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Issue 3, 2017
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Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I

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Abstract

By probing the quinone substrate binding site of mitochondrial complex I with a focused set of quinazoline-based compounds, we identified substitution patterns as being critical for the observed inhibition. The structure activity relationship study also resulted in the discovery of the quinazoline 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (EVP4593) as a highly potent inhibitor of the multisubunit membrane protein. EVP4593 specifically and effectively reduces the mitochondrial complex I-dependent respiration with no effect on the respiratory chain complexes II–IV. Similar to established Q-site inhibitors, EVP4593 elicits the release of reactive oxygen species at the flavin site of mitochondrial complex I. Recently, EVP4593 was nominated as a lead compound for the treatment of Huntingtons disease. Our results challenge the postulated primary mode-of-action of EVP4593 as an inhibitor of NF-κB pathway activation and/or store-operated calcium influx.

Graphical abstract: Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I

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Publication details

The article was received on 26 Nov 2016, accepted on 17 Feb 2017 and first published on 20 Feb 2017


Article type: Research Article
DOI: 10.1039/C6MD00655H
Citation: Med. Chem. Commun., 2017,8, 657-661
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    Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I

    R. Krishnathas, E. Bonke, S. Dröse, V. Zickermann and H. R. Nasiri, Med. Chem. Commun., 2017, 8, 657
    DOI: 10.1039/C6MD00655H

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