Diversity-oriented optimization of 1,2,4-oxadiazole pharmacophore for the discovery of nematicides

Plant-parasitic nematodes are primary pathogen that cause global crop yield losses, the economic cost to global agriculture is $157 billion a year. With the prohibition of highly toxic chemical nematicides, there are few nematicides available for prevention and control of nematodes. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a new broad-spectrum nematicide with good control effects against various nematodes. In order to discover new and environmentally friendly chemical nematicides, five series of 43 novel compounds containing 1,2,4-oxadiazole pharmacophore were designed and synthesized by diversity-oriented optimization. The nematocidal activity of the target compounds against Bursaphelenchus xylophilus, Aphelenchoides besseyi and Ditylenchus destructor were systematically evaluated. Bioassay results show that E3((E)-1-(4-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-N-(4-(trifluoromethyl)phenyl)methanimine) had good nematicidal activity, and its corrected mortality rates were 85.7%, 75.9% and 83.4% to three nematodes at 200 μg/mL, respectively, which was superior to tioxazafen (40.7%, 70.7%, 38.5%). The preliminary mechanisms indicate that compound E3 can inhibit the egg hatching rate, the feeding, and reproductive capabilities of B. xylophilus, and then affect the population of nematodes. In addition, compound E3 can significantly enhance oxidative stress in B. xylophilus. This study revealed that compound E3 has the potential to be a lead candidate for the development of new nematicides.