N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide as a new inhibitor of mitochondrial complex III: Synthesis,biological evaluation and computational simulations

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.