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

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. (C) 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.