Cryptolepine Derivatives Are Insecticide Leads by Targeting Insect Chitinolytic Enzymes and Bilin-Binding Protein

Multitarget inhibitors (MIs) against insect chitinolytic enzymes are potential pesticide candidates. However, currently known Mis suffers from low biological activity and limited possibilities for structural modification. Here, cryptolepine and its halogenated derivatives were discovered as MIs against all of four insect chitinolytic enzymes from <i>Ostrinia furnacalis</i> (<i>Of</i>ChtI, <i>Of</i>ChtII, <i>Of</i>Chi-h and <i>Of</i>Hex1) with <i>K</i>_i values at μM level. Notably, the inhibitory activities of cryptolepine can be increased by 1 order of magnitude through a simple two-site halogenation (CD-4). Molecular docking results indicated that halogen modifications may directly form halogen bonds with polar residues or change the electrostatic potential of the conjugation plane to enhance its π-π stacking interaction with tryptophan residues. Cryptolepine and CD-4 showed insecticidal activities toward both <i>O. furnacalis</i> and <i>Plutella xylostella</i>. Interestingly, CD-4, but not cryptolepine, prevents the formation of the protective color in <i>P. xylostella</i> by competing with biliverdin for binding to the bilin-binding protein. This study not only reports new MIs as insecticide leads, but also provides a new idea for pest control by inhibiting its protective color.