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N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress.
Chem Biol Drug Des 2019; 94(3):1680-1693CB

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.

Authors+Show Affiliations

Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.Drug Discovery Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.Drug Discovery Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.Drug Discovery Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.Neural Signalling Group, The Wolfson Institute for Biomedical Research, University College London, London, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31127979

Citation

Keynes, Robert G., et al. "N10 -carbonyl-substituted Phenothiazines Inhibiting Lipid Peroxidation and Associated Nitric Oxide Consumption Powerfully Protect Brain Tissue Against Oxidative Stress." Chemical Biology & Drug Design, vol. 94, no. 3, 2019, pp. 1680-1693.
Keynes RG, Karchevskaya A, Riddall D, et al. N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress. Chem Biol Drug Des. 2019;94(3):1680-1693.
Keynes, R. G., Karchevskaya, A., Riddall, D., Griffiths, C. H., Bellamy, T. C., Chan, A. W. E., ... Garthwaite, J. (2019). N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress. Chemical Biology & Drug Design, 94(3), pp. 1680-1693. doi:10.1111/cbdd.13572.
Keynes RG, et al. N10 -carbonyl-substituted Phenothiazines Inhibiting Lipid Peroxidation and Associated Nitric Oxide Consumption Powerfully Protect Brain Tissue Against Oxidative Stress. Chem Biol Drug Des. 2019;94(3):1680-1693. PubMed PMID: 31127979.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N10 -carbonyl-substituted phenothiazines inhibiting lipid peroxidation and associated nitric oxide consumption powerfully protect brain tissue against oxidative stress. AU - Keynes,Robert G, AU - Karchevskaya,Anastasia, AU - Riddall,Dieter, AU - Griffiths,Charmaine H, AU - Bellamy,Tomas C, AU - Chan,A W Edith, AU - Selwood,David L, AU - Garthwaite,John, Y1 - 2019/06/12/ PY - 2019/02/18/received PY - 2019/05/15/revised PY - 2019/05/21/accepted PY - 2019/5/28/pubmed PY - 2019/5/28/medline PY - 2019/5/26/entrez KW - XED KW - antioxidant KW - ferroptosis KW - lipid peroxidation KW - neurodegeneration KW - nitric oxide KW - phenothiazine SP - 1680 EP - 1693 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 94 IS - 3 N2 - 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. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/31127979/N10_-carbonyl-substituted_phenothiazines_inhibiting_lipid_peroxidation_and_associated_nitric_oxide_consumption_powerfully_protect_brain_tissue_against_oxidative_stress L2 - https://doi.org/10.1111/cbdd.13572 DB - PRIME DP - Unbound Medicine ER -