1,2,3-Triazole based xanthene and acridine linkers as potential α-glucosidase and α-amylase inhibitors: design, green synthesis, kinetics, and in silico studies

In an ongoing endeavor to discover new α-glucosidase as well as α-amylase inhibitors for the treatment of type 2 diabetes mellitus (T2DM), herein we introduced the synthesis of xanthene and acridine linked 4-(phenoxymethyl)-1-phenyl-1H-1,2,3-triazole derivatives 6(a-j) and 7(a-j). This approach utilized ultrasound-promoted deep eutectic solvent (DES) as a biodegradable medium, resulting in a highly efficient and environmentally friendly process with high yields. This DES boasts affordability, a dual catalytic effect, and reusability, rendering it task specific solvent. Upon inhibiting α-glucosidase and α-amylase enzymes, compounds 6g, 6h, 6i, 6j, 7g, 7h, 7i, and 7j demonstrated significant inhibition, with IC50 values ranging from 3.24 ± 0.07 to 5.03 ± 0.05 μM and 4.68 ± 0.07 to 3.28 ± 0.07 μM respectively. Kinetic studies on the most effective compounds revealed a mixed-type inhibition mechanism for both enzymes. In vitro cytotoxicity assay on the MCF-7 breast cancer cell line demonstrated that most tested compounds were non-toxic. Molecular docking studies have corroborated the findings, showing that these active compounds engage in multiple binding interactions within the active pockets of both enzymes. DFT calculations were performed on all synthesized molecules to compare the biological activity of key compounds with theoretical quantum descriptors and MESP 3D plots. Based on these significant findings, the derivatives provide promising pathways for future research on type 2 diabetes and may pave the way for innovative treatments.