Structure-guided design of aspalathin-inspired chalcone analogs as direct AMPK activators with superior...

AMP-activated protein kinase (AMPK) is a crucial molecular target that has gained significant interest for the treatment of type 2 diabetes (T2D).

The study aimed to design and synthesize benign antidiabetic molecules derived from aspalathin for direct AMPK activation, thereby alleviating hyperglycemia and related hepatorenal toxicity in T2D.

Aspalathin was structurally modified; ADME and toxicity profiling were performed to identify drug-like candidates for docking at the ADaM site (PDB: 6B2E/α2β1 and 4CFF/α2β2). The top analogs (Asp-01, Asp-02, and Asp-03), designed as chalcone derivatives, were synthesized and characterized using IR, ¹H and ¹³C NMR, and ESI-MS. Their antihyperglycemic efficacy and hepatorenal safety were assessed in alloxan-nicotinamide-induced diabetic Wistar rats. Molecular dynamics (MD) simulations validated binding stability.

All derivatives complied with Lipinski's rule and showed superior LD₅₀ values (2100 mg/kg) versus metformin (>680 mg/kg) and co-crystallized standards (1000 and 400 mg/kg). Docking (-5.06 to -7.95 kcal/mol) and MM/GBSA energies (-46.8 to -66.7 kcal/mol) indicated stable α2β1/α2β2 binding. Asp-02 demonstrated the highest antihyperglycemic response (82.2-85.4%) compared to Asp-03 (48.2-65.5%) and metformin (48.7-55.1%). Treatment with Asp-02 and Asp-03 significantly improved body weight and normalized SGOT, SGPT, ALP, urea, and creatinine levels (p < 0.05). A 200 ns MD simulation confirmed ASP-02's stable binding at the AMPK ADaM site.

Asp-02 emerged as the lead compound exhibiting a favourable electrostatic balance, strong electronic stability, potent antihyperglycemic efficacy, and notable hepatorenal protection, establishing aspalathin-inspired chalcone analogs as promising AMPK activators for the safe and effective management of type 2 diabetes.