{"title":"设计和合成新型吲哚衍生 N-甲基氨基甲酰基胍基几丁质酶抑制剂,显著提高杀虫活性","authors":"Fang Li, Wei Chen, Yin Ai, Xingyue Zhou, Juncheng Xiang, Huizhe Lu, Yanhong Dong, Qing Yang, Jianjun Zhang","doi":"10.1021/acs.jafc.4c03536","DOIUrl":null,"url":null,"abstract":"Chitinases play an important role in the molting process of insects and are potential targets for the development of green insecticides. Based on the feature that the +1/+2 sites in <i>Of</i>ChtI, <i>Of</i>ChtII, and <i>Of</i>Chi-h have tryptophan residues in mismatch-parallel position, a strategy to introduce indole scaffold into chitinase inhibitors was proposed, and multitarget chitinase inhibitors containing <i>N</i>-methylcarbamoylguanidinyl and indole scaffold were successfully synthesized. The inhibitory activity showed that compound <b>8u</b> exhibited significant inhibitory activity against <i>Of</i>ChtI, <i>Of</i>ChtII, and <i>Of</i>Chi-h, with IC<sub>50</sub> values of 0.7, 0.79, and 0.58 μM, and <i>K</i><sub><i>i</i></sub> values of 0.05 ± 0.005, 0.065 ± 0.004, and 0.025 ± 0.006 μM, respectively. <i>In vivo</i> insecticidal activity showed that compounds <b>8a</b> and <b>8g</b> exhibited excellent insecticidal activity against <i>Plutella xylostella</i> and <i>Mythimna separata</i>, with LC<sub>50</sub> values of 0.79 and 9.17 mg/L against <i>P. xylostella</i>, respectively, and 3.58 and 83.09 mg/L against <i>M. separata</i>, respectively, making them the most potent chitinase inhibitors with <i>in vivo</i> insecticidal activity discovered to date. The inhibition mechanism and binding free energy results suggested that <i>N</i>-methylcarbamoylguanidinyl binds to the −1 catalytic site, while additional interactions acquired by π–π stacking and hydrophobic interactions of the indole scaffold with tryptophan increase the binding affinity of the targets to chitinases. This work provides a new direction for the development of chitinase inhibitors with compounds <b>8a</b> and <b>8g</b> potentially serving as promising candidates for pesticide development.","PeriodicalId":41,"journal":{"name":"Journal of Agricultural and Food Chemistry","volume":null,"pages":null},"PeriodicalIF":5.7000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design and Synthesis of Novel Indole-Derived N-Methylcarbamoylguanidinyl Chitinase Inhibitors with Significantly Improved Insecticidal Activity\",\"authors\":\"Fang Li, Wei Chen, Yin Ai, Xingyue Zhou, Juncheng Xiang, Huizhe Lu, Yanhong Dong, Qing Yang, Jianjun Zhang\",\"doi\":\"10.1021/acs.jafc.4c03536\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Chitinases play an important role in the molting process of insects and are potential targets for the development of green insecticides. Based on the feature that the +1/+2 sites in <i>Of</i>ChtI, <i>Of</i>ChtII, and <i>Of</i>Chi-h have tryptophan residues in mismatch-parallel position, a strategy to introduce indole scaffold into chitinase inhibitors was proposed, and multitarget chitinase inhibitors containing <i>N</i>-methylcarbamoylguanidinyl and indole scaffold were successfully synthesized. The inhibitory activity showed that compound <b>8u</b> exhibited significant inhibitory activity against <i>Of</i>ChtI, <i>Of</i>ChtII, and <i>Of</i>Chi-h, with IC<sub>50</sub> values of 0.7, 0.79, and 0.58 μM, and <i>K</i><sub><i>i</i></sub> values of 0.05 ± 0.005, 0.065 ± 0.004, and 0.025 ± 0.006 μM, respectively. <i>In vivo</i> insecticidal activity showed that compounds <b>8a</b> and <b>8g</b> exhibited excellent insecticidal activity against <i>Plutella xylostella</i> and <i>Mythimna separata</i>, with LC<sub>50</sub> values of 0.79 and 9.17 mg/L against <i>P. xylostella</i>, respectively, and 3.58 and 83.09 mg/L against <i>M. separata</i>, respectively, making them the most potent chitinase inhibitors with <i>in vivo</i> insecticidal activity discovered to date. The inhibition mechanism and binding free energy results suggested that <i>N</i>-methylcarbamoylguanidinyl binds to the −1 catalytic site, while additional interactions acquired by π–π stacking and hydrophobic interactions of the indole scaffold with tryptophan increase the binding affinity of the targets to chitinases. This work provides a new direction for the development of chitinase inhibitors with compounds <b>8a</b> and <b>8g</b> potentially serving as promising candidates for pesticide development.\",\"PeriodicalId\":41,\"journal\":{\"name\":\"Journal of Agricultural and Food Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2024-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Agricultural and Food Chemistry\",\"FirstCategoryId\":\"97\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jafc.4c03536\",\"RegionNum\":1,\"RegionCategory\":\"农林科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"AGRICULTURE, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Agricultural and Food Chemistry","FirstCategoryId":"97","ListUrlMain":"https://doi.org/10.1021/acs.jafc.4c03536","RegionNum":1,"RegionCategory":"农林科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"AGRICULTURE, MULTIDISCIPLINARY","Score":null,"Total":0}
Design and Synthesis of Novel Indole-Derived N-Methylcarbamoylguanidinyl Chitinase Inhibitors with Significantly Improved Insecticidal Activity
Chitinases play an important role in the molting process of insects and are potential targets for the development of green insecticides. Based on the feature that the +1/+2 sites in OfChtI, OfChtII, and OfChi-h have tryptophan residues in mismatch-parallel position, a strategy to introduce indole scaffold into chitinase inhibitors was proposed, and multitarget chitinase inhibitors containing N-methylcarbamoylguanidinyl and indole scaffold were successfully synthesized. The inhibitory activity showed that compound 8u exhibited significant inhibitory activity against OfChtI, OfChtII, and OfChi-h, with IC50 values of 0.7, 0.79, and 0.58 μM, and Ki values of 0.05 ± 0.005, 0.065 ± 0.004, and 0.025 ± 0.006 μM, respectively. In vivo insecticidal activity showed that compounds 8a and 8g exhibited excellent insecticidal activity against Plutella xylostella and Mythimna separata, with LC50 values of 0.79 and 9.17 mg/L against P. xylostella, respectively, and 3.58 and 83.09 mg/L against M. separata, respectively, making them the most potent chitinase inhibitors with in vivo insecticidal activity discovered to date. The inhibition mechanism and binding free energy results suggested that N-methylcarbamoylguanidinyl binds to the −1 catalytic site, while additional interactions acquired by π–π stacking and hydrophobic interactions of the indole scaffold with tryptophan increase the binding affinity of the targets to chitinases. This work provides a new direction for the development of chitinase inhibitors with compounds 8a and 8g potentially serving as promising candidates for pesticide development.
期刊介绍:
The Journal of Agricultural and Food Chemistry publishes high-quality, cutting edge original research representing complete studies and research advances dealing with the chemistry and biochemistry of agriculture and food. The Journal also encourages papers with chemistry and/or biochemistry as a major component combined with biological/sensory/nutritional/toxicological evaluation related to agriculture and/or food.