Synthesis, Characterization and Antioxidant Properties of a New Lipophilic Derivative of Edaravone.

Cristina Minnelli,Dario Rusciano,Tatiana Armeni,Emiliano Laudadio,Mattia Cantarini,Roberta Galeazzi,Giovanna Mobbili,Pierluigi Stipa

doi:10.3390/antiox8080258

Cristina Minnelli, Dario Rusciano + Show 6 more

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https://doi.org/10.3390/antiox8080258

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Journal: Antioxidants	Publication Date: Jul 31, 2019
Citations: 23	License type: CC BY 4.0

Affiliation: Marche Polytechnic University

Abstract

As part of a program aimed to obtain antioxidants able to interact with cell membrane, edaravone (EdV, 3-methyl-1-phenyl-2-pyrazolin-5-one), a well-known free radical scavenger, has been modified by alkylation at its allylic position (4) with a C-18 hydrocarbon chain, and the increased lipophilicity has been determined towards the interaction with liposomes. The obtained derivative has been studied by means of density functional theory (DFT) methods in order to characterize its lowest energy conformers and predict its antioxidant properties with respect to the parent compound EdV. The in vitro antioxidant activity of C18-edaravone was studied by means of the α,α-diphenyl-β-picrylhydrazyl (DPPH) assay and in lipid peroxidation experiments performed on artificial lipid membranes using water-soluble as well as lipid-soluble radical initiators. Moreover, since oxidative stress is involved in numerous retinal degenerative diseases, the ability of C18-edaravone to contrast 2,2-azobis (2-amidinopropane hydrochloride) (AAPH)-induced cell death was assessed in adult retinal pigmented epithelium (ARPE-19) cells. Overall, the results demonstrated that the newly synthesized molecule has a high affinity for lipid membrane, increasing the efficacy of the unmodified edaravone under stress conditions.

Highlights

Pyrazolones are synthetic oxo-derivatives of five-membered unsaturated heterocycles with two adjacent nitrogen atoms
The purpose was to synthesize an aromatic heterocyclic structure where a hydroxyl group would be generated by keto-enol tautomerization to obtain the key functional group responsible for the radical-scavenging activity as in phenol derivatives
In the hydrogen atom transfer (HAT) mechanism, the efficiency of an antioxidant is related to its ability to transfer an H atom to an incoming free radical, efficiency of an antioxidant is related to its ability to transfer an H atom to an incoming free radical, leading to the termination of further chain reactions [31]

Summary

Introduction

Pyrazolones are synthetic oxo-derivatives of five-membered unsaturated heterocycles with two adjacent nitrogen atoms. They are usefully employed in many fields and, in particular, as pharmaceuticals, they exhibit bioactivity as an analgesic, antibacterial, anti-inflammatory, antioxidant and antitumoral [1,2,3]. (Figure 1) represents the first free radical scavenger clinically approved in Japan since 2001 as neuroprotective agent [4,5] This molecule was discovered in the course of a research program aimed at developing antioxidants for the treatment of acute cerebral infarction, characterized by a phenol-like free radical-scavenging activity (H-donors antioxidants). After pre-treatment of ARPE-19 with increasing concentrations of both both antioxidants for h, cells were washed twice with ARPE-19cells cellsfrom from physiological stressors, oxidative damage mediated by was induced [37,38], comparing physiological stressors, oxidative damage mediated by AAPH was induced [37,38], comparing the the

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