Structure–Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury

Sepsis-associated acute kidney injury (AKI) is a serious
clinical
problem without effective drugs. Inhibition of sirtuin 5 (SIRT5) has
been confirmed to protect against AKI, suggesting that SIRT5 inhibitors
might be a promising therapeutic approach for AKI. Herein, structural
optimization was performed on our previous compound 1 (IC50 = 3.0 μM), and a series of 2,4,5-trisubstituted
pyrimidine derivatives have been synthesized. The structure–activity
relationship (SAR) analysis led to the discovery of three nanomolar
level SIRT5 inhibitors, of which the most potent compound 58 (IC50 = 310 nM) was demonstrated to be a substrate-competitive
and selective inhibitor. Importantly, 58 significantly
alleviated kidney dysfunction and pathological injury in both lipopolysaccharide
(LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice.
Further studies revealed that 58 regulated protein succinylation
and the release of proinflammatory cytokines in the kidneys of septic
AKI mice. Collectively, these results highlighted that targeting SIRT5
has a therapeutic potential against septic AKI.