Unraveling the structure-activity relationships of herbicide Metamifop polymorphs: Enhanced weed control efficacy

Agrochemical crystal engineering has emerged as a promising approach to enhance herbicide efficacy while reducing non-target environmental risks, yet the structure-activity relationships and soil microbial safety of herbicide polymorphs remain largely unexplored. Herein, we reported the selective preparation of two polymorphs of Metamifop, a widely used post-emergent herbicide, the differences in absorption and metabolism within the weeds, evaluated their performance via enzymatic assays, molecular dynamics simulations, and non-target toxicity tests. This study systematically evaluated the differences in absorption and metabolism of polymorphs among various weed species. The results showed that the absorption rate of polymorph A was higher and the metabolic rate was lower than that of polymorph B, which ensured that the polymorph A achieves a high steady-state drug concentration and long-lasting target inhibition within the weeds. Polymorph A exhibits 0.04 mol·min^-1·mg^-1 higher ACCase inhibitory activity and superior thermodynamic stability compared to polymorph B, which is attributed to its 7 kcal·mol^-1 higher binding affinity to the target enzyme as revealed by molecular dynamics simulations. Preliminary assessments of polymorphs herbicides on soil nitrogen-fixing bacteria were first conducted, which demonstrated that polymorph A inhibits Azotobacter vinelandii growth in a concentration-dependent manner, with no significant suppression of growth or nitrogen fixation activity observed below 100 mg·L^-1. This work not only provided a high-performance Metamifop crystalline candidate for sustainable weed control, but also offered a general framework for evaluating the environmental safety of agrochemical polymorphs, supporting the green innovation of agricultural chemical processes.