Synthesis and Evaluation of alpha-Asaronol Esters with LDH and GABA k Receptor Modulation as Anticonvulsant Agents

Background: Our previous studies showed that alpha-asaronol was a potential antiepileptic candidate. Here, twelve O-terminus modified ester derivatives of alpha-asaronol were designed, synthesized and evaluated their anticonvulsant activity. Methods: All synthetic compounds were subjected to three animal models of seizure (MES, scPTZ and sc3-MP models) combined with neurotoxicity test, as well as the LDH inhibitory test. Furthermore, GABA(A) Receptor modulation and pharmacokinetic evaluation of compound 4k were also performed. Results: Five compounds (4a, 4b, 4d, 4e and 4k) showed significant anticonvulsant properties at the dose of 30-300 mg/kg in MES and scPTZ test, but weak activity in sc3-MP model. Meanwhile, 4a, 4b, 4d and 4k showed good LDH inhibitory activity in vitro. Specifically, 4k was the best compound in above evaluation, and better than that of alpha-asaronol and reference compound (stiripentol). In addition, 4k could increase chloride ion influx by modulating GABA(A) receptor alpha 1 beta 2 gamma 2 subtype with EC50 of 48.65 +/- 10.31 mu M and showed good PK profiles in rats with moderate oral bioavailability (51.5%). Conclusion: These results suggested 4k possesses potential effectiveness in treatment of therapy-resistant seizures and is expected to be developed as a novel molecule for safer and efficient anticonvulsants having neuroprotective effects as well as low toxicity.