Design, synthesis, and pharmacological evaluation of 7-substituted 1,2,4-triazolo[1,5-a]pyrimidine derivatives as novel antiepileptic lead candidates targeting Nav1.2 channels

IF 5.1 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2026-11-15 Epub Date: 2026-10-18 DOI:10.1016/j.bioorg.2026.110668

Luqian He, Qiaoliang Zhang, Wenjuan Ma, Meiqi Qian, Yifan Dong, Feifei Xin, Chuanlong Guo, Guorui Cao, Fang Tuo, Longjiang Huang

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引用次数: 0

Abstract

The limitations of current antiepileptic drugs, including drug resistance and adverse effects, necessitate the development of novel therapeutic agents with improved efficacy and safety. Herein, we describe the design, synthesis, and pharmacological evaluation of a series of novel 1,2,4-triazolo[1,5-a]pyrimidine derivatives. Through strategic modification at the C-7 position, we identified compound 5m as a highly potent anticonvulsant agent. In the pentylenetetrazole (PTZ) epilepsy model, 5m exhibited exceptional antiseizure activity (ED₅₀ = 8.84 mg/kg) with a high protective index (PI > 14.80), demonstrating superior efficacy and safety profiles compared to valproate, carbamazepine, and phenobarbital. Notably, 5m showed no neurotoxicity at its maximum soluble concentration. Preliminary structure–activity relationship (SAR) analysis at the C-7 position suggested that the trifluoromethanesulfonate substituent, the pyrimidine nitrogen atoms, and the ortho-fluoro substitution pattern on the phenyl ring are important for potent activity. Mechanism of action studies combining electrophysiological patch-clamp recordings and molecular docking simulations established Nav1.2 channels as a primary molecular target, with 5m exhibiting inhibitory activity against Nav1.2 channels (23% ± 17% inhibition at 10 μM) and forming key interactions with residues LEU329, LEU336, ASN388, GLN391, and ARG395, while showing no significant effect on GABA_A receptors. Furthermore, in silico ADMET prediction confirmed that 5m possesses excellent drug-like properties, including favorable gastrointestinal absorption and blood-brain barrier permeability, with no predicted toxicity. In summary, compound 5m represents a promising novel antiepileptic lead candidate with high efficacy, low neurotoxicity, and a favorable drug-like profile, warranting further preclinical development.

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靶向Nav1.2通道的7-取代1,2,4-三唑[1,5-a]嘧啶衍生物抗癫痫先导药物的设计、合成和药理学评价

目前抗癫痫药物的局限性，包括耐药和不良反应，需要开发新的治疗药物，提高疗效和安全性。在这里，我们描述了一系列新的1,2,4-三唑[1,5-a]嘧啶衍生物的设计，合成和药理学评价。通过对C-7位点的战略性修饰，我们发现化合物5m是一种高效的抗惊厥剂。在戊四唑（PTZ）癫痫模型中，5m表现出异常的抗癫痫活性（ED50 = 8.84 mg/kg），具有高保护指数（PI > 14.80），与丙戊酸盐、卡马西平和苯巴比妥相比，显示出更高的疗效和安全性。值得注意的是，5m在其最大可溶浓度下无神经毒性。初步的构效关系（SAR）分析表明，三氟甲磺酸取代基、嘧啶氮原子和苯基环上的邻氟取代模式是影响活性的重要因素。结合电生理膜片钳记录和分子对接模拟的作用机制研究发现，5m对Nav1.2通道具有抑制活性（在10 μM时抑制率为23% ± 17%），并与LEU329、LEU336、ASN388、GLN391和ARG395等残基形成关键相互作用，而对GABAA受体无显著影响。此外，计算机ADMET预测证实5m具有优异的药物样特性，包括良好的胃肠道吸收和血脑屏障通透性，没有预测的毒性。综上所述，化合物5m是一种有前景的新型抗癫痫先导候选药物，具有高效、低神经毒性和良好的药物样特征，值得进一步的临床前开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.