Design and synthesis of sulfonamide phenothiazine derivatives as novel ferroptosis inhibitors and their therapeutic effects in spinal cord injury.

Autor: Bai X; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Yang Y; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Luo Y; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Zhang D; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Zhai T; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Hu Q; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Zhang N; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Dai Q; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Liang J; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Bian H; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China., Liu X; Yan'an Small Molecule Innovative Drug R&D Engineering Research Center, School of Medicine, Yan'an University, Yan'an, China. Electronic address: liuxiaolong@yau.edu.cn.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Jul; Vol. 148, pp. 107458. Date of Electronic Publication: 2024 May 19.
DOI: 10.1016/j.bioorg.2024.107458
Abstrakt: Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure-activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC 50  = 0.001 μM) and demonstrated a low hERG inhibition activity (IC 50  > 30 μM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b, a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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