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Design, synthesis, and biological activity of novel heptacyclic pyrazolamide derivatives : a new candidate of dual-target insect growth regulators

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Abstract
Insect growth regulators (IGRs) can cause abnormal growth and development in insects, resulting in incomplete metamorphosis or even death of the larvae. Ecdysone receptor (EcR) and chitinase in insects play indispensable roles in the molting process. Ecdysone analogues and chitinase inhibitors are considered as potential IGRs. In order to find new and highly effective IGR candidates, based on the structure-activity relationship and molecular docking results of the active compound 6i (3-(tert-butyl)-N-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole-5-carboxamide) discovered in our previous work, we changed the t-butyl group on the pyrazole ring into heptacycle to enhance the hydrophobicity. Consequently, a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized. The bioassay results demonstrated that some compounds showed obvious insecticidal activity. Especially, D-27 (N-(4-(tert-butyl)phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) showed good activities against Plutella xylostella (LC50, 51.50 mg.L-1) and Mythimna separata (100% mortality at 2.5 mg.L-1). Furthermore, protein validation indicated that D-27 acts not only on the EcR but also on chitinase Of ChtI. Molecular docking and molecular dynamics simulation explained the vital factors in the interaction between D-27 and receptors. D-27 may be a new lead candidate with a dual target in which Of ChtI shall be the main one. This work created a new starting point for discovering a novel type of IGRs.
Keywords
MOLECULAR-DYNAMICS, ECDYSONE RECEPTOR, LIGAND-BINDING, CHITINASE, SIMULATIONS, EXPRESSION, AGONISTS, insect growth regulator, pyrazole amide, ecdysone receptor, chitinase, molecular docking

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MLA
Jiang, Biaobiao, et al. “Design, Synthesis, and Biological Activity of Novel Heptacyclic Pyrazolamide Derivatives : A New Candidate of Dual-Target Insect Growth Regulators.” JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 68, no. 23, 2020, pp. 6347–54, doi:10.1021/acs.jafc.0c00522.
APA
Jiang, B., Jin, X., Dong, Y., Guo, B., Cui, L., Deng, X., … Smagghe, G. (2020). Design, synthesis, and biological activity of novel heptacyclic pyrazolamide derivatives : a new candidate of dual-target insect growth regulators. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, 68(23), 6347–6354. https://doi.org/10.1021/acs.jafc.0c00522
Chicago author-date
Jiang, Biaobiao, Xiaoyu Jin, Yawen Dong, Bingbo Guo, Li Cui, Xile Deng, Li Zhang, et al. 2020. “Design, Synthesis, and Biological Activity of Novel Heptacyclic Pyrazolamide Derivatives : A New Candidate of Dual-Target Insect Growth Regulators.” JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 68 (23): 6347–54. https://doi.org/10.1021/acs.jafc.0c00522.
Chicago author-date (all authors)
Jiang, Biaobiao, Xiaoyu Jin, Yawen Dong, Bingbo Guo, Li Cui, Xile Deng, Li Zhang, Qing Yang, Yuxin Li, Xinling Yang, and Guy Smagghe. 2020. “Design, Synthesis, and Biological Activity of Novel Heptacyclic Pyrazolamide Derivatives : A New Candidate of Dual-Target Insect Growth Regulators.” JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 68 (23): 6347–6354. doi:10.1021/acs.jafc.0c00522.
Vancouver
1.
Jiang B, Jin X, Dong Y, Guo B, Cui L, Deng X, et al. Design, synthesis, and biological activity of novel heptacyclic pyrazolamide derivatives : a new candidate of dual-target insect growth regulators. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY. 2020;68(23):6347–54.
IEEE
[1]
B. Jiang et al., “Design, synthesis, and biological activity of novel heptacyclic pyrazolamide derivatives : a new candidate of dual-target insect growth regulators,” JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 68, no. 23, pp. 6347–6354, 2020.
@article{8678558,
  abstract     = {Insect growth regulators (IGRs) can cause abnormal growth and development in insects, resulting in incomplete metamorphosis or even death of the larvae. Ecdysone receptor (EcR) and chitinase in insects play indispensable roles in the molting process. Ecdysone analogues and chitinase inhibitors are considered as potential IGRs. In order to find new and highly effective IGR candidates, based on the structure-activity relationship and molecular docking results of the active compound 6i (3-(tert-butyl)-N-(4-(tert-butyl)phenyl)-1-phenyl-1H-pyrazole-5-carboxamide) discovered in our previous work, we changed the t-butyl group on the pyrazole ring into heptacycle to enhance the hydrophobicity. Consequently, a series of novel heptacyclic pyrazolamide derivatives were designed and synthesized. The bioassay results demonstrated that some compounds showed obvious insecticidal activity. Especially, D-27 (N-(4-(tert-butyl)phenyl)-2-phenyl-2,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-5-carboxamide) showed good activities against Plutella xylostella (LC50, 51.50 mg.L-1) and Mythimna separata (100% mortality at 2.5 mg.L-1). Furthermore, protein validation indicated that D-27 acts not only on the EcR but also on chitinase Of ChtI. Molecular docking and molecular dynamics simulation explained the vital factors in the interaction between D-27 and receptors. D-27 may be a new lead candidate with a dual target in which Of ChtI shall be the main one. This work created a new starting point for discovering a novel type of IGRs.},
  author       = {Jiang, Biaobiao and Jin, Xiaoyu and Dong, Yawen and Guo, Bingbo and Cui, Li and Deng, Xile and Zhang, Li and Yang, Qing and Li, Yuxin and Yang, Xinling and Smagghe, Guy},
  issn         = {0021-8561},
  journal      = {JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY},
  keywords     = {MOLECULAR-DYNAMICS,ECDYSONE RECEPTOR,LIGAND-BINDING,CHITINASE,SIMULATIONS,EXPRESSION,AGONISTS,insect growth regulator,pyrazole amide,ecdysone receptor,chitinase,molecular docking},
  language     = {eng},
  number       = {23},
  pages        = {6347--6354},
  title        = {Design, synthesis, and biological activity of novel heptacyclic pyrazolamide derivatives : a new candidate of dual-target insect growth regulators},
  url          = {http://dx.doi.org/10.1021/acs.jafc.0c00522},
  volume       = {68},
  year         = {2020},
}

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