Integrating Synthesis, Pharmacological Activity, and Molecular Modeling to Explore 1,2,4-Triazine Fused...

Epilepsy is a common neurological disorder managed with anti-epileptic drugs (AEDs), which often cause side effects and limited efficacy. This study aims to evaluate a novel series of 1,2,4-triazine fused thiazolidin-4-one derivatives for their anticonvulsant and antioxidant potential as safer and more effective therapeutic options.

Twelve 1,2,4-triazine fused thiazolidin-4-one derivatives (HRSP1-HRSP12) were synthesized. Anticonvulsant activity was assessed using the maximal electroshock (MES) model, while antioxidant potential was evaluated through DPPH and FRAP assays. Cortical GABA and glutamate levels were quantified in mice. Safety was evaluated via acute toxicity studies. In silico studies included molecular docking, induced fit docking, MM-GBSA, and molecular dynamics simulations to assess GABAA receptor interactions.

HRSP8 showed the strongest anticonvulsant activity among the synthesized compounds, reducing hind limb tonic extension (HLTE) to 7.91 ± 0.25 s (30 mg/kg) and 6.89 ± 0.09 s (100 mg/kg), comparable to standard drugs (phenytoin and carbamazepine). It exhibited an ED50 of 27.49 mg/kg, TD50 >565 mg/kg, and a protective index >20.51. HRSP8 also increased cortical GABA and decreased glutamate levels. Antioxidant assays confirmed strong radical scavenging activity. Docking (-7.80 kcal/mol) and MM-GBSA (-82.42 kcal/mol) suggested high GABAA receptor affinity, supported by stable molecular dynamics.

HRSP8's effects appear to involve GABAA receptor modulation and neurochemical balance restoration, with additional antioxidant support. Its safety margin and stable receptor binding indicate therapeutic promise. These results align with existing GABAergic strategies in epilepsy. Further validation in chronic models and pharmacokinetic studies is needed.

HRSP8 demonstrated notable anticonvulsant and antioxidant activities, a wide safety margin, and strong affinity for the GABAA receptor. These findings support its potential as a lead compound for further preclinical evaluation in epilepsy therapy.