New lead discovery of insect growth regulators based on the scaffold hopping strategy

Biaobiao Jiang; Bingbo Guo; Jialin Cui; Yawen Dong; Li Cui; Li Zhang; Qing Yang; Xinling Yang

doi:10.1016/j.bmcl.2020.127500

New lead discovery of insect growth regulators based on the scaffold hopping strategy

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127500. doi: 10.1016/j.bmcl.2020.127500. Epub 2020 Aug 18.

Authors

Biaobiao Jiang¹, Bingbo Guo¹, Jialin Cui¹, Yawen Dong¹, Li Cui², Li Zhang³, Qing Yang⁴, Xinling Yang⁵

Affiliations

¹ Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China.
² Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
³ Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China. Electronic address: zhang_li@cau.edu.cn.
⁴ State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
⁵ Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China. Electronic address: yangxl@cau.edu.cn.

PMID: 32822762
DOI: 10.1016/j.bmcl.2020.127500

Abstract

Insect growth regulators (IGRs), which can interrupt or inhibit pest life cycles, are low-toxicity pesticides widely used in integrated pest management (IPM). Ecdysone analogues and chitinase inhibitors are familiar IGRs that have attracted considerable attention because of their unique modes of action and low toxicity to non-target organisms. To find new and highly effective candidate IGRs with novel mechanisms, D-08 (N-(4-(tert-butyl)phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) was chosen as a lead compound, and a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized using the scaffold hopping strategy. The bioassay showed that III-27 (N-(2-methylphenethyl)-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) had excellent activity against Plutella xylostella. Protein verification and molecular docking indicated that III-27 could act on both the ecdysone receptor (EcR) and Ostrinia furnacalis chitinase (Of ChtI) and is a promising new lead IGRs. The interaction mechanism of III-27 with EcR and Of ChtI was then studied by molecular docking. These results provide important guidance for the study of new dual-target IGRs.

Keywords: Chitinase; Ecdysone receptor; Insect growth regulator; Molecular docking; Pyrazolamide; Scaffold hopping.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Chitinases / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Juvenile Hormones / chemical synthesis
Juvenile Hormones / chemistry
Juvenile Hormones / pharmacology*
Molecular Docking Simulation
Molecular Structure
Moths / drug effects*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, Steroid / metabolism
Structure-Activity Relationship

Substances

Amides
Juvenile Hormones
Pyrazoles
Receptors, Steroid
ecdysone receptor
pyrazole-5-carboxamide
Chitinases