A New Class of Diaryl Ether Herbicides: Structure-Activity Relationship Studies Enabled by a Rapid Scaffold Hopping Approach

Wereport on the development of a novel class of diaryl ether herbicides.After the discovery of a phenoxybenzoic acid with modest herbicidalactivity, optimization led to several molecules with improved controlof broadleaf and grass weeds. To facilitate this process, we firstemployed a three-step combinatorial approach, then pivoted to a one-stepUllmann-type coupling that provided faster access to new analogs.After determining that the primary target site of our benchmark diarylethers was acetolactate synthase (ALS), we further leveraged thiscopper-catalyzed methodology to conduct a scaffold hopping campaignin the hope of uncovering an additional mode of action with fewerdocumented cases of resistance. Our comprehensive and systematic investigationrevealed that while the herbicidal activity of this area seems tobe exclusively linked to ALS inhibition, our molecules represent astructurally distinct class of Group 2 herbicides. The structure-activityrelationships that led us to this conclusion are described herein.

Automated summary

In this study, we developed a novel class of diaryl ether herbicides. After optimization, several molecules with improved control over broadleaf and grass weeds were discovered. A three-step combinatorial approach was initially employed, followed by a one-step Ullmann-type coupling for faster access to new analogs. The primary target of these diaryl ethers was found to be acetolactate synthase (ALS), and a scaffold hopping campaign using a copper-catalyzed methodology was conducted to explore alternative modes of action with reduced resistance cases. Our investigation revealed that while ALS inhibition is the exclusive mechanism of herbicidal activity in this class, our molecules represent a structurally distinct Group 2 herbicides. The structure-activity relationships leading to this conclusion are described herein.