Design and Syntheses of Proherbicides Targeting 4-Hydroxyphenylpyruvate Dioxygenase

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is regarded as a crucial target in the domain of herbicide discovery. Herein, we adopted the proherbicides concept, based on the initially discovered lead compound II-aa. Our group has designed four derivatives by incorporating alkyl, carbonyl ester, sulfonyl ester, and phosphate ester fragments. Although these derivatives did not exhibit very strong inhibitory activity against HPPD in vitro, and in vivo studies demonstrated their efficacy in suppressing HPPD activity. This was demonstrated by a reduction in HPPD protein levels and the emergence of significant bleaching symptoms in treated plants. Among these derivatives, the acetyl (III-ag), cyclopropyl carbonyl (III-ak), and pyridine-sulfonyl (III-bm) substituted derivatives demonstrated herbicidal activity that surpassed that of II-aa, exhibiting complete control over nine weed species at a concentration of 120 g of active ingredient per hectare (g ai/ha). It is worth noting that a dose of 30 g ai/ha was sufficient to achieve complete control of seven weed species. It is worth noting that one compound, III-ay (diethylamino carbonyl), exhibited selective inhibition of the growth of six weed species by over 90% at 30 g ai/ha while demonstrating no adverse effects on the normal growth of crops such as corn, wheat, and peanuts. A structure–activity relationship study demonstrated that carbonyl ester derivatives exhibited reduced herbicidal activity relative to their sulfonyl ester counterparts yet demonstrated enhanced crop tolerance. The results of our research indicate that the proherbicide approach has the potential to significantly enhance the efficacy and selectivity of herbicides. This strategy is poised to play a pivotal role in the advancement of next-generation herbicides.