title: Design and synthesis of N-alkyl-N'-substituted 2,4-dioxo-3,4-dihydropyrimidin-1-diacylhydrazine derivatives as ecdysone receptor agonist.
abstract: Based on the discovery of thymine as an ecdysteroid agonist, a series of 1,4-disubstituted diacylhydrazine derivatives with a thymine moiety were designed and synthesized. The activities of these compounds against Spodoptera litura (Fabricius) were evaluated by the insect immersion method. Results showed that compound 2h with an N-cyclohexylmethyl substituent exhibits the most potent agonist activity with a median lethal concentration of 23.21 μg/mL. This compound also caused malformation of molting larvae and adults. Compound 2 h was further demonstrated as an ecdysteroid agonist by reporter gene assay on the Spodoptera frugiperda cell line (Sf9 cells). A molecular docking study indicated that hydrophobic interactions and the formation of hydrogen bonds between the compounds and the ecdysone receptor play critical roles in promoting the binding affinity of the compound. The structure of compound 2h may serve as a favorable template for the development of new ecdysteroid agonists with a pyrimidinedione moiety.
authors.affiliation: State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, PR China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Jin-Guo
authors.initials: JG
authors.lastname: Tan
authors.forename: Han-Hong
authors.initials: HH
authors.lastname: Xu
mesh_terms: D000818:Animals; D015195:Drug Design; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011987:Receptors, Steroid / Q000819:agonists* / Q000737:chemistry; D018411:Spodoptera / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D006131:Growth Inhibitors; D006834:Hydrazines; D011743:Pyrimidines; D011987:Receptors, Steroid; C055469:ecdysone receptor