Efficient synthesis of promising antidiabetic triazinoindole analogues <i>via</i> a solvent-free method: investigating the reaction of 1,3-diketones and 2,5-dihydro-3 <i>H</i> -[1,2,4]triazino[5,6- <i>b</i> ]indole-3-thione

Diabetes poses a significant global health challenge, driving the search for effective management strategies. In the past years, α-amylase inhibitors have emerged as promising candidates for regulating blood sugar levels. In this concern, we have synthesized a series of novel 3-methyl-2-aroylthiazolo[3',2':2,3][1,2,4]triazino[5,6-<i>b</i>]indole derivatives <i>via</i> the regioselective reaction of 2,5-dihydro-3<i>H</i>-[1,2,4]triazino[5,6-<i>b</i>]indole-3-thione and 1,3-diketones in the presence of NBS under solvent-free conditions. Subsequently, the inhibitory potential of the newly synthesized 3-methyl-2-aroylthiazolo[3',2':2,3][1,2,4]triazino[5,6-<i>b</i>]indole derivatives was assessed against the α-amylase enzyme to probe their antidiabetic properties. <i>In vitro</i> studies revealed moderate to excellent α-amylase inhibitory activity, with IC₅₀ values ranging from 16.14 ± 0.41 to 27.69 ± 0.58 μg ml^-1. Furthermore, SAR analysis showed that compounds containing halogen groups exhibited superior inhibition potential, surpassing the standard drug Acarbose (IC₅₀ = 18.64 ± 0.42 μg ml^-1), particularly derivatives substituted with 4-fluoro and 2,4-dichloro groups, with IC₅₀ values of 16.14 ± 0.41 μg ml^-1 and 17.21 ± 0.15 μg ml^-1, respectively. Additionally, molecular docking unveiled the binding modes of ligands with the active site of <i>A. oryzae</i> α-amylase. Encouragingly, the theoretical analyses closely mirrored the experimental findings, further underlining the promise of these synthetic molecules as potent α-amylase inhibitors.