Design, Synthesis, and Herbicidal Activity of -Benzyl-5-cyclopropyl-isoxazole-4-carboxamides.

Based on the structures of isoxaflutole (IFT) and -isobutyl--(4-chloro-benzyl)-4-chloro-2-pentenamide, a series of -benzyl-5-cyclopropyl-isoxazole-4-carboxamides was designed by connecting their pharmacophores (, a multitarget drug design strategy). A total of 27 -benzyl-5-cyclopropyl-isoxazole-4-carboxamides were prepared from 5-cyclopropylisoxazole-4-carboxylic acid and substituted benzylamines, and their structures were confirmed by NMR and MS. Laboratory bioassays indicated that showed 100% inhibition against and at a concentration of 10 mg/L, better than the positive control butachlor (50% inhibition for both weeds). A strong growth inhibition was observed, but a typical bleaching phenomenon of IFT could not be observed in the Petri dish assay. displayed excellent postemergence herbicidal activity against and at a rate of 150 g/ha, and bleaching symptoms were observed in the leaves of treated weeds. The bleaching effect of treated by could be reversed by adding homogentisate. Enzymatic bioassays indicated that could not inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPD) activity, but , an isoxazole ring-opening product of , could inhibit HPPD activity with an EC value of 1.05 μM, similar to that of mesotrione (with an EC value of 1.35 μM). Detailed discussion about observed herbicidal symptoms is provided in the Results and Discussion section. This investigation provided a proof-of-concept foundation that a multitarget drug design strategy could be applied in agrochemical research.