Discovery of Aromatic Amide Derivatives Bearing Oxime Ethers Targeting Succinate Dehydrogenase

Based on analyzing the pharmacophore model of commercial succinate dehydrogenase inhibitor (SDHI) fungicides, a molecular database was reasonably designed for computer-aided molecular design, and the potential heterocyclic oxime-ether-containing skeleton was found for derivation. A fungicidal bioassay indicated that the EC₅₀ values of the compounds <b>I-5</b> (2.23 μg/mL), <b>I-6</b> (2.15 μg/mL), <b>I-9</b> (0.07 μg/mL), and <b>I-11</b> (0.81 μg/mL) showed better <i>in vitro</i> activity against <i>Rhizoctonia solani</i> than that of trifloxystrobin (4.88 μg/mL). Especially, <b>I-9</b> showed comparable activity to thifluzamide, with EC₅₀ of 0.07 μg/mL vs 0.06 μg/mL, and better activity than fluxapyroxad and boscalid, with EC₅₀ of 0.10 and 2.49 μg/mL, respectively. Like thifluzamide and fluxapyroxad, compounds <b>I-1</b>, <b>I-3</b>, and <b>I-9</b> showed excellent <i>in vivo</i> activity against <i>R. solani</i> at 200 μg/mL. The IC₅₀ of the <i>R. solani</i> SDH (RsSDH) enzyme of compound <b>I-9</b> was 0.35 μg/mL, which was near that of fluxapyroxad (0.28 μg/mL). The high potency of <b>I-9</b> against RsSDH was also reflected in a steeper dose-response tendency in the fluorescence quenching assay, and it was well-docked into the active site of the target enzyme SDH. Molecular docking and molecular dynamics studies have provided a reasonable explanation for compound <b>I-9</b> being able to act as a SDHI. Our studies supported that <b>I-9</b> was a promising SDH-based fungicide highly active compound deserving of further study.