Design, synthesis, and biological evaluation of 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinones as a new series of AMPKɑ1β1γ1 activators.

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) plays a key role in maintaining whole-body homeostasis and has been regarded as a therapeutic target for the treatment of diabetic nephropathy (DN). Herein, a series of 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinone derivatives is reported as AMPKɑ1β1γ1 activators. The in vitro biological assay demonstrated that compounds 12k (EC50 [AMPKα1γ1β1] = 180 nM) and 13q (EC50 [AMPKα1γ1β1] = 2 nM) displayed significant enzyme activation. Mechanism studies indicated that both compounds reduced the levels of reactive oxygen species in a rat kidney fibroblast cell line (NRK-49F) stimulated by transforming growth factor-β and induced early apoptosis of NRK-49F cells at 10 μM. Molecular docking studies suggested that 13q exhibited critical hydrogen-bond interactions with the critical amino acid residues Lys29, Lys31, Asn111, and Asp88 at the binding site of the AMPK protein. These results enrich the structure pool of AMPK activators and provide novel lead compounds for the subsequent development of compounds with a promising therapeutic potential against DN.