Design, Synthesis, and Herbicidal Activity of <i>N</i>-Benzyl-5-cyclopropyl-isoxazole-4-carboxamides

Abstract

Based on the structures of isoxaflutole (IFT) and <i>N</i>-isobutyl-<i>N</i>-(4-chloro-benzyl)-4-chloro-2-pentenamide, a series of <i>N</i>-benzyl-5-cyclopropyl-isoxazole-4-carboxamides was designed by connecting their pharmacophores (<i>i.e.</i>, a multitarget drug design strategy). A total of 27 <i>N</i>-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 <b>I-26</b> showed 100% inhibition against <i>Portulaca oleracea</i> and <i>Abutilon theophrasti</i> 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. <b>I-05</b> displayed excellent postemergence herbicidal activity against <i>Echinochloa crusgalli</i> and <i>A. theophrasti</i> at a rate of 150 g/ha, and bleaching symptoms were observed in the leaves of treated weeds. The bleaching effect of <i>Chlamydomonas reinhardtii</i> treated by <b>I-05</b> could be reversed by adding homogentisate. Enzymatic bioassays indicated that <b>I-05</b> could not inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPD) activity, but <b>II-05</b>, an isoxazole ring-opening product of <b>I-05</b>, could inhibit HPPD activity with an EC₅₀ value of 1.05 μM, similar to that of mesotrione (with an EC₅₀ 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.