Computer-Assisted Proposition of Promising Aryloxyacetic Acid Derivatives as HPPD Inhibitors

A series of aryloxyacetic acid derivatives have demonstrated promising herbicidal performance by inhibition of the hydroxyphenylpyruvate deoxygenase (HPPD) enzyme. We hereby applied quantitative structure-activity relationship (QSAR) and docking strategies to model and chemically understand the bioactivities of these compounds and subsequently propose unprecedented analogues aiming at improving the herbicidal and environmental properties. Bulky halogens at the 2-, 3-, 4-, and 6-positions of an aromatic ring, CF₃ in 4-position, and the 2-NO₂ group in a phenyl ring appear to favor the HPPD inhibition. At the same time, Me and OMe substituents contribute to decreasing the pK_i values. Accordingly, a few compounds were proposed and the candidate with 2,4,6-triBr substituents demonstrated an estimated pK_i similar to those of the best library compounds. This finding was corroborated by the docking scores of the ligand-enzyme interactions. In addition, the high calculated lipophilicity of some proposed agrochemicals suggests that they should have low soil mobility and, therefore, are not prone to easily leach out and reach groundwater, despite causing other ecological issues.