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

Hua Cheng, Lu Yang, Hong-Fu Liu, Rui Zhang, Cheng Chen, Yuan Wu, Wen Jiang

Bioorganic & medicinal chemistry letters 2020 Aug 15

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Mitochondrial complex III is one of the most promising targets for a number of pharmaceuticals and fungicides. Due to the wide-spreaduse 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 Qo site of complex III. We believe this work will be valuable for the preparation and discovery of more complex III inhibitors. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Hua Cheng, Lu Yang, Hong-Fu Liu, Rui Zhang, Cheng Chen, Yuan Wu, Wen Jiang. N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide as a new inhibitor of mitochondrial complex III: Synthesis, biological evaluation and computational simulations. Bioorganic & medicinal chemistry letters. 2020 Aug 15;30(16):127302