Synthesis, α-glucosidase inhibition, and antidiabetic evaluation of 2-phenylquinoline-indole hydrazine hybrids: In vitro, in vivo, and computational studies

α-Glucosidase inhibitors (α-GI) are a valuable therapeutic option for the treatment of postprandial hyperglycemia and continue to be a global health challenge, particularly with the rise of Type 2 diabetes mellitus (T2DM). In this regard, we describe the design, synthesis, and multi-target screening of seventeen new 2-phenylquinoline-indole hydrazine hybrids ( 9a-q ) as potential antidiabetic agents. Two privileged scaffolds, namely quinoline and indole with α-glucosidase inhibitory and antiglycation properties, were integrated into the design strategy. All synthesized compounds were evaluated for in vitro α-glucosidase inhibition, and machine learning was applied to rank the series and guide selection of the most promising derivative for advanced testing. Among them, compound 9j (bearing a 2-methylphenyl group) emerged as the most potent inhibitor (IC 50 = 1.1 μM), displaying approximately 682-fold more potent than acarbose (IC 50 = 750.0 μM). Kinetic studies showed that 9j is a competitive inhibitor with a Ki of 15.5 μM. It also showed notable in vitro antiglycation and protein-aggregation inhibitory activity. Confirming its antihyperglycemic activity, 9j decreased blood glucose levels by about 70% ( p < 0.0001) in vivo in a hyperglycemic zebrafish model. In conclusion, these results make 9j a potential lead compound for developing new multifunctional antidiabetic agents for T2DM.