RT Journal Article
T1 Hydroxybenzoic acid derivatives as dual-target ligands: mitochondriotropic antioxidants and cholinesterase inhibitors
A1 Oliveira, Catarina
A1 Cagide, Fernando
A1 Teixeira, José
A1 Amorim, Ricardo
A1 Sequeira, Lisa
A1 Mesiti, Francesco
A1 Silva, Tiago
A1 Garrido, Jorge
A1 Remião, Fernando
A1 Vilar Varela, Santiago
A1 Uriarte Villares, Eugenio
A1 Oliveira, Paulo J.
A1 Borges, Fernanda
K1 Hydroxybenzoic acids
K1 Oxidative stress
K1 Mitochondria-targeted antioxidants
K1 Cholinesterase inhibitors
K1 Acetyl and butyrylcholinesterase
AB Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.
PB Frontiers Media
SN 2296-2646
YR 2018
FD 2018
LK http://hdl.handle.net/10347/22614
UL http://hdl.handle.net/10347/22614
LA eng
NO Oliveira C, Cagide F, Teixeira J, Amorim R, Sequeira L, Mesiti F, Silva T, Garrido J, Remião F, Vilar S, Uriarte E, Oliveira PJ and Borges F (2018) Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors. Front. Chem. 6:126. doi: 10.3389/fchem.2018.00126
NO This work was funded by FEDER funds through the OperationalProgramme Competitiveness Factors-COMPETE and national funds by FCT – Foundation for Science and Technology under research grants (QUI/UI0081/2013, NORTE-01-0145-FEDER-000028 and PTDC/DTP-FTO/2433/2014, POCI-01-0145-FEDER-016659, POCI-01-0145-FEDER-007440. CO (SFRH/BD/88773/2012), FC (SFRH/BPD/74491/2010), JT (PTDC/DTP-FTO/2433/2014 and NORTE-01-0145-FEDER000028) RA (PTDC/DTP-FTO/2433/2014) grants are supported by FCT, POPH, and QREN. The authors also thank the COST action CA15135 for support
DS Minerva
RD 28 abr 2026