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New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments

Authors :
Maria A. Lapshina
Elena F. Shevtsova
Vladimir V. Grigoriev
Aleksey Yu. Aksinenko
Aleksey A. Ustyugov
Daniil A. Steinberg
Grigoriy V. Maleev
Elena S. Dubrovskaya
Tatiana V. Goreva
Tatiana A. Epishina
Vladimir L. Zamoyski
Galina F. Makhaeva
Vladimir P. Fisenko
Ivan M. Veselov
Daria V. Vinogradova
Sergey O. Bachurin
Source :
Molecules, Vol 28, Iss 22, p 7567 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs—edaravone and riluzole—have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone—phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.

Details

Language :
English
ISSN :
14203049
Volume :
28
Issue :
22
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.01932bd2b0347959d1155a33c3b5f8d
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules28227567