Epilepsy is one of the most common encountered neurological disorders. Many individuals continue to have seizures despite medical and surgical treatments, suggesting new antiepileptic/anticonvulsant drugs are required. Triazole compounds are widely used in pharmaceuticals and have gained significant importance in medicinal chemistry. This article is an attempt to systematically review the research of triazole derivatives in the design and development of anticonvulsant agents during the past two decades through extensive literature research. The results show that triazole occupy a distinct niche in heterocyclic chemistry and represent a key motif in medicinal chemistry because of their capability to exhibit an array of properties and bioactivities, Therefore, 1,2,4-triazole seems to be an important pharmacophore, especially in the field of antiepileptic, which is of great explored potentiality and utilized value. Through in-depth research on this type of structure, it is believed that more 1,2,4-triazole compounds will be developed as anti-epileptic drugs for clinical use.

Background: Epilepsy is one of the most common neurological disorders. Many individuals continue to have seizures despite medical and surgical treatments, suggesting that the discovery of novel anti-seizure drugs is vital. Triazole compounds are widely used as pharmaceuticals and have gained significant interest in medicinal chemistry. In this article, the development of triazoles, especially 1,2,4- triazole, in the field of anti-seizure therapeutics is reviewed. Methods: The relevant literature was investigated, classified, and analysed. This article attempts to systematically review the research of triazole derivatives in the design and development of anti-seizure agents during the past two decades through extensive literature research, which was based on the information accessible in PubMed, Science Direct, Google Scholar and other databases. Results: Research results demonstrate that triazoles occupy a distinct niche in heterocyclic chemistry and represent a key motif in medicinal chemistry because of their ability to exhibit an array of properties and bioactivities. Therefore, 1,2,4-triazole appears to be an important pharmacophore, especially in the field of anti-seizure therapeutics, where its promising potential value has been explored. Conclusion: This review presents a summary of the research related to 1,2,4-triazole, which acts as a potential anti-seizure pharmacophore that could be further developed. Compounds with 1,2,4-triazole or related structures had previously shown reasonable anti-seizure activity and safety. After thorough research of this structure, it is believed that 1,2,4-triazole-containing compounds will be further developed as anti-seizure drugs for clinical use.

A series of new benzothiazole derivatives containing dimethylpyrazole were synthesized and evaluated for their anticonvulsant activity, neurotoxicity and cytotoxicity by using the maximal electroshock (MES), rotarod neurotoxicity (TOX) and MTT colorimetric assay. Among the compounds studied, four compounds (6a, 6b, 6g and 6m) showed better anticonvulsant than the others at 300 mg/kg and they also showed anticonvulsant activity at the dose of 100 mg/kg. All the synthetic compounds showed lower neurotoxicity and little cytotoxicity, so that the compounds, which with better activities, also had higher protective index. In particular, the compound 6g, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-6-((2-fluorobenzyl)oxy)benzo[d]thiazole showed better activity with an ED50 value of 160.4 mg/kg and higher protective index (PI) values of 2.74 in the MES test than the standard drugs sodium valproate, which used as positive controls in this study. After that the compound 6g demonstrated antagonistic activity against seizures induced by pentylenetetrazol, which proved 6g maybe exert activity through effecting GABAergic neurotransmission.

Epilepsy is a serious chronic neurological disorder primarily characterized by abnormal neuronal discharges in the brain. Introducing a novel benzothiazine-triazole scaffold, a series of 6-alkoxy-2-(4H-1,2,4-triazol-4-yl)-4H-benzo[d][1,3]thiazine derivatives were designed and evaluated using whole-cell patch-clamp technique on human embryonic kidney (HEK)-293 cells stably expressing α1β3γ2 GABAA receptors (GABAARs). Among them, H-10 was identified as a potent positive allosteric modulator (PAM) for the α1β3γ2 subtype, enhancing GABA-induced currents by 16.24-fold (relative to baseline current induced by GABA alone) at a micromolar concentration (10 μM). The anticonvulsant activity was assessed in various seizure models. H-10 exhibited particularly promising efficacy in the pentylenetetrazol (PTZ)-induced seizure model with a median effective dose (ED₅₀) of 8.86 mg/kg and a high protective index (PI) of 10.6. Furthermore, multilevel mechanistic studies confirmed the action of H-10 in PTZ-induced mice via direct micromolar-affinity binding and allosteric modulation of GABAARs, as well as restoration of whole-brain GABA homeostasis and regulation of hippocampal GABAergic protein expression. Pharmacokinetic studies revealed rapid oral absorption with a bioavailability of 93.9%, and efficient brain distribution with a brain-to-plasma AUC ratio of 3.51, ensuring rapid target engagement. In both acute and chronic epilepsy models, H-10 showed significant dose-dependent suppression of seizures and alleviated PTZ-induced pathological damage in multiple organs. In conclusion, H-10 represents a potent, safe, and orally bioavailable GABAAR PAM, exhibiting efficacy across diverse seizure models (acute and chronic), thus demonstrating significant promise for further development as a novel broad-spectrum anticonvulsant agent.