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

Abstract

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 Qo 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.