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.
Highlights
Lipid peroxidation is a key factor in numerous disease states where oxidative stress has been implicated, including neurodegenerative disorders (Hambright, Fonseca, Chen, Na, & Ran, 2017) such as motor neurone disease (Cacabelos et al, 2014), multiple sclerosis (Hu et al, 2018)
A form of regulated cell death that is initiated by oxidative perturbations of the intracellular microenvironment and which can be inhibited by iron chelators and lipophilic antioxidants (Galluzzi et al, 2018; Gaschler & Stockwell, 2017)
A set of compounds based upon the phenothiazine structure of the most potent inhibitors were selected using similarity and substructure searching
Summary
Lipid peroxidation is a key factor in numerous disease states where oxidative stress has been implicated, including neurodegenerative disorders (Hambright, Fonseca, Chen, Na, & Ran, 2017) such as motor neurone disease (Cacabelos et al, 2014), multiple sclerosis (Hu et al, 2018). Other conditions such as cardiovascular disease, asthma and diabetes (Ozbayer et al, 2018). The brain is thought to be susceptible to oxidative stress because of its high unsaturated lipid content and mitochondrial activity, amongst other factors (Cobley, Fiorello, & Bailey, 2018)
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