Strobilurins are one of the most important natural products with fungicidal activities and well known for their novel action mode, broad fungicidal spectrum, lower toxicity against mammalian cells, and environmentally benign characteristics. Design and syntheses of strobilurin analogues therefore have attracted great attention in the field of agrochemistry. Previously, we successfully developed a new molecular design method of pharmacophore-linked fragment virtual screening (PFVS) and discovered a lead compound (E)-methyl-2-(2-(((3-(imino-(phenyl)methyl)phenyl)thio)methyl)phenyl)-3-methoxyacrylate (1). To discover new strobilurin analogues with higher fungicidal activity, the structural modification of compound 1 was carried out guided by bioisosterism. A series of benzophenone derivatives 2a–2j were synthesized, among which compound 2j with a Ki value of 1.89 nmol/L was identified as the most promising inhibitor of porcine cytochrome bc1 complex, 157-fold improved binding affinity compared to the commercially available bc1 inhibitor Azoxystrobin (AZ). In addition, most of the new compounds displayed excellent fungicidal activity against Sphaerotheca fuliginea at the concentration of 200 µmol/L. The present work indicates that strobilurin analogues containing benzophenone side chains may be the ideal leads for future fungicide discovery.