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Hybrid Derivatives Containing Dimethyl Fumarate and Benzothiazole Scaffolds for the Potential Treatment of Multiple Sclerosis; in Silico & in Vivo Study Publisher Pubmed



Mirmotahari SA1 ; Aliomrani M2 ; Hassanzadeh F1 ; Sirous H3 ; Rostami M1
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, I.R., Isfahan, Iran
  2. 2. Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
  3. 3. Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, I.R., Isfahan, Iran

Source: DARU, Journal of Pharmaceutical Sciences Published:2024


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 and conclusion: 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. Graphical Abstract: Summary of the design process, molecular docking, synthesis, and in vivo evaluation. (Figure presented.) © The Author(s), under exclusive licence to Tehran University of Medical Sciences 2024.
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