Design, Synthesis, and Biological Activity of Novel Benzo[d][1,3]dioxole-6-benzamide Derivatives: Multichitinase Inhibitors as Potential Insect Growth Regulator Candidates

Insect growth regulators (IGRs) disrupt normal development of physiological processes in insects and are recognized as green insecticides. Insect chitinases play a crucial role in cuticle degradation during molting, and OfChtI, OfChtII, and OfChi-h are the prospective targets for discovering new insecticides as IGRs. In our previous study, we identified the lead compound a12 as a promising multitarget inhibitor. Herein, we used the binding modes of a12 with three chitinases to recognize the critical interactions and residues favorable to the bioactivity. Subsequently, to improve the bioactivity of inhibitors via enhanced the interactions with important residues, a series of benzo[d][1,3]dioxole-6-benzamide derivatives were rationally designed and synthesized, and their inhibitory activities against Ostrinia furnacalis (O. furnacalis) chitinases, as well as insecticidal activities against O. furnacalis and Plutella xylostella (P. xylostella) were investigated. Among them, compound d29 acted simultaneously on OfChtI, OfChtII, and OfChi-h with Ki values of 0.8, 11.9, and 2.3 μM, respectively, a significant improvement over the inhibitory activity of the lead compound a12. Moreover, d29 exhibited superior activity than a12 against two lepidopteran pests by interfering with normal insect growth and molting, indicating that d29 is a potential lead candidate for novel IGRs with a multichitinase mechanism. The present study revealed that simultaneous inhibition on multiple chitinases could achieve excellent insecticidal activity. The elucidation of inhibition mechanisms and molecular conformations illustrated the interactions with the three chitinases, as well as the discrepancy in bioactivity, which will be beneficial for future work to improve the potency of bioactivity as IGRs for pest control in sustainable agriculture.