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

Guanglong       Li; Cong       Zhou; Chengchun       Zhu; Lujue       He; Xiaoyang       Li; Zhiping       Xu; Xiaoyong       Xu; Xusheng       Shao; Zhong       Li; Jiagao       Cheng

Abstract

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 1H NMR, 13C 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.

Keywords: Scaffold hopping, fipronil, low energy conformation, insecticidal activity, molecular modeling, GABA receptors.

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DOI https://dx.doi.org/10.2174/1570180816666190701101734	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

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

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