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
  • 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: [email protected].
  • 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
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.