Design, Synthesis, and Nematicidal Activity of Novel Amide Derivatives Containing an 1,2,4/1,3,4-Oxadiazole Moiety against <i>Bursaphelenchus xylophilus</i>

To discover novel structural nematicides, 79 amide compounds containing 1,2,4/1,3,4-oxadiazole moiety were designed, synthesized, and evaluated for nematicidal efficacy against second-stage juveniles of <i>Bursaphelenchus xylophilus</i> (<i>B. xylophilus</i>). Notably, some compounds exhibited superior nematicidal efficacy, for example, the LC₅₀ values of compounds <b>11</b>, <b>39</b>, <b>40</b>, <b>48</b>, <b>49</b>, <b>51</b>, <b>52</b>, and <b>54</b> were 7.4, 31.0, 35.3, 10.3, 12.7, 6.9, 21.5, and 52.2 mg/L, respectively, with nematicidal activities significantly surpassing that of tioxazafen (79.3 mg/L). Compound <b>51</b> exhibited multifaceted nematicidal activity through suppression of motility, feeding, and reproduction, combined with induction of oxidative stress. Compound <b>51</b> significantly reduced nematode protein content and impaired antioxidant capacity. Meanwhile, compound <b>51</b> demonstrates superior binding energy and interaction mode with succinate dehydrogenase (SDH), showing potent SDH inhibition (IC₅₀ = 15.0 μmol/L). Therefore, compound <b>51</b>, which may become a potential SDH inhibitor, interferes with nematode energy metabolism by inhibiting SDH activity, resulting in nematode death.