2. Academic Validation
  3. Design, synthesis and structure-activity relationship of novel 1,2,4-triazolopyrimidin-5-one derivatives targeting GABAA1 and Nav1.2 with antiepileptic activity

Design, synthesis and structure-activity relationship of novel 1,2,4-triazolopyrimidin-5-one derivatives targeting GABAA1 and Nav1.2 with antiepileptic activity

  • Eur J Med Chem. 2025 Mar 15:286:117316. doi: 10.1016/j.ejmech.2025.117316.
Tongtong Du 1,  Jun Wu 2,  Weina Wang 2,  Wenhui Liang 1,  Yunjie Li 1,  Chuanlong Guo 1,  Xiufen Li 1,  Longjiang Huang 3,  Haibo Yu 4
Affiliations

Affiliations

  • 1 State Key Laboratory Base for Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xiannongtan Street, Xicheng district, Beijing, 100050, China.
  • 3 State Key Laboratory Base for Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xiannongtan Street, Xicheng district, Beijing, 100050, China. Electronic address: huanglj@qust.edu.cn.
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xiannongtan Street, Xicheng district, Beijing, 100050, China. Electronic address: haiboyu@imm.ac.cn.
PMID: 39874632 DOI: 10.1016/j.ejmech.2025.117316
Abstract

A novel class of 7-phenyl-[1,2,4]triazol-5(4H)-one derivatives was designed and synthesized, and their in vivo anticonvulsant activities were evaluated using subcutaneous pentylenetetrazole (Sc-PTZ) and maximal electroshock (MES) tests. Compounds 3u, 4f and 4k exhibited significant anticonvulsant activities in the Sc-PTZ model with ED50 values of 23.7, 17.1 and 18.3 mg/kg, respectively. Neurotoxicity was accessed using the rotarod assay and none of the compounds demonstrated neurotoxicity at maximum solubility, with all TD50 values exceeding 267 mg/kg. This resulted in protective indexes (PI = TD50/ED50) values of greater than 11.3, 15.6 and 14.6, respectively. Compared to control drugs such as sodium phenytoin, sodium valproate, and carbamazepine, compounds 3u, 4f and 4k displayed superior anticonvulsant activities and reduced neurotoxicity. Mechanism results indicated that compounds 4k and 4f were sensitive to the subunit configuration of synaptic α1β2γ2 GABAA receptors, while compounds 3u and 4f dose-dependently reduced the peak amplitude of Nav1.2 currents. These structural compounds may provide a foundation for the further design of novel antiepileptic molecules with low neurotoxicity.

Keywords

1,2,4-Triazole pyrimidinone derivatives; Antiepileptic activity; GABA(A1); Na(v)1.2.

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