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

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 GABA_A receptors, while compounds 3u and 4f dose-dependently reduced the peak amplitude of Na_v1.2 currents. These structural compounds may provide a foundation for the further design of novel antiepileptic molecules with low neurotoxicity.