Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke …
W Yang, X Liu, C Song, S Ji, J Yang, Y Liu… - European Journal of …, 2021 - Elsevier
W Yang, X Liu, C Song, S Ji, J Yang, Y Liu, J You, J Zhang, S Huang, W Cheng, Z Shao, L Li…
European Journal of Medicinal Chemistry, 2021•ElsevierFerroptosis 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 …
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 …
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.
Elsevier
