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Title: Structure-activity relationship of imidazothiadiazole analogs for the binding to the ecdysone receptor of insect cells.
Authors: Yokoi, Taiyo
Minami, Saki
Nakagawa, Yoshiaki  kyouindb  KAKEN_id
Miyagawa, Hisashi
Author's alias: 中川, 好秋
Keywords: Ecdysone agonists
Molting inhibitor
Ecdysone receptor
Issue Date: May-2015
Publisher: Elsevier Inc.
Journal title: Pesticide biochemistry and physiology
Volume: 120
Start page: 40
End page: 50
Abstract: Diacylhydrazines are the first non-steroidal ecdysone agonists, and five compounds are used as insecticides in agriculture. After the discovery of diacylhydrazine-type compounds, numerous non-steroidal structures were reported as ecdysone agonists. Among various ecdysone agonists, imidazothiadiazoles are reported to be very potent in vitro; however, the experimental detail for the structure identification and bioassays are not stated in the paper (Holmwood and Schindler, Bioorg. Med. Chem. 17, 4064-4070, 2009). In our present study, we synthesized 18 imidazothiadiazole-type compounds and confirmed the chemical structures by spectrometric analyses. The binding activity of the synthesized compounds to the ecdysone receptor was evaluated in terms of the concentration required for 50% inhibition of [(3)H]ponasterone A incorporation [IC50 (M)] into lepidopteran (Sf-9), coleopteran (BCRL-Lepd-SL1), and dipteran (NIAS-AeAl2) cells. 6-(2-Chlorophenyl)-2-(trifluoromethyl)imidazo[2, 1-b] [1, 3, 4]-thiadiazol-5-yl)acrylamide analogs with CONHR (secondary amide) were very potent against Sf-9 cells, but further alkylation (tertiary amide: CONR2) decreased the activity dramatically. Additionally, a primary amide analog (CONH2) was inactive. The activity also decreased 150-fold by the saturation of olefin region of the acrylamide moiety. In addition, various substituents were introduced at the 2-position of the imidazothiadiazole ring to disclose the physicochemical properties of the substituents which are important for receptor binding. The activity increased by 7500-fold with the introduction of the CF2CF2CF3 group compared to the unsubstituted compound against Sf-9 cells. Quantitative structure-activity relationship analysis for these substituents indicated that hydrophobic and electron-withdrawing groups were favorable for binding. Some of the compounds with strong receptor binding activity showed good larvicidal activity against Spodoptera litura. In contrast, the binding affinity of imidazothiadiazole analogs was low or not observed against dipteran and coleopteran cells.
Rights: © 2014. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
The full-text file will be made open to the public on 31 May 2016 in accordance with publisher's 'Terms and Conditions for Self-Archiving'
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1016/j.pestbp.2014.12.008
PubMed ID: 25987219
Appears in Collections:Journal Articles

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