Citation: Lijuan Xu, Ye Tu, Jiao Li, Wannian Zhang, Zhibin Wang, Chunlin Zhuang, Lei Xue. Structure-based optimizations of a necroptosis inhibitor (SZM594) as novel protective agents of acute lung injury[J]. Chinese Chemical Letters, ;2022, 33(5): 2545-2549. doi: 10.1016/j.cclet.2021.09.059 shu

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

Lijuan Xu ^{a, 1} ,
Ye Tu ^{b, 1} ,
Jiao Li ^{c, 1} ,
Wannian Zhang ^a ,
Zhibin Wang ^a ,
Chunlin Zhuang ^{a, e, *,} ,
Lei Xue ^{d, *,}

a.
School of Pharmacy, Second Military Medical University, Shanghai 200433, China
b.
Department of Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China
c.
Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
d.
Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200433, China
e.
Department of Chemistry, Fudan University, Shanghai 200433, China

zclnathan@163.com

tommyxuel@smmu.edu.cn

Received Date: 2 August 2021
Revised Date: 11 September 2021
Accepted Date: 17 September 2021
Available Online: 24 September 2021

Figures(3)

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.
- Acute lung injury,
- RIPK1,
- RIPK3,
- Necroptosis,
- Design
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