Imidazo[1,2-a]pyridine Derivatives as AMPK Activators: Synthesis, Structure-Activity Relationships, and Regulation of Reactive Oxygen Species in Renal Fibroblasts

Abstract

Adenosine 5'-monophosphate activated protein kinase (AMPK) has emerged as a promising target for the discovery of drugs to treat diabetic nephropathy (DN). Herein, a series of imidazo[1,2-a]pyridines were designed and synthesized. Among them, the active compound (EC₅₀ =11.0 nM) showed good enzyme activation and molecular docking results showed hydrogen bonding interactions with the key amino acids Asn111 and Lys29 in the active site. Meanwhile, further cellular level experiments revealed that it could reduce reactive oxygen species (ROS) levels in NRK-49F cells induced by high glucose, and Western Blot experiments also demonstrate that it can increase the levels of p-AMPK and p-ACC and decrease the levels of TGF-β1. The results of this study extend the structural types of AMPK activators and provide novel lead compounds for the subsequent development.

Keywords: AMPK; activators; imidazo[1,2-a]pyridines; reactive oxygen species; renal fibroblasts.