Drug resistant epilepsy (DRE) is becoming more of an increasing burden in the epilepsy community. Statistics show that approximately 35% of epileptic patients are resistant to current treatment. Extensive research has been done and published to determine the overall therapeutic properties of analogs containing the cyclic enaminone system. From our fluorinated benzamide drug library, the lead enaminone THA40, was shown to be effective in the DRE 6Hz 44mA rodent seizure model with minimal neurotoxicity. A comprehensive structure activity relationship (SAR) exploration on THA40 was performed on THA40 by introducing various electron-withdrawing groups with the goal of determining the chemical components that will improve the overall efficacy and safety profile. All designed analogs passed the test for drug-likeness as it relates to cLogP values, LogBB coefficients, molecular weight and hydrogen bonding donors and acceptors. SAR studies and anticonvulsant evaluation of our substituted N-benzamide enaminones have shown 5 out of the 15 analogs tested were shown to protect 75-100% of animals in the MES and 6 Hz 44mA model for DRE at different doses and time intervals. For the in vitro cell-based mechanistic electrophysiology studies, a similar activity pattern was observed where modifications on the aromatic ring changes the channel blocking specificity of the enaminone benzamide analogs. Compounds with a trifluoromethyl (CF3) or trifluoromethoxy (OCF3) substitution on the para position seems to have an affinity for blocking the sodium channels. Conversely, analogs with a trifluoromethyl substitution on the meta position show greater inhibition for the calcium channels. The docking studies also shows that the new analogs interact with the sodium channel by three important hydrogen bonds between the hydrogen bond donors and acceptors on the analogs and two important amino residues in the open form sodium channel crystal structure, Lys166 and Tyr169. From our current results, we report that a novel class of enaminone benzamides possess anticonvulsant properties. We concluded that increased activity is observed in various position of the aromatic ring with a fluorine and CF3 group respectively. Our next step is to conduct lead optimization studies on active lead analogs to determine the best substitution patterns needed for optimum in-vivo and in-vitro activity. SAR studies and mechanistic characterization of these novel analogs will be presented in detail.

Design, synthesis, SAR study, and biological investigation of novel N-substituted benzamide enaminones as potential anticonvulsant agents

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.