Novel Thiochroman-4-One Derivatives Bearing a Sulfonyl Hydrazone Moiety: Synthesis, Bioactivity, Molecular...

Herein, a series of novel thiochroman-4-one derivatives bearing sulfonyl hydrazone moiety were rationally designed and synthesized via molecular hybridization strategy. The sulfonyl hydrazone pharmacophore with excellent hydrogen-bonding interaction ability was first introduced into the thiochroman-4-one parent skeleton to construct dual-active functional molecules, aiming to achieve synergistic α-glucosidase inhibition and antioxidant activity for antidiabetic therapy. All target compounds were structurally characterized by ¹H NMR, ^{1 3}C NMR, and HRMS. Bioactivity results showed that multiple derivatives exhibited excellent α-glucosidase inhibitory activity and antioxidant capacity, among which compound 5k displayed the optimal comprehensive pharmacological performance with IC₅₀ value of 4.57 µg/mL against α-glucosidase, which was significantly superior to the positive control acarbose (237.48 µg/mL). Molecular docking and molecular dynamics (MD) simulation verified that the optimal compound 5k could stably bind to the active pocket of α-glucosidase through multiple hydrogen bonds and hydrophobic interactions, with lower binding energy and better complex stability. Drug-likeness evaluation demonstrated that all synthesized derivatives complied with Lipinski's rule of five and had favorable pharmacokinetic properties. This work provides a novel structural scaffold for the development of high-efficiency antioxidant, α-glucosidase, and antibacterial inhibitors, and demonstrates its potential as a lead compound for pharmaceutical and agrochemical development.