Authors

*A. S.  CRUZ-CALDERON¹, C. P. VLAAR²; ¹University of Puerto Rico, Rio Piedras Campus, Dep. of Chemistry, San Juan, Puerto Rico; ²University of Puerto Rico, Medical Sciences Campus, School of Pharmacy, San Juan, Puerto Rico.

Disclosures

A.S. Cruz-Calderon: None. C.P. Vlaar: None.

Grant: 5R25NS080687

Abstract

INTRODUCTION: Epilepsy is a disorder that affects the central nervous system and manifests as repeated seizures. Research has shown that numerous factors may induce this disorder including genetic mutations in ion channels. Voltage-gated sodium channels (VGSC) play a central role in the generation and propagation of action potentials. Limitations in current drug treatments due to long-term adverse effects and drug-resistant epilepsy highlight the necessity for novel therapies. Channelopathies resulting from mutations in VGSC, especially the α subunit of Nav 1.1, have been identified in patients with epilepsy. Rufinamide is an antiepileptic drug that has been FDA-approved in 2008 as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome. It is suggested to act by modulation of the sodium channels.

OBJECTIVE: The aim of this study is to design and synthesize novel derivatives of Rufinamide with improved anti-epileptic activities via selective Nav 1.1 channel inhibition.

METHODS: Site-specific docking with molecular modeling software AutoDock Vina predicted the binding affinity of rufinamide to the VGSC Nav 1.1. Subsequent docking of a series of compounds in which its difluorophenyl group was isosterically replaced with other aromatic heterocycles was performed to predict novel derivatives with possibly increased potency. These derivatives were selected for synthesis.

RESULTS: Rufinamide was calculated to bind to Nav 1.1 with a binding energy of -6.3 kcal/mol. From the calculated derivatives that were designed, introduction of an indole or benzothiazole group appeared especially beneficial, increasing calculated binding affinity to -8.0 kcal/mol. Several azido-indoles were synthesized as the starting materials and via click chemistry will yield the triazole ring that is also present in rufinamide.

CONCLUSION: Molecular modeling software allow to predict the activity of the proposed derivatives and develop new compounds. Further research is needed to test the anticonvulsant activity of the novel compounds and evaluate their modulation of VGSC Nav 1.1.

ACKNOLEDGEMENTS: ACC receives a stipend from the Natural Institute of Health with grant number 5R25NS080687. Thanks to all the members of the Med Chem Laboratory, especially doctoral student Mitzy Santiago and Cornelis P. Vlaar, Ph.D.