Synthesis and Biological Evaluation of Quinolone-Based Hydrazones as Potential Antidiabetic Agents Targeting Key Metabolic Enzymes.

A series of novel structures featuring quinolone-based hydrazones (-) were synthesized, characterized, and screened for their potential inhibition of key enzymes involved in carbohydrate metabolism, namely human pancreatic α-amylase (HPA) and human lysosomal acid α-glucosidase, as well as aldose reductase, an enzyme associated with diabetes-related complications. The synthesized compounds exhibited a broad range of inhibitory activities against both α-glucosidase (IC: 7.44 ± 0.07 to 14.75 ± 0.15 μg/mL) and α-amylase (IC: 21.05 ± 0.17 to 31.43 ± 0.11 μg/mL). Notably, compound (5-nitrofuran) demonstrated the most potent inhibition against both enzymes (α-glucosidase IC = 7.44 ± 0.07 μg/mL; α-amylase IC = 21.05 ± 0.17 μg/mL), surpassing the standard drug acarbose. Furthermore, these hydrazones also showed promising aldose reductase inhibitory activities (IC: 4.12 ± 0.09 to 11.00 ± 0.05 μg/mL), with compound again exhibiting the highest potency (IC = 4.12 ± 0.09 μg/mL), even outperforming quercetin. Kinetic studies on revealed a reversible, noncompetitive inhibition mechanism against aldose reductase with an inhibition constant ( ) of 4.65 μM. Molecular docking studies against α-amylase, α-glucosidase, and aldose reductase demonstrated favorable binding interactions for several compounds, with showing particularly strong interactions with the active site of aldose reductase (docking score: -10.051). Molecular dynamics simulations of the -aldose reductase complex over 100 ns confirmed stable binding within the active site. Density functional theory (DFT) analysis of revealed a small HOMO-LUMO energy gap (0.112566 eV) and a soft nature, suggesting good chemical reactivity. These findings showcase the potential of quinolone-based hydrazones, particularly compound , as promising candidates aiming at the development of multitarget therapies for antidiabetic agents.