Mitochondrion-Targeted Triphenylphosphonium-Based Kresoxim-Methyl Analogues: Synthesis, Fungicidal Activity, and Action Mechanism Approach

β-Methoxyacrylate fungicides as complex III Q_o site inhibitors play a crucial role in the control of crop diseases. In this study, the triphenylphosphonium (TPP)-driven mitochondrion-targeting strategy was used to modify the kresoxim-methyl scaffold at the toxicophore or side chain to develop novel mitochondrion-targeted Q_oI fungicides. These kresoxim-methyl analogues exhibited different fungicidal activities, depending on the position of TPP conjugation and the linker length. Among them, 2A-5 and 2C-4 showed excellent characteristics superior to kresoxim-methyl as candidate fungicides, in which the activity enhancement against Phytophthora capsici was the most remarkable, with an EC₅₀ value of about 5 μM. Notably, both hyphal and zoospore structures of the pathogens were severely damaged after treatment with them. The action mechanism approach revealed that they might cause a significant decrease in ATP synthesis and ROS outbreak in different ways. The results also provided a new insight into the contribution of targeting group TPP to the fungicidal activity in TPP-driven fungicides.

cytochrome bc1 complex inhibitor; fungicidal activity; kresoxim-methyl analogues; mitochondrion-targeted fungicides; triphenylphosphonium (TPP).