Total synthesis and structure-activity-relationship of Alternaric acid delivers an herbicide vector

Abstract

Global food security is one of the foremost challenges of our time and requires a multifaceted solution. Crop protection strategies are an essential part of this response; however, there is increasing resistance to known modes of action. Since its discovery in 1949, the natural product alternaric acid has been proposed as a starting point for herbicide development. However, this target is undeveloped due to its poor synthetic accessibility and a lack of knowledge of the associated pharmacology. Here we report the discovery of herbicidal compounds from alternaric acid that operate via a potentially unknown mode of action. Development of a total synthesis enabled structure–activity relationship profiling of compound libraries, which, combined with phenotypic screening and molecular modelling data, identified small-molecule lead compounds with enhanced and broader spectrum herbicidal activity than alternaric acid.