Synthesis and structure-activity optimization of hydroxypyridinones against rhabdomyolysis-induced acute kidney injury

The important role of accumulated iron is well recognized in the pathophysiology of rhabdomyolysis-induced acute kidney injury (RM-AKI). Our previous work further confirmed the labile iron triggered iron-dependent ferroptosis thus leading to the renal failure. In view of this, a series of hydroxypyridinones (HOPOs) with excellent iron chelation capability have been designed and synthesized in this study. A lead compound 6k was identified with good ferroptosis inhibition (EC50 = 20 mu M) and no obvious cytotoxicity (CC50 > 100 mu M), indicating a good therapeutic window (safety index = CC50/EC50 > 5.00). Moreover, intraperitoneal treatment of 6k (10 mg/kg) displayed a superior protective effect than deferiprone (50 mg/kg) in glycerol-induced RM-AKI mice with alleviating kidney dysfunction and pathological injury, decreasing the renal iron level as well as downregulating the mRNA level of ferroptosis associated genes (Acls4 and Ptgs2). Also, 6k exhibited a good in vivo safety profile, even at single high dose up to 1 g/kg without inducing mortality or toxic symptoms. Importantly, 6k could significantly upregulate the protein hypoxia-inducible factor 1 alpha, possibly involving HIF pathway against the ferroptosis. These results collectively highlighted that the strategy of iron chelation and downstream ferroptosis inhibition has a therapeutic potential against RM-AKI.