Molecular Modeling Study and Proposition of Novel Diaryl Ether Derivatives as Protoporphyrinogen Oxidase Inhibitors

Protoporphyrinogen oxidase (PPO) inhibitors are an effective class of herbicides with broad-spectrum applications. Recently, auspicious diaryl ether derivatives have been developed as PPO inhibitors and, herein, we report the optimization of these compounds guided by in silico approaches. First, the herbicidal activities of 28 substituted diaryl ethers were modeled using multivariate image analysis applied to quantitative structure–activity relationships (MIA-QSAR), resulting in a reliable and highly predictive model (r² = 0.97, q² = 0.84, and r²_pred = 0.96). The model regression parameters were then applied to predict the bioactivities of proposed derivatives, whose design was oriented by MIA plots of variable importance in projection (VIP) scores and PLS regression coefficients (b); these contour maps give insight into how much and how (decreasing or increasing) the substituents affect the biological activities, respectively. Finally, docking studies and molecular dynamics validated the MIA-QSAR predictions and explained the ligand–enzyme interactions responsible for the predicted effects. Overall, a proposed fluorinated derivative demonstrated higher potential than the library compounds, and a possible synthetic route was suggested to obtain it.