Mitochondrial complex III is one of the most promising targets for a number of pharmaceuticals and fungicides. Due to the wide-spread use of complex III-inhibiting fungicides, a considerable increase of resistance has occurred worldwide. Therefore, inhibitors with novel scaffolds and potent activity against complex III are still in great demand. In this article, a new series of amide compounds bearing the diaryl ether scaffold were designed and prepared, followed by the biological evaluation. Gratifyingly, several compounds demonstrated potent activity against succinate-cytochrome c reductase (SCR, a mixture of mitochondrial complex II and complex III), with compound 3w possessing the best inhibitory activity (IC₅₀ = 0.91 ± 0.09 μmol/L). Additional studies verified that 3w was a new inhibitor of complex III. Moreover, computational simulations elucidated that 3w should bind to the Q_o site of complex III. We believe this work will be valuable for the preparation and discovery of more complex III inhibitors.

线粒体复合物III是许多药物和杀真菌剂最有希望的目标之一。由于复杂的抑制III族复合杀真菌剂的广泛使用，在世界范围内已经产生了很大的耐药性。因此，仍然强烈需要具有新颖支架和对复合物III有效活性的抑制剂。在本文中，设计并制备了一系列带有二芳基醚支架的酰胺化合物，然后进行了生物学评估。令人欣喜的是，几种化合物对琥珀酸-细胞色素c还原酶（SCR，线粒体复合物II和复合物III的混合物）表现出有效的活性，而化合物3w具有最佳的抑制活性（IC ₅₀ = 0.91±0.09μmol/ L）。其他研究证实3w是复合物III的新抑制剂。此外，计算模拟表明3w应与复合物III的Q _o位结合。我们相信这项工作对于制备和发现更复杂的III抑制剂将是有价值的。