N¹⁰‐carbonyl‐substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress

Abstract

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.

Antiferroptotic Activity of Phenothiazine Analogues: A Novel Therapeutic Strategy for Oxidative Stress Related Disease

“…The lipid peroxyl radical is a key molecule during the onset of ferroptosis and the treatment with radical scavengers specific for lipid peroxyl radicals represents a promising pharmacologic approach to prevent ferroptosis. Phenothiazines were previously reported to show lipid peroxidation-preventing effects of ferroptosis that were considered to be due to their antioxidant functions. − Again, when MB was acetylated to eliminate its redox activity, it completely lost its ability to suppress lipid peroxidation despite glutathione depletion in RSL3-treated FRDA lymphocytes (Figure c, Table ). These findings support the interpretation that the MB/MV analogues function primarily as lipid peroxyl radical scavengers, contributing to the prevention of ferroptosis primarily by suppressing lipid peroxidation.…”

Phenothiazines: Nrf2 activation and antioxidant effects

“…TF, promethazine, methotrimeprazine, N‐Me‐PTZ, and chlorpromazine, Compounds 7 , 8 , 9 , 10 , 11 , respectively, in Table 1, are all able to significantly inhibit NO consumption in different experimental models. [ 37 ] Interestingly, unsubstituted PTZ has shown a 1000‐times more potent activity at inhibiting NO, than standard antioxidants such as trolox and edaravone. [ 37 ] The PTZ derivative 12 (Table 1) has been reported as a lipid peroxidation inhibitor as well as a cytoprotective agent.…”

“…[ 37 ] Interestingly, unsubstituted PTZ has shown a 1000‐times more potent activity at inhibiting NO, than standard antioxidants such as trolox and edaravone. [ 37 ] The PTZ derivative 12 (Table 1) has been reported as a lipid peroxidation inhibitor as well as a cytoprotective agent. [ 38 ] Although several PTZs exhibit antioxidant protection to erythrocytes against 2,2‐azobis(2‐ amidinopropane hydrochloride)‐induced hemolysis, Compound 12 exhibits a pro‐oxidant activity only at very high concentrations.…”

“…[ 37 ] In biological systems, PTZs exhibit antioxidant and pro‐oxidant effect depending on concentration and availability of reacting radicals, and in particularly Compound 6 , due to its ability to exhibit high potency in both simple antioxidant systems and hippocampal slices, has been suggested as a potential therapeutic agent for neurodegenerative disorders and other conditions associated with oxidative stress. [ 37 ]…”

“…[37] In biological systems, PTZs exhibit antioxidant and pro-oxidant effect depending on concentration and availability of reacting radicals, and in particularly Compound 6, due to its ability to exhibit high potency in both simple antioxidant systems and hippocampal slices, has been suggested as a potential therapeutic agent for neurodegenerative disorders and other conditions associated with oxidative stress. [37] TF, promethazine, methotrimeprazine, N-Me-PTZ, and chlorpromazine, Compounds 7, 8, 9, 10, 11, respectively, in Table 1, are all able to significantly inhibit NO consumption in different experimental models. [37] Interestingly, unsubstituted PTZ has shown a 1000-times more potent activity at inhibiting NO, than standard antioxidants such as trolox and edaravone.…”