Title:Synthesis and Evaluation of α-Asaronol Esters with LDH and GABAA Receptor Modulation as Anticonvulsant Agents
Volume: 17
Issue: 7
Author(s): Yajun Bai, Bin Li, Jing Xie, Xufei Chen, Shu Cheng, Yujun Bai, Ying Sun, Fanggang Qin, Jing Liang, Yanrui Ding*Xiaohui Zheng*
Affiliation:
- School of Science, Jiangnan University, Wuxi 214122,China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, Xi’an 710069,China
Keywords:
Drug design, α-asaronol ester derivatives, anticonvulsant, GABAA receptor α1β2γ2, LDH inhibitory, pharmacokinetics.
Abstract:
Background: Our previous studies showed that α-asaronol was a potential antiepileptic
candidate. Here, twelve O-terminus modified ester derivatives of α-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,
GABAA 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 α-asaronol and reference compound (stiripentol).
In addition, 4k could increase chloride ion influx by modulating GABAA receptor α1β2γ2 subtype
with EC50 of 48.65 ± 10.31 μM and showed good PK profiles in rats with moderate oral bioavailability
(51.5%).
Conclusion: These results suggested 4k possesses potential effectiveness in treatment of therapyresistant
seizures and is expected to be developed as a novel molecule for safer and efficient anticonvulsants
having neuroprotective effects as well as low toxicity.
