Discovery of N-phenyl-isoindole-1,3-dione derivatives as potent insect chitinase ofChi-h inhibitors through virtual screening

doi:10.1016/j.jia.2025.08.019

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Jiahao Zhang¹, Shenmeng Bai¹,Jiaxin Chu¹,Baokang Ding¹,Bohou Li¹, Yanzhu Li¹, Jingwen Guo¹, Fengyue Suo¹, Shujie Ma¹, Jingao Dong¹, Lihui Zhang^1#,Shengqiang Shen^{1, 2#},and Lili Dong^1#

¹College of Plant Protection/State Key Laboratory of North China Crop Improvement and Regulation, Hebei Agricultural University, Baoding 071001, China

²Exosome Origin (Zhejiang) Technology Co., Ltd., Wenzhou 325024, China

Highlights

• A novel class of N-phenyl-isoindole-1,3-dione (PI) derivatives was identified as potent inhibitors of OfChi-h via virtual screening. Compound PI-17 demonstrated strong inhibitory activity against OfChi-h (K_i=2.3 μmol L^-1) and superior insecticidal efficacy against Ostrinia furnacalis.

• PI-series induced morphological aberrations in the cuticles of O. furnacalis larvae. The mechanism of this efficient insecticidal action was elucidated at atomic and electronic levels through Electrostatic potential (ESP) and density functional theory (DFT) analyses.

• PI-series compounds demonstrated significant potential as eco-friendly insect growth regulators, with comprehensive safety assessments confirming minimal effects on natural enemies and non-target organisms.

Abstract
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摘要

亚洲玉米螟是一种极具破坏性的鳞翅目害虫，可导致全球玉米减产 30%，其幼虫蛀食组织、传播病害，加剧粮食安全风险。目前防治以合成杀虫剂为主，但长期使用也导致了昆虫的抗药性。靶向几丁质代谢是绿色农药开发的重要方向，OfChi-h作为亚洲玉米螟蜕皮及生存所必需的关键几丁质酶，已成为潜在的防治靶点。本研究通过虚拟筛选策略，成功获得了一类新型OfChi-h抑制剂—N-苯基-异吲哚-1,3-二酮（PI）骨架化合物。其中，化合物PI-17对OfChi-h 表现出强效抑制活性，其抑制常数（K_i）为2.3 μM。同时PI-17对鳞翅目害虫亚洲玉米螟也展现出与对照药剂氟铃脲相当的杀虫活性。此外，本研究利用扫描电子显微镜（SEM）观察了经PI系列化合物处理后的亚洲玉米螟幼虫的表皮形态变化。通过静电势（ESP）及密度泛函理论（DFT）计算，从原子和电子层面探究了PI系列化合物生物活性的差异。同时，这些化合物也对天敌昆虫玉米螟赤眼蜂及非靶标生物具有很高的安全性。研究结果表明，N-苯基-异吲哚-1,3-二酮衍生物作为一类新型先导化合物，有望开发成为作用于几丁质酶的环境友好型昆虫生长调节剂。

Abstract

Ostrinia furnacalis represents a destructive lepidopteran pest causing up to 30% yield losses in maize crops globally. Its larvae penetrate plant tissues, disrupt nutrient transport, and transmit viral and microbial pathogens, exacerbating food security concerns. Current management approaches for O. furnacalis primarily rely on synthetic pesticides. Targeting chitin metabolism presents a promising strategy for green insecticide development. Specifically, OfChi-h, an essential chitinase for O. furnacalis molting and survival, has emerged as a viable target. This study identified a N-phenyl-isoindole-1,3-dione (PI) scaffold as a novel class of OfChi-h inhibitor through virtual screening strategy. Notably, compound PI-17 demonstrated potent inhibitory activity against OfChi-h with a K_i value of 2.3 μmol L^-1. PI-17 exhibited significant insecticidal activity against lepidopteran pests O. furnacalis, comparable to the control drug hexaflumuron. scanning electron microscopy (SEM) analysis revealed morphological alterations in the cuticles of O. furnacalis larvae treated with PI-series compounds. ESP and DFT calculations explored the variations in biological activities of the PI-series compounds at atomic and electronic levels. Additionally, comprehensive safety evaluations assessed the impact on the natural enemy Trichogramma ostriniae and nontarget organisms. These findings introduce a novel class of lead compounds, N-phenyl-isoindole-1,3-dione derivatives, showing significant potential for developing eco-friendly insect growth regulators to control O. furnacalis.

Keywords: insect growth regulators chitinase inhibitors OfChi-h phenyl-isoindole-1,3-dione virtual screening

Online: 21 August 2025

Fund:

We acknowledge the financial support by the National Natural Science Foundation of China (32472591), the Key Research and Development Project of Hebei Province, China (22326508D), the Talents Introduction Program in Hebei Agricultural University, China (YJ2021021), the Central guide Local Science and Technology Development Fund Project of Hebei Province, China (236Z6506G).

About author: #Correspondence Lili Dong, Tel: +86-312-7520235, E-mail: lilidong@hebau.edu.cn; Shengqiang Shen, E-mail: shenshengqiang@pku.edu.cn; Lihui Zhang, E-mail: zhanglihui@hebau. edu.cn

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Jiahao Zhang, Shenmeng Bai, Jiaxin Chu, Baokang Ding, Bohou Li, Yanzhu Li, Jingwen Guo, Fengyue Suo, Shujie Ma, Jingao Dong, Lihui Zhang, Shengqiang Shen, and Lili Dong. 2025. Discovery of N-phenyl-isoindole-1,3-dione derivatives as potent insect chitinase ofChi-h inhibitors through virtual screening. Journal of Integrative Agriculture, Doi:10.1016/j.jia.2025.08.019

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