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 developmentof physiological processes in insects and are recognized as greeninsecticides. Insect chitinases play a crucial role in cuticle degradationduring molting, and OfChtI, OfChtII,and OfChi-h are the prospective targets for discoveringnew insecticides as IGRs. In our previous study, we identified thelead compound a12 as a promising multitarget inhibitor.Herein, we used the binding modes of a12 with three chitinasesto recognize the critical interactions and residues favorable to thebioactivity. Subsequently, to improve the bioactivity of inhibitorsvia enhanced the interactions with important residues, a series ofbenzo-[d]-[1,3]-dioxole-6-benzamide derivatives wererationally designed and synthesized, and their inhibitory activitiesagainst Ostrinia furnacalis (O. furnacalis) chitinases, as well as insecticidalactivities against O. furnacalis and Plutella xylostella (P. xylostella) were investigated. Among them, compound d29 actedsimultaneously on OfChtI, OfChtII,and OfChi-h with K (i) valuesof 0.8, 11.9, and 2.3 mu M, respectively, a significant improvementover the inhibitory activity of the lead compound a12. Moreover, d29 exhibited superior activity than a12 against two lepidopteran pests by interfering with normalinsect growth and molting, indicating that d29 is a potentiallead candidate for novel IGRs with a multichitinase mechanism. Thepresent study revealed that simultaneous inhibition on multiple chitinasescould achieve excellent insecticidal activity. The elucidation ofinhibition mechanisms and molecular conformations illustrated theinteractions with the three chitinases, as well as the discrepancyin bioactivity, which will be beneficial for future work to improvethe potency of bioactivity as IGRs for pest control in sustainable agriculture.

Automated summary

Insect growth regulators (IGRs) are considered as green insecticides for disrupting normal physiological processes in insects. In this study, the lead compound a12 was identified as a promising multitarget inhibitor. By studying the binding modes of a12 with three chitinases, the critical interactions and favorable residues were recognized for the bioactivity. A series of benzo-[d]-[1,3]-dioxole-6-benzamide derivatives were then designed and synthesized to improve the bioactivity. Compound d29 showed significantly improved inhibitory activity against Ostrinia furnacalis chitinases and demonstrated superior insecticidal activity against O. furnacalis and Plutella xylostella.