Design, Synthesis, Spectral Elucidation and Antidiabetic in Silico Evaluation of Novel 3-Methyl-6-Substituted 1,2,4-Triazine Derivatives

The 1,2,4-triazine scaffold is a recognized pharmacophore in medicinal chemistry, particularly in antidiabetic drug design. Herein, we report the synthesis and comprehensive spectral characterization of 3-methyl-6-amino-1,2,4-triazine and six novel derivatives substituted at the C-6 position. Functional modifications include aniline, nitrophenylazo, chloro, hydroxyethoxy, and benzylamino groups. All compounds were structurally confirmed using IR, 1H NMR, 13C NMR Spectroscopy, and mass spectrometry. In silico prediction of antidiabetic activity against key targets, such as PPAR-γ and α-glucosidase, indicates significant potential, establishing these molecules as promising candidates for further pharmacological studies. In this study, the parent scaffold, 3-methyl-6-amino-1,2,4-triazine, and six novel derivatives were successfully synthesized and comprehensively characterized. Structural confirmation was achieved through FT-IR, ¹H NMR, ¹³C NMR which collectively verified the presence of triazine-associated functional groups and the expected molecular ion peaks for each compound. Physical characterization, including melting point determination and TLC profiling, further supported the purity and identity of the synthesized molecules. Molecular docking studies were performed using AutoDock Vina against the PPAR-γ receptor (PDB: 3VI8). All compounds showed stable binding within the ligand-binding pocket, with the 4-nitrophenylazo and benzylamino derivatives exhibiting the highest binding affinities through key hydrogen bonding and π–π interactions with residues such as Ser289, His323, and Phe363. These computational findings were consistent with the predicted IC₅₀ outcomes and structure–activity relationships derived from the substituent patterns. Overall, the combined experimental and in silico analyses revealed that the synthesized triazine derivatives possess promising structural, pharmacokinetic, and molecular interaction profiles suitable for further exploration as potential antidiabetic agents, with the azo and benzylamino analogs emerging as the most compelling candidates for future biological validation.