyde derivatives by Knoevenagel condensation. The total antioxidant capacity of these hydroxycinnamyl esters was evaluated using DPPH and ABTS assays. The observed antioxidant activity was highest for esters of caffeic acid followed by sinapic esters and ferulic esters. The parameters for drug-likeness of these hydroxycinnamyl esters were also evaluated according to the Lipinski’s ‘rule-of-five’. All the ester derivatives were found to violate one of the Lipinski’s parameters (cLogP >5), even though they have been found to be soluble in protic solvents. The predictive topological polar surface area (TPSA) data allow concluding that they could have a good capacity for penetrating cell membranes. Therefore, one can propose these novel lipophilic compounds as potential antioxidants for tackling oxidative processes.