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

Abstract The cytochrome bc 1 complex (the bc 1 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 bc 1 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 bc 1 complex). Further studies confirmed that 3e′ , a representative compound in this paper, was identified as an inhibitor of the bc 1 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 bc 1 complex. Consequently, we harbor the idea that this paper can provide a solid platform for synthesis and discovery of other bc 1 complex inhibitors.