Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases.

Daniel Chavarria,Paulo J Oliveira,Fernanda Borges,Sandra Barreiro,Jorge Garrido,Fernando Cagide,José Dias,Florian Nachon,Sofia Benfeito,Ophelie Da Silva,Pedro Soares,Fernando Remião,Xavier Brazzolotto

doi:10.3390/antiox10020329

Abstract

Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2–5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2–5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2–5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2–5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.

Highlights

Our research group recently developed mitochondria-targeted antioxidants, in which lipophilic TPP+ cations were conjugated with hydroxycinnamic (AntiOXCINs) and hydroxybenzoic (AntiOXBENs) acids [17,18,19,20,21,22]. We showed that these compounds accumulated within the mitochondrial matrix of rat liver mitochondria [18,19] and exhibited remarkable antioxidant properties [17,18,19,20,21]
We aim to evaluate whether the elongation of the α,β- unsaturated chain of AntiOXCINs while maintaining the compounds’ overall lipophilicity affects their bioactivity and safety profiles
Co-crystallization studies with human ChEs (hChEs) demonstrated that the TPP+ derivatives bind differently to the active sites of hAChE

Summary

Introduction

The main neuropathological hallmarks of Alzheimer’s disease creativecommons.org/licenses/by/ 4.0/). Based on these observations, enzymes involved in neurotransmitters breakdown (e.g., cholinesterases (ChEs); monoamine oxidases (MAOs)) are among the main biological targets for the development of new therapeutics [1]. Mitochondria are central players involved in the pathogenesis of AD and PD [4], since they are both one of the primary sources and one of the critical targets of reactive species (RS) [5]. The high energy demand required for neuronal survival and excitability in the central nervous system (CNS)

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