Benzoylbiuret Insect Chitin Inhibitors: Structure-Activity Correlations Derived from an In vitro Clasper Assay and an In vitro Mosquito Adult Emergence Assay2

Abstract

Chitin-synthesis inhibitory effects of nine l-benzoyl-5-phenyl-biurets and six l-benzoyl-5-phenyl-4-thiobiurets were determined in an in vitro assay using male pharate adult claspers of the European corn borer, Ostrinia nubilalis (Hübner). Incorporation of labeled N-acetylglucosamine into the clasper tissue was effectively inhibited by the benzoylbiurets (IC50 values ranged from 0.032 to 8.2 ppm). Quantitative structure-activity relationships of the benzoylbiurets were analyzed by linear regression analysis. The analysis used yellowfever mosquito (Aedes aegypti (L.)) adult emergence data (LC50 values) and in vitro chitin-synthesis inhibition data (IC50 values) as biological endpoints and a set of physicochemical parameters (independent variables) of the para substituent of the anilide moiety. Stepwise regression analysis of the in vivo data provided a significant four-parameter equation involving Hammett σp and Hansch-Fujita π constants, and two indicator variables. Analysis of the in vitro chitin-synthesis inhibition data yielded a significant two-parameter equation incorporating σp and an indicator variable. In vitro larvicidal activity against A. aegypti and the house fly (Musca domestica L.) was enhanced by electron-withdrawing and lipophilic substituents in the para position of the anilide moiety. In contrast, in vitro chitin-synthesis inhibition was favored by electron-donating substituents. It was suggested that the equations derived from in vivo activity data describe mainly pharmacokinetic processes such as transport and metabolism. Structural requirements for intrinsic activity of the benzoylbiurets at the putative receptor site were better represented by the equation derived from the in vitro chitin-synthesis inhibition data.