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

中文翻译：

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N-苄基-5-环丙基-异恶唑-4-羧酰胺的设计，合成及除草活性

基于异氟丁环（IFT）和N-异丁基-N-（4-氯苄基）-4-氯-2-戊酰胺的结构，设计了一系列N-苄基-5-环丙基-异恶唑-4-羧酰胺通过连接其药效团（即多目标药物设计策略）。由5-环丙基异恶唑-4-羧酸和取代的苄胺总共制备了27种N-苄基-5-环丙基-异恶唑-4-羧酰胺，其结构通过NMR和MS证实。实验室生物测定表明，I-26显示出对100％抑制马齿苋和苘麻浓度为10 mg / L，优于阳性对照丁草胺（两种杂草均抑制50％）。观察到强烈的生长抑制，但是在培养皿测定中未观察到典型的IFT漂白现象。I-05以150 g / ha的速率显示出优异的除草cru和嗜碱芽孢杆菌的除草活性，并且在处理过的杂草叶片中观察到漂白症状。I-05处理的莱茵衣藻的漂白作用可以通过添加尿黑素来逆转。酶促生物测定表明，I-05不能抑制4-羟苯基丙酮酸双加氧酶（HPPD）的活性，而II-05I-05的异恶唑开环产物可以抑制HPPD活性，其EC ₅₀值为1.05μM，与甲基磺草酮相似（EC ₅₀值为1.35μM）。结果和讨论部分提供了有关所观察到的除草症状的详细讨论。这项研究提供了概念证明的基础，即多目标药物设计策略可用于农业化学研究。