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

Catarina Oliveira,Paulo J Oliveira,Lisa Sequeira,Ricardo Amorim,Fernanda Borges,Fernando Cagide,Francesco Mesiti,Eugenio Uriarte,Fernando Remião,Jorge Garrido,Tiago Silva,José Teixeira,Santiago Vilar

doi:10.3389/fchem.2018.00126

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.

Highlights

Alzheimer’s disease (AD) is a multifactorial age-related disease, closely associated with impaired cholinergic transmission and oxidative stress (OS), among other factors (Guo et al, 2013; Zheng et al, 2014; Talevi, 2015; Nikolic et al, 2016)
The novel hydroxybenzoic acid (HBAc) derivatives were obtained following a four-step synthetic strategy depicted in Scheme 1, using 3,4-dimethoxybenzoic acid (1) and 3,4,5-trimethoxybenzoic acid (2) as starting compounds
Results showed that pyrogallol derivatives AntiOxBEN2, 16, 18 displayed a superior antioxidant activity over the corresponding catechols AntiOxBEN1, 15, 17 (Table 1)

Summary

Introduction

Alzheimer’s disease (AD) is a multifactorial age-related disease, closely associated with impaired cholinergic transmission and oxidative stress (OS), among other factors (Guo et al, 2013; Zheng et al, 2014; Talevi, 2015; Nikolic et al, 2016). The levels of acetylcholine (ACh) in the synaptic cleft are tightly regulated by cholinesterases enzymes (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are the key regulators of cholinergic tone and transmission (Anand and Singh, 2013; Colovicet al., 2013). It has been shown that ChEs are proteins that colocalize with Aβ deposits and directly promotes Aβ assembly and aggregation into insoluble plaques, a classic biochemical hallmark of AD pathology (Morán et al, 1993). These secondary non-cholinergic functions of ChEs are attributed to the peripheral active site (PAS) of the enzyme’s active site (Bajda et al, 2013; Silva et al, 2014). While deposition of Aβ plaques is the hallmark of the disease, the neurotoxicity of Aβ oligomers was shown to be stronger than that of the fibrils

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Results

Conclusion