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 I-5 (2.23 μg/mL), I-6 (2.15 μg/mL), I-9 (0.07 μg/mL), and I-11 (0.81 μg/mL) showed better in vitro activity against Rhizoctonia solani than that of trifloxystrobin (4.88 μg/mL). Especially, I-9 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 I-1, I-3, and I-9 showed excellent in vivo activity against R. solani at 200 μg/mL. The IC₅₀ of the R. solani SDH (RsSDH) enzyme of compound I-9 was 0.35 μg/mL, which was near that of fluxapyroxad (0.28 μg/mL). The high potency of I-9 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 I-9 being able to act as a SDHI. Our studies supported that I-9 was a promising SDH-based fungicide highly active compound deserving of further study.

fungicidal activity; oxime ether; rational design; succinate dehydrogenase inhibitor.