Design, synthesis, and biological evaluation of 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinones as a new series of AMPKα1β1γ1 activators

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 AMPK alpha 1 beta 1 gamma 1 activators. The in vitro biological assay demonstrated that compounds 12k (EC50[AMPK alpha 1 gamma 1 beta 1] = 180 nM) and 13q (EC50[AMPK alpha 1 gamma 1 beta 1] = 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-beta and induced early apoptosis of NRK-49F cells at 10 mu M. 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.

Automated summary

A series of compounds containing 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinone derivatives were reported as AMPK activators, with compounds 12k and 13q showing significant enzyme activation and ability to reduce reactive oxygen species levels, inducing cell apoptosis.