Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

Abstract

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.

Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors

“…The discovery of new chemical agents endowed with a potent AChE inhibitory activity is still a relevant subject for AD treatment. In this context, the study by Oliveira et al [ 34 ] was performed with two mitochondriotropic antioxidants, which are catechol and pyrogallol derivative, and hydroxybenzoic acid derivatives, which have longer spacers. The compounds were shown to be potent AChE (IC 50 s: 7.2 ± 0.5 to 40.5 ± 7.0 μM) and BChE inhibitors (IC 50 s: 85 ± 5 and 553 ± 22 μM) by a noncompetitive mechanism.…”

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

“…The cholinesterase inhibitors that interact simultaneously with AChE (catalytic and peripheral sites) and Aβ plaque deposition coupled with added properties such as antioxidant action [122], neuroprotective or voltage-dependent calcium channel antagonistic activity [123][124][125][126], histamine H3 receptor antagonism [127][128][129][130], cannabinoid CB1 receptor antagonism [131,132], and beta-site APP cleaving enzyme (BACE1) inhibition [70,125,133,134] display the potential of ameliorating the cognitive deficit in AD by restoring cholinergic activities [135][136][137].…”

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

“…Pharmacological results led to the identification of the most promising hybrids 146a and 146d with the highest antioxidant potential and highly potent BuChE inhibition with IC 50 values of 85 and 106 nM, respectively and compounds 146b and 146c with inhibition of AChE (IC 50 = 7.7 and 7.2 µM). Further cytotoxicity assays showed no significant effects on human neuroblastoma (SH-SY5Y) and hepatocarcinoma (HepG2) cell lines [ 153 ].…”