Scaffold hopping approach to the novel hexacyclic pyrazol-3-amide derivatives as potential multi-target insect growth regulators candidates.

Autor: Guo B; Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China., Luo S; Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China., Chen L; State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, No 97 Buxin Road, Shenzhen 518120, China., Wang C; Engineering Research Center of Plant Growth Regulator, Ministry of Education & College of Agronomy and Biotechnology, China Agricultural University, Beijing 100193, China., Feng Y; Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China., Cao C; Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China., Zhang L; Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China., Yang Q; State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, No 97 Buxin Road, Shenzhen 518120, China. Electronic address: qingyang@caas.cn., Yang X; Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China. Electronic address: yangxl@cau.edu.cn.
Jazyk: angličtina
Zdroj: Pesticide biochemistry and physiology [Pestic Biochem Physiol] 2024 Nov; Vol. 205, pp. 106163. Date of Electronic Publication: 2024 Oct 02.
DOI: 10.1016/j.pestbp.2024.106163
Abstrakt: Ecdysone receptor (EcR) and three insect chitinases (OfChtI, OfChtII, and OfChi-h) are considered as attractive targets for the development of novel insect growth regulators (IGRs) since they are closely related to the insect molting. In this study, to develop potent multi-target IGRs, a series of hexacyclic pyrazol-3-amide derivatives were rationally designed by utilizing the scaffold hopping strategy with the previously reported compound 6j (N-(4-bromobenzyl)-2-phenyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide) as a lead compound. The bioassay results indicated that most of the target compounds exhibited obvious insecticidal activity. Especially, compounds a5 and a21 displayed excellent insecticidal activities against P. xylostella with LC 50 values of 82.29 and 69.45 mg/L, respectively, exceeding that of 6j (263.78 mg/L). Compounds a5 and a21 also dramatically disturbed the growth and development of O. furnacalis larvae, and their LC 50 values were 124.71 and 127.54 mg/L, respectively, superior to the lead 6j (267.33 mg/L). The action mechanism study revealed that the most active compound a21 could act simultaneously on EcR (21.4 % binding activity at 8 mg/L), OfChtI (94.9 % inhibitory at 10 μM), OfChtII (23.1 % inhibitory at 10 μM), and OfChi-h (94.3 % inhibitory at 10 μM), significantly higher than that of the lead compound 6j. The result of molecular docking indicated that transferring the carboxamide group from pyrazole position 5 to 3 enhanced the interactions of a21 with the key amino acid residues of the OfChtI, OfChtII, and OfChi-h, resulting in stronger affinity to the three targets than 6j. The present work offers a useful guidance for the further development of novel multi-target IGRs.
Competing Interests: Declaration of competing interest The authors declare no competing financial interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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