Designing New Protoporphyrinogen Oxidase-Inhibitors Carrying Potential Side Chain Isosteres to Enhance Crop Safety and Spectrum of Activity

There are several methods to control weeds, which imposeparticularchallenges for farmers in all parts of the world, although applyingsmall molecular compounds still remains the most efficient technologyto date. However, plants can evolve to become resistant toward activeingredients which is also the case for protoporphyrinogen oxidase(PPO) inhibitors, a class of highly effective herbicides in use formore than 50 years. Hence, it is essential to continuously discoverand develop new herbicidal PPO inhibitors with enhanced intrinsicactivity, an improved resistance profile, enhanced crop safety, favorablephysicochemical properties, and a clean toxicological profile. Bymodifying structural key features from known PPO inhibitors such astiafenacil, inspired by isostere and mix&match concepts in combinationwith modeling investigations based on a wild-type Amaranthus crystal structure, we have found new promising lead structures showingstrong activity in vitro and in vivo against several notorious dicotyledon and monocotyledon weeds withemerging resistance (e.g., Amaranthus palmeri, Amaranthus tuberculatus, Lolium rigidum, and Alopecurus myosuroides). While several phenyluracils carrying an isoxazoline motif in their thio-linked side chainshowed promising resistance-breaking potential against different Amaranthus species, introducing a thioacrylamide side chainafforded outstanding efficacy against resistant grass weeds.