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

The cytochrome bc₁ complex (the bc₁ complex 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 bc₁ complex-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 succinate-cytochrome reductase (SCR, a mixture of mitochondrial complex II and the bc₁ complex). Further studies confirmed that 3e′ a representative compound in this paper, was identified as an inhibitor of the bc₁ complex. Furthermore, computational simulations were also performed to better understand binding of 3e′ to the enzyme complex, which indicated that 3e′ should bind to the Q_o site of the bc₁ complex. Consequently, we harbor the idea that this paper can provide a solid platform for synthesis and discovery of other bc₁ complex inhibitors.