2. Academic Validation
  3. Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model

Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model

  • Eur J Med Chem. 2021 Jan 1:209:112842. doi: 10.1016/j.ejmech.2020.112842.
Wei Yang 1,  Xiaolong Liu 2,  Chunli Song 3,  Sen Ji 1,  Jianhong Yang 3,  Yang Liu 1,  Jing You 1,  Jie Zhang 1,  Shenzhen Huang 1,  Wei Cheng 1,  Zhenhua Shao 1,  Linli Li 4,  Shengyong Yang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; College of Medicine, Yan'an University, Yan'an, Shanxi, 716000, China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 4 Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: ysylilinli@sina.com.cn.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: yangsy@scu.edu.cn.
PMID: 33065375 DOI: 10.1016/j.ejmech.2020.112842
Abstract

Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of Ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC50 (half maximal effective concentration) value of 0.0005 μM in the erastin-induced HT1080 cell Ferroptosis model. In the MCAO (middle cerebral artery occlusion) ischemic stroke model, 51 presented an excellent therapeutic effect. This compound also displayed favorable pharmacokinetic properties, in particular, a good ability to permeate the blood-brain barrier. Overall, 51 could be a promising lead compound for the treatment of Ferroptosis related diseases and deserves further investigations.

Keywords

Ferroptosis inhibitor; Ischemic stroke; Promethazine derivatives; Structure-activity relationship.

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