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†

Abstract

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-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 α-amylase enzyme to probe their antidiabetic properties. In vitro 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 A. oryzae α-amylase. Encouragingly, the theoretical analyses closely mirrored the experimental findings, further underlining the promise of these synthetic molecules as potent α-amylase inhibitors.