Synthesis and <i>In vitro</i> Biological Evaluation of Quinolone-Based Hydrazones as Potential Antidiabetic Agents Targeting Key Metabolic Enzymes
Naik Jui Pravin, Rohini S. Kavalapure, Shankar Gharge, Shankar G. Alegaon, Shriram D. Ranade, Ling Shing Wong, Ramith Ramu, C. Ramya
Abstract
High Resolution Image Download MS PowerPoint Slide A series of novel structures featuring quinolone-based hydrazones ( 5a – 5q ) 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 50: 7.44 ± 0.07 to 14.75 ± 0.15 μg/mL) and α-amylase (IC 50: 21.05 ± 0.17 to 31.43 ± 0.11 μg/mL). Notably, compound 5o (5-nitrofuran) demonstrated the most potent inhibition against both enzymes (α-glucosidase IC 50 = 7.44 ± 0.07 μg/mL; α-amylase IC 50 = 21.05 ± 0.17 μg/mL), surpassing the standard drug acarbose. Furthermore, these hydrazones also showed promising aldose reductase inhibitory activities (IC 50: 4.12 ± 0.09 to 11.00 ± 0.05 μg/mL), with compound 5o again exhibiting the highest potency (IC 50 = 4.12 ± 0.09 μg/mL), even outperforming quercetin. Kinetic studies on 5o revealed a reversible, noncompetitive inhibition mechanism against aldose reductase with an inhibition constant ( K i ) of 4.65 μM. Molecular docking studies against α-amylase, α-glucosidase, and aldose reductase demonstrated favorable binding interactions for several compounds, with 5o showing particularly strong interactions with the active site of aldose reductase (docking score: −10.051). Molecular dynamics simulations of the 5o -aldose reductase complex over 100 ns confirmed stable binding within the active site. Density functional theory (DFT) analysis of 5o 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 5o, as promising candidates aiming at the development of multitarget therapies for antidiabetic agents.