Structure-Activity Relationships of Diphenyl Ethers and Other Oxygen-Bridged Protoporphyrinogen Oxidase Inhibitors

Abstract

The first commercial inhibitors of protoporphyrinogen oxidase (Protox) were diphenyl ether (DPE) molecules (Matsunaka 1976; see Chapter 1). Nitrofen was introduced in the early 1960s and was followed by several other, more potent Protox inhibitors (Dayan and Duke 1996, 1997). The molecular site of action of this class of herbicides was unknown until 1989 (Matringe et al. 1989). Thus, all quantitative structure-activity relationship (QSAR) studies conducted before this time were done solely on the correlation of structure with biological activity in intact tissues (e.g., Lambert et al. 1983). In some of these studies, the “activity” portion of the QSAR study may not have been completely or even at all associated with Protox inhibition, in that diphenyl ether compounds have several other potential secondary sites of action (Kunert et al. 1987). In 1992, we published the first QSAR study of DPE herbicides in which inhibition of Protox was correlated with molecular parameters (Nandihalli et al. 1992). This earlier work and subsequent published work on the QSAR of Protox inhibitors have largely been performed at a two dimensional level (Nandihalli and Duke 1994; Reddy et al. 1995). This chapter reviews this previous work and extends QSAR studies with DPEs to three-dimensional descriptors that more precisely describe the requisites for activity of Protox inhibitors at the molecular level. The scope of this chapter will be limited to the Protoxinhibiting herbicides that are bicyclic molecules connected by an oxygen bridge, although several second generation Protox inhibitors have been developed on non-bridged bicyclic structures (e.g., phenyl triazolinones, isoxazole carboxamides and phenyl imides). The QSAR analysis of several classes of first and second generation Protox inhibitors has recently been reviewed by Reddy et al. (1997).