Water bridges are essential to neonicotinoids: Insights from synthesis, bioassay and molecular modelling studies

Abstract

Water-bridged H-bonds have been observed in many cases of ligand-receptor recognitions. To explore the roles of water bridges in the binding of neonicotinoids with receptors, twenty-four neonicotinoid compounds with nine fragments, including 1H-1,2,3-triazole, CN, COOMe, CONHNH2, CONHMe, NO2, NH2, NHCOMe and NHCSNH2 were synthesized and evaluated, of which, compounds with cyano group showed the best activities against Aphis craccivora. Accordingly, the cyano group is the optimal fragment mimicking the water bridge. Two cyano-substituted cis-nitromethylene compounds display good insecticidal activities, whereas the LC50 values are lower than those of their corresponding prototypes. Docking study showed that the cyano group acts only as H-bond acceptor, while the water bridge can act as both donor and acceptor. It revealed that the water bridge might be stable in the active site and was not suitable to be replaced by other groups. The findings illustrated that the water bridge is necessary for high insecticidal activities of neonicotinoids, which should be also helpful in better understanding the binding mode of neonicotinoids.