Synthesis, Optimization, and Evaluation of Glycosylated Naphthalimide Derivatives as Efficient and Selective Insect β-N-Acetylhexosaminidase OfHex1 Inhibitors

Insect chitinolytic beta-N-acetylhexosaminidase OfHex1, from the agricultural pest Ostrinia furnacalis (Guenee), is considered as a potential target for green pesticide design. In this study, rational molecular design and optimization led to the synthesis of compounds 15r (K-i = 5.3 mu M) and 15y (K-i = 2.7 mu M) that had superior activity against OfHex1 than previously reported lead compounds. Both compounds 15r and 15y had high selectivity toward OfHex1 over human beta-N-acetylhexosaminidase B (HsHexB) and human O-GlcNAcase (hOGA). In addition, to investigate the basis for the potency of glycosylated naphthalimides against OfHex1, molecular docking and molecular dynamics simulations were performed to study possible binding modes. Furthermore, the in vivo biological activity of target compounds with efficient OfHex1 inhibitory potency was assayed against Myzus persicae, Plutella xylostella, and O. furnacalis. This present work indicates that glycosylated naphthalimides can be further developed as potential pest control and management agents targeting OfHex1.