title: Structure-activity relationship of imidazothiadiazole analogs for the binding to the ecdysone receptor of insect cells.
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.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Taiyo
authors.initials: T
authors.lastname: Yokoi
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Minami
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: naka@kais.kyoto-u.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Miyagawa
mesh_terms: D000818:Animals; D002460:Cell Line; D001517:Coleoptera; D004175:Diptera; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D019476:Insect Proteins / Q000378:metabolism*; D007814:Larva / Q000187:drug effects; D007915:Lepidoptera / Q000187:drug effects; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D011987:Receptors, Steroid / Q000378:metabolism*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D007093:Imidazoles; D019476:Insect Proteins; D011987:Receptors, Steroid; D013830:Thiadiazoles; C055469:ecdysone receptor
keywords: Ecdysone agonists; Ecdysone receptor; Imidazothiadiazole; Molting inhibitor; Sf-9