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

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.

Monoalkylated Epigallocatechin-3-gallate (C18-EGCG) as Novel Lipophilic EGCG Derivative: Characterization and Antioxidant Evaluation

“…As previously reported, even though the EGCG structure enables it to interact with the the polar heads of phospholipids present in the bilayer [15,51], only part of EGCG molecules is efficiently bound to the lipid mambrane. Part of EGCG molecules lies in the water phase, thus able to react with the radicals generated from AAPH decomposition, preventing them to interact with membrane lipids.…”

“…The stabilization of EGCG can be obtained by different approaches including the employment of reducing agents, structural modification and/or drug delivery systems [12][13][14]. Among these, the application of derivatization strategies designed to increase the molecule hydrophobicity and the interaction with cellular membrane [15][16][17][18][19][20] is considered as a feasible approach to improve the activity of bioactive molecules.…”

Edaravone reduces oxidative stress and intestinal cell apoptosis after burn through up-regulating miR-320 expression

“…Edaravone (ED) is a free radical scavenger that protects the cerebral functions, and is a first-line drug in clinical treatment of cerebral infarction (Parikh et al, 2017; Tokumaru et al, 2018). ED scavenges free radicals, inhibits lipid peroxidation and alleviates ischemia-reperfusion injury (Fujisawa & Yamamoto, 2016; Uchiyama et al, 2015) , moreover, as it has antioxidant properties, ED is the first free radical scavenger clinically proved to be a neuroprotective agent in Japan since 2001 (Minnelli et al, 2019) , and it plays an important role in alleviating oxidative stress in some diseases (Kikuchi et al, 2012) . Takeo Koizumi et al (Koizumi et al, 2006) showed that ED could reduce the free radical precursors and their metabolites in extensively burned rats.…”

Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway

“…Edaravone combined with the lipid system enhanced the antioxidant function of edaravone. 35 Caspase-3, as a member of the caspase family, is S-nitrosylated on its catalytic site Cys163, which inhibits its protease activity. 18 , 36 The levels of cleaved caspase 3 were significantly increased in the propofol group, leading to cell death.…”