Design of environmentally friendly neonicotinoid insecticides with bioconcentration tuning and Bi-directional selective toxic effects

A 3D-QSAR model was established with CoMSIA to characterize neonicotinoid insecticides. LgBCF values were used as the dependent variable and the molecular structures of 30 compounds were used as the independent variable. This model was used to design neonicotinoid insecticides with reduced bioconcentration. The contour maps from the 3D-QSAR model were used to evaluate substituted sites and different substituents that significantly affected the bioconcentration of neonicotinoid insecticides. The CoMSIA model showed that neonicotinoid insecticide bioconcentration was strongly affected by steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. Using compound 20 as a template, 105 new substituted derivatives with lower bioconcentrations (reduced by 21.34–77.21%) were designed. The toxicities of these derivatives were evaluated, which showed that 100 of the derivatives retained the original toxicity (increased by 0.10–5.67%). Next, a 2D-QSAR model showed that the decreased bioconcentration of the new neonicotinoid insecticides was mainly caused by the total energy and dipole moment. Homology modeling was used to obtain the genetic recombination AChR in sucking-type pests (i.e. aphid, leafhopper, thrips, and Bemisia tabaci) and bees (i.e. Apis mellifera ligustica and Apis cerana). The neonicotinoid insecticides before and after modification were docked with AChRs to complete the screening of derivatives with bi-directional selective toxic effects. LibDock scores showed that Derivative-5, Derivative-18, Derivative-31, and Derivative-65 had bi-directional selective effects on pests and bees. The effects of the Derivative-18 were the most significant, with toxicity increasing by 14.66% in pests and decreasing by 19.42% in bees. We determined via analysis of amino acid residues that Derivative-18 had more hydrophobic amino acids interacting with pest AChRs, and the mode of action was predominantly hydrogen bonding. Conversely, Derivative-18 had fewer hydrophobic amino acids interacting with bee AChRs, and the mode of action there was more reliant on van der Waals forces with weak binding power.