Novel 2,4-thiazolidinedione derivatives as selective AMPKα1 activators for renal ischemia-reperfusion injury therapeutics.

AMP-activated protein kinase (AMPK) plays a key catalytic role in renal energy metabolism. Its activation confers renoprotection through regulating various downstream pathways. Critically, AMPKα2 activation can exacerbate renal injury by promoting uric acid deposition, highlighting the therapeutic advantage of highly selective AMPKα1 activation for renal ischemia-reperfusion injury (RIRI). Given these considerations, we established an effective screening platform to identify initial hits with AMPKα1 activity. Leveraging these hits, we designed and synthesized a series of thiazolidinedione derivatives as selective AMPKα1 activators. Among these, 22f demonstrated superior in vitro AMPKα1 activity (EC50 = 35.1 ± 1.20 nM) and selectivity (176-fold over AMPKα2), coupled with a significant protective effect in NRK-52E cells subjected to hypoxia-reoxygenation injury. Furthermore, in an RIRI mice model, 22f selectively activated renal AMPKα1, significantly attenuating serum creatinine and blood urea nitrogen levels. Notably, 22f outperformed the comparator 991 in alleviating kidney damage and reducing cellular infiltration. More importantly, our study provided compelling evidence that selective activation of AMPKα1 could effectively protect against RIRI pathogenesis. 22f thus emerged as a promising lead compound for the development of novel anti-RIRI therapeutics offering potent efficacy and improved safety profile.