DESIGN, MOLECULAR DOCKING, SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL EVALUATION OF NOVEL MANNICH BASES OF 1,2,4-TRIAZINE DERIVATIVES AS POTENTIAL ANTICONVULSANT AGENTS

Raju Kumar, Ravi Kumar Saini*, Omprakash Goshain

ABSTRACT

Background: Epilepsy is a chronic neurological disorder characterized by recurrent seizures and remains a major global health challenge due to the limited efficacy and adverse effects of currently available antiepileptic drugs. The development of novel anticonvulsant agents with improved efficacy and reduced neurotoxicity is therefore of considerable therapeutic interest. In the present study, a series of novel Mannich base-derived 1,2,4-triazine derivatives were designed, synthesized, characterized, and evaluated for their anticonvulsant potential. Methods: Novel Mannich base-derived 1,2,4-triazine derivatives were synthesized through a multistep synthetic approach involving Mannich base formation. The synthesized compounds were characterized using physicochemical parameters, FT-IR spectroscopy, and ¹H NMR spectroscopy. Molecular docking studies were performed to investigate ligand–target interactions. Anticonvulsant activity was evaluated in Swiss albino mice using the maximal electroshock seizure (MES) model, while neurotoxicity was assessed using the rotarod test. Results: The synthesized derivatives were obtained with satisfactory yields and successfully characterized by spectroscopic techniques. Biological evaluation demonstrated that compounds A, B, E, H, I, f, h, and i exhibited anticonvulsant activity in the MES model, whereas compounds C, a, b, c, d, and e showed no significant protection. The active compounds displayed minimal neurotoxicity, suggesting a favorable therapeutic profile. Molecular docking studies supported the experimental findings by indicating favorable interactions of the active derivatives with the selected biological target, and structure–activity relationship analysis highlighted the importance of appropriate Mannich base substitution for enhanced anticonvulsant activity. Conclusion: The present study identified several Mannich base-derived 1,2,4-triazine derivatives as promising anticonvulsant lead compounds. The integration of synthetic chemistry, spectroscopic characterization, molecular docking, and biological evaluation supports further structural optimization and preclinical investigations to develop safer and more effective anticonvulsant agents.

Keywords: 1,2,4-Triazine; Mannich bases; Anticonvulsant activity; Molecular docking; Epilepsy; Structure–activity relationship; Neurotoxicity.