Novel Thiochroman‐4‐One Derivatives Bearing a Sulfonyl Hydrazone Moiety: Synthesis, Bioactivity, Molecular Simulation, and Drug‐Likeness Evaluation

ABSTRACT

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 ¹ H 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 IC ₅₀ 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.