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

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 LC₅₀ 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 LC₅₀ 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.