AMPK Activation by 2′-Hydroxy-2,4,5-Trimethoxychalcone Derivatives in Podocyte Cells

Activating AMP-activated protein kinase (AMPK) using chalcones has emerged as a potential therapeutic strategy for managing diabetes mellitus (DM) and diabetic nephropathy. This research focuses on discovering new chalcone derivatives with a stronger ability to stimulate AMPK in podocytes compared to 2′-hydroxychalcones 1, 2, and 3 reported from the earlier research. The results show that hydrogenated products (4–6) cannot exhibit considerably improved activity. Additionally, 2′-hydroxychalcone bearing 2,4,5-triethoxy groups on the B-ring (10) and 2,4,5-trimethoxychalcones bearing 2′,4′-, 2′,5′-, or 2′,6′-dimethoxy groups on the A-ring (17–19) demonstrate potent AMPK activation with fold changes of 2.69, 2.36, 3.22, and 2.17, respectively, surpassing both the reference compound 1 (1.28) and metformin (1.88). The structure–activity relationship shows that inserting dimethoxy groups on the A-ring can strengthen the activity better than without inserting any group or inserting other moieties such as hydroxy, methylenedioxy, amino, trifluoromethyl, bromo, acetyl, 2,3-dihydro-1,4-dioxin ring, and benzene ring. Notably, 2,4,5-trimethoxychalcone 23 possessing 2′,4′,5′-trimethoxy groups, bis-chalcones 35 and 36, and tris-chalcone 37 is poorly soluble in the experiments. Compound 18 exhibits more potent activity than compounds 2 and 3 (2.48 and 2.73, respectively); therefore, it would be a promising candidate for further studies on AMPK-stimulating activity.