Design, syntheses, and kinetic evaluation of 3-(phenylamino)oxazolidine-2,4-diones as potent cytochrome bc1 complex inhibitors

The cytochrome bc1 complex (EC 1.10.2.2, bc1) is one of the most promising targets for new drugs and agricultural fungicides. Among the existing bc1 complex inhibitors specifically binding to the Qo site, oxazolidinedione derivatives have attracted great attention. With the aim to understand the substituent effects of oxazolidinedione derivatives on the inhibition activity against the bc1 complex, a series of new oxazolidinedione derivatives were designed, synthesized, and biologically evaluated. The further inhibitory kinetics studies against porcine succinate–cytochrome c reductase (SCR) revealed that the representative compound 8d and famoxadone are both non-competitive inhibitors with respect to the substrate cytochrome c, but competitive inhibitors with respect to substrate decylubiquinol (DBH2). In addition, compound 8d and famoxadone showed, respectively, 35-fold and 15-fold greater inhibitory activity against the porcine SCR than the porcine bc1 complex, indicating that these two inhibitors not only inhibited the activity of the bc1 complex, but possibly affect the interaction between the complex II and the bc1 complex. To our knowledge, this is the first report that famoxadone and its analogs have effects on the interaction between the complex II and the bc1 complex.

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