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Concise Synthesis of 1,4‐Benzoquinone‐Based Natural Products as Mitochondrial Complex I Substrates and Substrate‐Based Inhibitors

A short, efficient one‐step synthesis of 2‐methyl‐5‐(3‐methyl‐2‐butenyl)‐1,4‐benzoquinone, a natural product from Pyrola media is described. The synthesis is based on a direct late C−H functionalization of the quinone scaffold. The formation of the natural product was confirmed by means of 2D‐NMR spectroscopy. Additional derivatives were synthesized and tested alongside the natural product as potential substrate and substrate‐based inhibitors of mitochondrial complex I (MCI). The structure‐activity relationship study led to the discovery of 3‐methylbuteneoxide‐1,4‐anthraquinone (1 i), an inhibitor with an IC50 of 5 μM against MCI. The identified molecule showed high selectivity for MCI when tested against other quinone‐converting enzymes, including succinate dehydrogenase, and the Na (+)‐translocating NADH:quinone oxidoreductase. Moreover, the identified inhibitor was also active in cell‐based proliferation assays. Therefore, 1 i can be considered as a novel chemical probe for MCI.