Design, synthesis and herbicidal activity of novel 2,4-dichlorobenzene-3-morpholine derivatives as potential hydroxyphenylpyruvate dioxygenase inhibitors

Abstract

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is a key target for herbicide development, especially in the management of herbicide-resistant weeds. However, many existing HPPD inhibitors suffer from poor crop selectivity, limiting their widespread application. To address this problem, a series of novel 2,4-dichlorobenzene-3-morpholine derivatives were designed and synthesized. Greenhouse activity tests demonstrated that a large class of molecules obviously inhibited dwarfing in the tested weeds. Notably, compound B₂ exhibited superior herbicidal activity against broadleaf weeds, such as Abutilon theophrasti, Zinnia elegans, and Portulaca oleracea, at 9.375 g ai/ha, which is superior to that of the widely used herbicide mesotrione. Moreover, compared with mesotrione, compound B₂ showed no obvious injury on the growth of peanuts at 150 g ai/ha and was safer for peanuts, even at the higher dosage of 600 g ai/ha. These results suggest that B₂ is a promising new candidate herbicide for use in peanut fields. Molecular simulations of the representative molecule further revealed a binding mode that fit into the active site of HPPD, similar to most known HPPD inhibitors. Met338 in P. oleracea HPPD plays a crucial role in the binding of compound B₂, whereas Ile453 and Ile455 in peanut HPPD may contribute to reduced inhibition in peanuts. Additionally, the entry pathways of compounds, along with their polarity and lipophilicity, could increase their selectivity for different plant species. This study provides valuable insights for the future development of highly selective HPPD inhibitors.