Jiang Zhiyang, Shi Dongmei, Fu Haoyu, Li Yan, Zou Renxuan, He Ziqi, Shi Jie, Shen Lijuan, Tang Bin, Xu Zhijian, Yang Qing, Duan Hongxia
Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science; Key Laboratory of National Forestry and Grassland Administration on Pest Chemical Control, China Agricultural University, Beijing 100193, China.
College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China.
Int J Biol Macromol. 2025 May;306(Pt 4):141805. doi: 10.1016/j.ijbiomac.2025.141805. Epub 2025 Mar 5.
Chitinases are recognized as potential targets to develop novel insecticides to control lepidopteran pests. However, the design and development of effective multi-chitinase inhibitors remains a huge challenge. Based on the backgrounds, in this study, we designed and synthesized a series of cinnamyl-thiazolidinedione compounds as potential inhibitors against OfChtI, OfChtII and OfChi-h, for the first time, by integrating strategies including fragment replacement, 3D QSAR-guided design, and bioelectronic isosteric replacement. Among all synthesized compounds, those displayed substantial activities against three chitinases, such as 5f and 9m, simultaneously demonstrated significant larvicidal activities and growth regulation effects against various lepidopteran pests. Inhibition mechanism studies indicated that the π interactions, hydrophobic stacking, and electrostatic interactions between cinnamyl-thiazolidinone compounds and the conserved aromatic tryptophan and phenylalanine residues, as well as the polar asparagine residues in three chitinases, were crucial for their interactions. Furthermore, the qPCR experiment suggested that cinnamyl-thiazolidinone compounds could regulate the chitin metabolism pathway of Ostrinia furnacalis in vivo. This study provides the first successful example of developing novel multi-chitinase inhibitors through ligand-based optimization strategies, offering promising candidates for controlling lepidopteran pests.
几丁质酶被认为是开发新型杀虫剂以控制鳞翅目害虫的潜在靶点。然而，设计和开发有效的多几丁质酶抑制剂仍然是一个巨大的挑战。基于这些背景，在本研究中，我们首次通过整合片段替换、3D QSAR引导设计和生物电子等排体替换等策略，设计并合成了一系列肉桂基噻唑烷二酮化合物，作为针对OfChtI、OfChtII和OfChi-h的潜在抑制剂。在所有合成的化合物中，那些对三种几丁质酶（如5f和9m）表现出显著活性的化合物，同时对各种鳞翅目害虫表现出显著的杀幼虫活性和生长调节作用。抑制机制研究表明，肉桂基噻唑烷酮化合物与三种几丁质酶中保守的芳香族色氨酸和苯丙氨酸残基以及极性天冬酰胺残基之间的π相互作用、疏水堆积和静电相互作用对它们之间的相互作用至关重要。此外，qPCR实验表明，肉桂基噻唑烷酮化合物可以在体内调节亚洲玉米螟的几丁质代谢途径。本研究通过基于配体的优化策略开发新型多几丁质酶抑制剂提供了首个成功范例，为控制鳞翅目害虫提供了有前景的候选化合物。
