Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury

Abstract

Targeting RIPK1 is a promising strategy for the treatment or alleviation of acute lung injury (ALI). SZM594, a benzothiazole compound previously developed by our research group, possessed good dual-targeting receptor-interacting protein kinase 1 (RIPK1) and RIPK3 activity and anti-necroptosis activity as well as acceptable in vivo efficacy. In this study, the cyclopropyl moiety of SZM594 was modified based on a structure-based design strategy. The resulting cyclohexanone-containing analogue 41 improved the selectivity toward RIPK1 over RIPK3 and the anti-necroptosis activity was also increased compared with those of SZM594. More importantly, compound 41 could inhibit the tumor necrosis factor-α (TNF-α) expression in lipopolysaccharide (LPS)-induced peritoneal macrophage cell model, and significantly alleviate LPS-induced ALI in a mouse model. This compound could significantly inhibit the expressions of the phosphorylation of RIPK1 and down-stream RIPK3 and mixed lineage kinase domain-like protein (MLKL). Thus, these cyclohexanone-containing benzothiazole analogues represent promising lead structures for the discovery of novel protective agents of ALI.