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.