Next-Generation\nCarbazole-Linked 1,2,4-Triazole-Thione\nDerivatives: Strategic Design, Synthesis, Molecular Docking, and Evaluation\nof Antidiabetic Potential

Currently, available therapies for diabetes cannot achieve\nnormal\nsugar values in a high percentage of treated patients. This work synthesized\na series of carbazole-triazole-thione derivatives, and their potential\nantidiabetic activity was investigated against the key diabetic enzymes\nα-amylase and glycosidase. Normal human hepatic stellate cells\n(LX-2) were employed to assess their cytotoxicity and safety, followed\nby in vivo testing to investigate the hypoglycemic effect of the most\npromising agent. As a result, a set of 18 carbazole-1,2,4-triazole-thione\nderivatives were synthesized. Seven structures demonstrated potential\ninhibitory activity against α-amylase enzyme, with IC<sub>50</sub> lower than 6.4 μM. Among them, compounds <b>C5f</b>, <b>C5o</b>, and <b>C5r</b> exhibited the highest potency, with\nIC<sub>50</sub> values of 0.56, 0.53, and 0.97 μM, respectively,\ncompared to the well-known α-amylase inhibitor acarbose, which\nhas an IC<sub>50</sub> value of 5.31 μM. Exploring the inhibition\npotency of these series against α-glucosidase enzyme revealed\nthat <b>C5f</b> and <b>C5r</b> compounds act as moderate\ninhibitors, with IC<sub>50</sub> values of 11.03 and 13.76 μM,\nrespectively. Moreover, at 100 μM concentration, most of the\nevaluated compounds showed negligible cytotoxic effect against LX-2\ncell lines, particularly compounds <b>C5o</b> and <b>C5s</b>, that demonstrated lower cytotoxic activity by 3-fold compared to\nthe positive control 5-Flururicle (cell viability 13.45%). Thus, the <b>C5f</b> compound was selected for in vivo evaluation, and after\nadministering five doses of this compound (10 mg/kg) to group III\nof mice, a significant reduction in glucose concentration was observed,\nbringing it down from 290.54 to 216.15 mg/dL, in comparison with the\ncontrol group which did not show a reduction in blood glucose level.\nThese observed in vitro and in vivo results were upheld by performing\na set of chemoinformatic studies that elucidated the binding interactions\nof the most active derivatives within the enzyme’s active site\nand highlighted the critical roles of both the 1,2,4-triazole-3-thione\nand carbazole scaffolds in these interactions. Finally, the drug-likeness\nprofiles of our carbazole-triazole-thione derivatives suggest their\npotential as candidates for further in vivo studies and clinical trials.