SAR and QSAR Studies For In Vivo and In Vitro Activities of Ecdysone Agonists

Insect molting is regulated by the steroid 20-hydoxyecdysone interacting with the ecdysone receptor (EcR) together with either the retinoid X receptor (RXR) or its homolog, ultraspiracle (USP). Similarly, the non-steroidal diacylhydrazines (DAHs) also bind to EcR, but regulate molting in a dysfunctional manner; they are therefore insecticidal. The four DAHs tebufenozide, methoxyfenozide, chromafenoz-ide and halofenozide have been commercialized to control Lepidoptera and Coleoptera. DAH congeners with various substituents at both benzene rings were synthesized and their ecdysonergic activity in whole body, tissue, cell and protein was quantified. Insecticidal potency (whole body) was measured against three insect species: rice stem borer Chilo suppressalis, beet armyworm Spodoptera exigua, and Colorado potato beetle Leptinotarsa decemlineata. Substituent effects on the activity were analyzed using quantitative structure-activity relationship (QSAR) methods such as the classical (Hansch-Fujita) QSAR and comparative molecular field analysis (CoMFA). These QSAR methods were also applied to analyse in vitro ecdysonergic potency (tissue and cell level) and EcR binding (protein level). Molecular hydrophobicity was extracted as an important physicochemical property to activity at all biosystem levels. CoMFA results for activation of gene expression in the silkworm Bombyx mori are consistent with the milieu of the ligand binding pocket homology-modeled from the crystal structure of DAH-bound EcR of the tobacco budworm Heliothis virescens.