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

Diabetes poses a significant global health challenge, driving the search for effective management strategies. In the past years, alpha-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-b]indole derivatives via the regioselective reaction of 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]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-b]indole derivatives was assessed against the alpha-amylase enzyme to probe their antidiabetic properties. In vitro studies revealed moderate to excellent alpha-amylase inhibitory activity, with IC50 values ranging from 16.14 +/- 0.41 to 27.69 +/- 0.58 mu g 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 mu g ml-1), particularly derivatives substituted with 4-fluoro and 2,4-dichloro groups, with IC50 values of 16.14 +/- 0.41 mu g ml-1 and 17.21 +/- 0.15 mu g ml-1, respectively. Additionally, molecular docking unveiled the binding modes of ligands with the active site of A. oryzae alpha-amylase. Encouragingly, the theoretical analyses closely mirrored the experimental findings, further underlining the promise of these synthetic molecules as potent alpha-amylase inhibitors.