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

Abstract

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 K i 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.

A Potential Multitarget Insect Growth Regulator Candidate: Design, Synthesis, and Biological Activity of Novel Acetamido Derivatives Containing Hexacyclic Pyrazole Carboxamides

“…The insecticidal activity against O. furnacalis was evaluated according to a previously described method . The artificial feed was mixed uniformly with the test solution containing the target compound and then placed in a 9 cm Petri dish.…”

“…To date, five commercialized dibenzoylhydrazine (DBH) ecdysone agonists (Figure ) have demonstrated resistance owing to their single chemical structure skeleton and long-term irrational use, thereby limiting their practical application. , In recent years, a wide range of non-DBH ecdysone agonists have been successively reported but not commercialized for lack of ideal activity. − Based on the clear crystal structures of chitinases from the Asian corn borer Ostrinia furnacalis ( Of ChtI, Of ChtII, and Of Chi-h) and their indispensable function in the insect molting, a number of inhibitors with high inhibitory activity have been discovered, such as natural products and their derivatives, substrate analogues, and other new chemical skeletons. − However, no commercial chitinase inhibitors have been reported on account of their complex chemical synthesis or unsatisfied in vivo insecticidal activity. , Consequently, the use of efficient strategies to design IGRs with high activity and novel action mechanisms is of great significance.…”

A Novel Peptidomimetic Insecticide: Dippu-AstR-Based Rational Design and Biological Activity of Allatostatin Analogs

“…To broaden the insecticidal spectrum of AST analog and explore its application value, the analog Q6 , with the best in vitro JH-inhibiting activity, was selected to evaluate the effect of insect growth regulation on P. xylostella. The method is described elsewhere, , and the assay details are provided in the Supporting Information. Student’s t test was applied to determine statistically significant differences.…”

Novel Inhibitor of Glutamate-Cysteine Ligase Catalytic Subunit against Tribolium castaneum: High-Throughout Virtual Screening, Molecular Docking and Dynamics Simulation, and Bioassay

“…Morphological defects were assessed using an Olympus SZX16 stereomicroscope (Olympus Corp., Tokyo, Japan). Mortality rates were calculated after 10 days as follows: 34 corrected mortality (%) mortality of treatment (%) mortality of negative control (%) 1 mortality of negative control (%) 100% = ×…”