Synthesis,biochemical evaluation and computational simulations of new cytochrome bc1 complex inhibitors based on N-(4-aryloxyphenyl)phthalimides

The cytochrome bc1complex(the bc1complex or complex Ⅲ) is an attractive target for the discovery of numerous pharmaceuticals and pesticides. In order to identify new lead structures for this target, a new series of molecules, N-(4-aryloxyphenyl)phthalimides, were designed and synthesized in a straightforward manner. Our design strategy was to introduce a 4-aryloxyphenyl group, a fragment which exhibited promising bc1complex-inhibiting properties, into the aryl group of the valuable N-arylphthalimide backbone. Afterward, the biochemical evaluation of the newly synthesized compounds was carried out,and the results implied that several compounds demonstrated good activities against succinatecytochrome reductase(SCR, a mixture of mitochondrial complex Ⅱ and the bc1complex). Further studies confirmed that 3e’, a representative compound in this paper, was identified as an inhibitor of the bc1complex. Furthermore, computational simulations were also performed to better understand binding of 3e’ to the enzyme complex, which indicated that 3e’ should bind to the Qosite of the bc1complex.Consequently, we harbor the idea that this paper can provide a solid platform for synthesis and discovery of other bc1complex inhibitors.