Discovery of cytochrome bc1 complex inhibitors inspired by the natural product karrikinolide

Abstract

The cytochrome bc₁ complex (cyt bc₁ or complex III) is a promising target of numerous antibiotics and fungicides. With an aim to indentify new lead structures for the bc₁ complex, a series of novel inhibitors were discovered from the natural product karrikinolide for the first time. Extensive screening results suggested variable inhibitory activities of these compounds against succinate-cytochrome reductase [SCR, a mixture of respiratory complex II (SQR) and complex III (the bc₁ complex)], implying the essential role of a 4-substituted phenyl group for the high potency. Exceptionally, compound 12g showed excellent inhibition potency having an IC₅₀ value in the sub-micromolar range, demonstrating its higher potency than the commercial control amisulbrom by over two orders of magnitude. Further experiments inferred that these newly prepared compounds mainly target the bc₁ complex. Seemingly, this work has presented a new lead scaffold for further development of bc₁ complex inhibitors.