Study of two combined series of triketones with HPPD inhibitory activity by molecular modelling

Triketones are suitable compounds for 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition and are important compounds for eliminating agricultural weeds. We report herein quantitative structure-activity relationship (QSAR) modelling and docking studies for a series of triketone-quinoline hybrids and 2-(aryloxyacetyl)cyclohexane-1,3-diones with the aim of proposing new chemical candidates that exhibit improved performance as herbicides. The QSAR models obtained were reliable and predictive (average r², q², and r²_pred of 0.72, 0.51, and 0.71, respectively). Guided by multivariate image analysis of the PLS regression coefficients and variable importance in projection scores, the substituent effects could be analysed, and a promising derivative with R¹ = H, R² = CN, and R³ = 5,7,8-triCl at the triketone-quinoline scaffold (P18) was proposed. Docking studies demonstrated that π-π stacking interactions and specific interactions between the substituents and amino acid residues in the binding site of the Arabidopsis thaliana HPPD (AtHPPD) enzyme support the desired bioactivity. In addition, compared to a benchmark commercial triketone (mesotrione), the proposed compounds are more lipophilic and less mobile in soil rich in organic matter and are less prone to contaminate groundwater.