Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico & in vivo study.
Daru
; 2024 Aug 06.
Article
en En
| MEDLINE
| ID: mdl-39106020
ABSTRACT
BACKGROUND:
Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways.OBJECTIVES:
Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment.METHODS:
Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model. RESULTS ANDCONCLUSION:
The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.
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Base de datos:
MEDLINE
Idioma:
En
Revista:
Daru
Año:
2024
Tipo del documento:
Article
País de afiliación:
Irán