Next-Generation Carbazole-Linked 1,2,4-Triazole-Thione Derivatives: Strategic Design, Synthesis, Molecular Docking, and Evaluation of Antidiabetic Potential.

Currently, available therapies for diabetes cannot achieve normal sugar values in a high percentage of treated patients. This work synthesized a series of carbazole-triazole-thione derivatives, and their potential antidiabetic activity was investigated against the key diabetic enzymes α-amylase and glycosidase. Normal human hepatic stellate cells (LX-2) were employed to assess their cytotoxicity and safety, followed by in vivo testing to investigate the hypoglycemic effect of the most promising agent. As a result, a set of 18 carbazole-1,2,4-triazole-thione derivatives were synthesized. Seven structures demonstrated potential inhibitory activity against α-amylase enzyme, with IC lower than 6.4 μM. Among them, compounds , , and exhibited the highest potency, with IC values of 0.56, 0.53, and 0.97 μM, respectively, compared to the well-known α-amylase inhibitor acarbose, which has an IC value of 5.31 μM. Exploring the inhibition potency of these series against α-glucosidase enzyme revealed that and compounds act as moderate inhibitors, with IC values of 11.03 and 13.76 μM, respectively. Moreover, at 100 μM concentration, most of the evaluated compounds showed negligible cytotoxic effect against LX-2 cell lines, particularly compounds and , that demonstrated lower cytotoxic activity by 3-fold compared to the positive control 5-Flururicle (cell viability 13.45%). Thus, the compound was selected for in vivo evaluation, and after administering five doses of this compound (10 mg/kg) to group III of mice, a significant reduction in glucose concentration was observed, bringing it down from 290.54 to 216.15 mg/dL, in comparison with the control group which did not show a reduction in blood glucose level. These observed in vitro and in vivo results were upheld by performing a set of chemoinformatic studies that elucidated the binding interactions of the most active derivatives within the enzyme's active site and highlighted the critical roles of both the 1,2,4-triazole-3-thione and carbazole scaffolds in these interactions. Finally, the drug-likeness profiles of our carbazole-triazole-thione derivatives suggest their potential as candidates for further in vivo studies and clinical trials.