文献类型：期刊文献

英文题名：Design, Synthesis, Insecticidal Evaluation and Modeling Studies on 1,4,6,7-tetrahydropyrazolo[3,4-d][1,3]oxazine Derivatives: An Application of Scaffold Hopping Strategy on Fipronil

作者：Li, Guanglong[1];Zhou, Cong[1,2];Zhu, Chengchun[1];He, Lujue[1,2];Li, Xiaoyang[1];Xu, Zhiping[1];Xu, Xiaoyong[1];Shao, Xusheng[1];Li, Zhong[1];Cheng, Jiagao[1,2]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Sch Pharm, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China

年份：2019

卷号：16

期号：10

起止页码：1175

外文期刊名：LETTERS IN DRUG DESIGN & DISCOVERY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000486625000008)】；

基金：We thank for the financial support from the National Natural Science Foundation of China (21572059), the National Key Research and Development Plan (2017YFD0200300), and Innovation Program of Shanghai Municipal Education Commission (201701070002E00037).

语种：英文

外文关键词：Scaffold hopping; fipronil; low energy conformation; insecticidal activity; molecular modeling; GABA receptors

摘要：Background: As the first phenylpyrazole pesticide, fipronil has been widely used in crop protection and public hygiene. In the low energy conformation of fipronil, a pseudo-six-membered ring is observed through an intramolecular hydrogen bond. Methods: A scaffold hopping strategy was applied to mimic the pseudo-six-membered ring of fipronil by non-aromatic ring. All compounds were synthesized with a proper synthetic route and characterized by H-1 NMR, C-13 NMR and high-resolution mass spectra. Insecticidal activities of all target compounds against Plutella xylostella were assessed by a professional organization. Physicochemical property prediction and docking study of these compounds with GABA receptor were also performed. Results: A series of 1,4,6,7-tetrahydropyrazolo[3,4-d][1,3]oxazine derivatives containing twenty-five compounds were designed, synthesized and evaluated. Several compounds exhibited moderate activities against Plutella xylostella. The strong electron-withdrawing groups are conducive to improve activities of this series of compounds against Plutella xylostella. Docking study showed that the most active compound 10 with nitro group could bind within the TM2 domain of GABA receptor, in which a hydrogen bond was observed with residue 6'Thr. The activity of 10 was weaker than fipronil due to the differences in physicochemical properties. Conclusion: More attention should be paid to physicochemical properties during novel pesticide hit or lead design through scaffold hopping.