{"title":"1,2,4-恶二唑药效团的多样性优化与杀线虫剂的发现。","authors":"Yuqin Ou, Qi Zhang, Xue Guo, Ruirui Zhao, Jixiang Chen, Xiuhai Gan","doi":"10.1007/s11030-025-11288-2","DOIUrl":null,"url":null,"abstract":"<p><p>Plant-parasitic nematodes are primary pathogen that cause global crop yield losses, the economic cost to global agriculture is $157 billion a year. With the prohibition of highly toxic chemical nematicides, there are few nematicides available for prevention and control of nematodes. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a new broad-spectrum nematicide with good control effects against various nematodes. In order to discover new and environmentally friendly chemical nematicides, five series of 43 novel compounds containing 1,2,4-oxadiazole pharmacophore were designed and synthesized by diversity-oriented optimization. The nematocidal activity of the target compounds against Bursaphelenchus xylophilus, Aphelenchoides besseyi and Ditylenchus destructor were systematically evaluated. Bioassay results show that E3((E)-1-(4-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-N-(4-(trifluoromethyl)phenyl)methanimine) had good nematicidal activity, and its corrected mortality rates were 85.7%, 75.9% and 83.4% to three nematodes at 200 μg/mL, respectively, which was superior to tioxazafen (40.7%, 70.7%, 38.5%). The preliminary mechanisms indicate that compound E3 can inhibit the egg hatching rate, the feeding, and reproductive capabilities of B. xylophilus, and then affect the population of nematodes. In addition, compound E3 can significantly enhance oxidative stress in B. xylophilus. This study revealed that compound E3 has the potential to be a lead candidate for the development of new nematicides.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Diversity-oriented optimization of 1,2,4-oxadiazole pharmacophore for the discovery of nematicides.\",\"authors\":\"Yuqin Ou, Qi Zhang, Xue Guo, Ruirui Zhao, Jixiang Chen, Xiuhai Gan\",\"doi\":\"10.1007/s11030-025-11288-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Plant-parasitic nematodes are primary pathogen that cause global crop yield losses, the economic cost to global agriculture is $157 billion a year. With the prohibition of highly toxic chemical nematicides, there are few nematicides available for prevention and control of nematodes. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a new broad-spectrum nematicide with good control effects against various nematodes. In order to discover new and environmentally friendly chemical nematicides, five series of 43 novel compounds containing 1,2,4-oxadiazole pharmacophore were designed and synthesized by diversity-oriented optimization. The nematocidal activity of the target compounds against Bursaphelenchus xylophilus, Aphelenchoides besseyi and Ditylenchus destructor were systematically evaluated. Bioassay results show that E3((E)-1-(4-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-N-(4-(trifluoromethyl)phenyl)methanimine) had good nematicidal activity, and its corrected mortality rates were 85.7%, 75.9% and 83.4% to three nematodes at 200 μg/mL, respectively, which was superior to tioxazafen (40.7%, 70.7%, 38.5%). The preliminary mechanisms indicate that compound E3 can inhibit the egg hatching rate, the feeding, and reproductive capabilities of B. xylophilus, and then affect the population of nematodes. In addition, compound E3 can significantly enhance oxidative stress in B. xylophilus. This study revealed that compound E3 has the potential to be a lead candidate for the development of new nematicides.</p>\",\"PeriodicalId\":708,\"journal\":{\"name\":\"Molecular Diversity\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Diversity\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1007/s11030-025-11288-2\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-025-11288-2","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
摘要
植物寄生线虫是造成全球作物产量损失的主要病原体,每年给全球农业造成的经济损失为1570亿美元。随着剧毒化学杀线虫剂的禁用,用于防治线虫的杀线虫剂很少。噻沙芬(3-苯基-5-噻吩-2-基-1,2,4-恶二唑)是一种新型广谱杀线虫剂,对多种线虫具有良好的防治效果。为了发现新型的环境友好型化学杀线虫剂,采用多样性优化的方法设计合成了5个系列43个含1,2,4-恶二唑药效团的新化合物。系统评价了目标化合物对嗜木疏线虫、贝氏疏线虫和双叶螟线虫的杀线虫活性。生物测定结果表明,E3((E)-1-(4-(3-(4-氯苯基)-1,2,4-恶二唑-5-基)甲氧基)苯基)- n -(4-(三氟甲基)苯基)甲亚胺)具有良好的杀线虫活性,在200 μg/mL浓度下对3种线虫的校正死亡率分别为85.7%、75.9%和83.4%,优于噻沙芬(40.7%、70.7%和38.5%)。初步机制表明,化合物E3能够抑制嗜木芽孢杆菌的卵孵化率、取食和繁殖能力,进而影响线虫的种群数量。此外,化合物E3还能显著增强嗜木芽孢杆菌的氧化应激。该研究表明,化合物E3有潜力成为开发新型杀线虫剂的主要候选物。
Diversity-oriented optimization of 1,2,4-oxadiazole pharmacophore for the discovery of nematicides.
Plant-parasitic nematodes are primary pathogen that cause global crop yield losses, the economic cost to global agriculture is $157 billion a year. With the prohibition of highly toxic chemical nematicides, there are few nematicides available for prevention and control of nematodes. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a new broad-spectrum nematicide with good control effects against various nematodes. In order to discover new and environmentally friendly chemical nematicides, five series of 43 novel compounds containing 1,2,4-oxadiazole pharmacophore were designed and synthesized by diversity-oriented optimization. The nematocidal activity of the target compounds against Bursaphelenchus xylophilus, Aphelenchoides besseyi and Ditylenchus destructor were systematically evaluated. Bioassay results show that E3((E)-1-(4-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-N-(4-(trifluoromethyl)phenyl)methanimine) had good nematicidal activity, and its corrected mortality rates were 85.7%, 75.9% and 83.4% to three nematodes at 200 μg/mL, respectively, which was superior to tioxazafen (40.7%, 70.7%, 38.5%). The preliminary mechanisms indicate that compound E3 can inhibit the egg hatching rate, the feeding, and reproductive capabilities of B. xylophilus, and then affect the population of nematodes. In addition, compound E3 can significantly enhance oxidative stress in B. xylophilus. This study revealed that compound E3 has the potential to be a lead candidate for the development of new nematicides.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;