Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lapshina, Maria A., Shevtsova, Elena F., Grigoriev, Vladimir V., Aksinenko, Aleksey Yu., Ustyugov, Aleksey A., Steinberg, Daniil A., Maleev, Grigoriy V., Dubrovskaya, Elena S., Goreva, Tatiana V., Epishina, Tatiana A., Zamoyski, Vladimir L., Makhaeva, Galina F., Fisenko, Vladimir P., Veselov, Ivan M., Vinogradova, Daria V., Bachurin, Sergey O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673157/
https://www.ncbi.nlm.nih.gov/pubmed/38005288
http://dx.doi.org/10.3390/molecules28227567
_version_ 1785149584454975488
author Lapshina, Maria A.
Shevtsova, Elena F.
Grigoriev, Vladimir V.
Aksinenko, Aleksey Yu.
Ustyugov, Aleksey A.
Steinberg, Daniil A.
Maleev, Grigoriy V.
Dubrovskaya, Elena S.
Goreva, Tatiana V.
Epishina, Tatiana A.
Zamoyski, Vladimir L.
Makhaeva, Galina F.
Fisenko, Vladimir P.
Veselov, Ivan M.
Vinogradova, Daria V.
Bachurin, Sergey O.
author_facet Lapshina, Maria A.
Shevtsova, Elena F.
Grigoriev, Vladimir V.
Aksinenko, Aleksey Yu.
Ustyugov, Aleksey A.
Steinberg, Daniil A.
Maleev, Grigoriy V.
Dubrovskaya, Elena S.
Goreva, Tatiana V.
Epishina, Tatiana A.
Zamoyski, Vladimir L.
Makhaeva, Galina F.
Fisenko, Vladimir P.
Veselov, Ivan M.
Vinogradova, Daria V.
Bachurin, Sergey O.
author_sort Lapshina, Maria A.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-10673157
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-106731572023-11-13 New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments Lapshina, Maria A. Shevtsova, Elena F. Grigoriev, Vladimir V. Aksinenko, Aleksey Yu. Ustyugov, Aleksey A. Steinberg, Daniil A. Maleev, Grigoriy V. Dubrovskaya, Elena S. Goreva, Tatiana V. Epishina, Tatiana A. Zamoyski, Vladimir L. Makhaeva, Galina F. Fisenko, Vladimir P. Veselov, Ivan M. Vinogradova, Daria V. Bachurin, Sergey O. Molecules Article 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. MDPI 2023-11-13 /pmc/articles/PMC10673157/ /pubmed/38005288 http://dx.doi.org/10.3390/molecules28227567 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lapshina, Maria A.
Shevtsova, Elena F.
Grigoriev, Vladimir V.
Aksinenko, Aleksey Yu.
Ustyugov, Aleksey A.
Steinberg, Daniil A.
Maleev, Grigoriy V.
Dubrovskaya, Elena S.
Goreva, Tatiana V.
Epishina, Tatiana A.
Zamoyski, Vladimir L.
Makhaeva, Galina F.
Fisenko, Vladimir P.
Veselov, Ivan M.
Vinogradova, Daria V.
Bachurin, Sergey O.
New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments
title New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments
title_full New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments
title_fullStr New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments
title_full_unstemmed New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments
title_short New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments
title_sort new adamantane-containing edaravone conjugates as potential neuroprotective agents for als treatments
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673157/
https://www.ncbi.nlm.nih.gov/pubmed/38005288
http://dx.doi.org/10.3390/molecules28227567
work_keys_str_mv AT lapshinamariaa newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT shevtsovaelenaf newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT grigorievvladimirv newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT aksinenkoalekseyyu newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT ustyugovalekseya newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT steinbergdaniila newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT maleevgrigoriyv newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT dubrovskayaelenas newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT gorevatatianav newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT epishinatatianaa newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT zamoyskivladimirl newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT makhaevagalinaf newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT fisenkovladimirp newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT veselovivanm newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT vinogradovadariav newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments
AT bachurinsergeyo newadamantanecontainingedaravoneconjugatesaspotentialneuroprotectiveagentsforalstreatments