N 10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress

• Published in: Chemical biology & drug design Vol. 94; no. 3; pp. 1680 - 1693
• Main Authors: Keynes, Robert G, Karchevskaya, Anastasia, Riddall, Dieter, Griffiths, Charmaine H, Bellamy, Tomas C, Chan, A W Edith, Selwood, David L, Garthwaite, John
• Format: Journal Article
• Language: English
• Published: England 01-09-2019
• Subjects: Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacology; Brain; Chromans - pharmacology; Drug Evaluation, Preclinical; Humans; Lipid Peroxidation - drug effects; Models, Molecular; Molecular Structure; Neurodegenerative Diseases - drug therapy; Nitric Oxide - metabolism; Oxidation-Reduction; Oxidative Stress - drug effects; Phenothiazines - chemistry; Phenothiazines - pharmacology; Protective Agents - chemistry; Protective Agents - pharmacology; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Vitamin E - pharmacology; phenothiazine; antioxidant; nitric oxide; ferroptosis; XED; neurodegeneration; lipid peroxidation
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13572

During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure-activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure-activity relationships. A representative compound N-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-10H-phenothiazine-10-carboxamide (DT-PTZ-C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30- to 100-fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug-like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress.