Design, synthesis and screening of herbicidal activity for new phenyl pyrazole‐based protoporphyrinogen oxidase‐inhibitors (PPO) overcoming resistance issues

• Published in: Pest management science 2023-06, Vol.79 (6), p.2264-2280
• Main Authors: Mattison, Rebecca L., Beffa, Roland, Bojack, Guido, Bollenbach‐Wahl, Birgit, Dörnbrack, Christine, Dorn, Nicole, Freigang, Jörg, Gatzweiler, Elmar, Getachew, Rahel, Hartfiel, Claudia, Heinemann, Ines, Helmke, Hendrik, Hohmann, Sabine, Jakobi, Harald, Lange, Gudrun, Lümmen, Peter, Willms, Lothar, Frackenpohl, Jens
• Format: Article
• Language: English
• Subjects: Amaranthus; bioisosteres; Cereal crops; Commercialization; Control methods; Corn; Crystal structure; Economic importance; herbicide; Herbicides; Herbicides - chemistry; Inhibitors; Physicochemical properties; Plague; Plant Weeds; PPO‐inhibitors; Protoporphyrinogen Oxidase; Pyrazole; Pyrazoles; Pyrazoles - pharmacology; Receptors; resistance; structure–activity relationship; Substitutes; Uracil; Weed control; Weeds
• ISSN: 1526-498X; 1526-4998
• DOI: 10.1002/ps.7425

BACKGROUND Whilst there are several methods to control weeds, which continuously plague farmers around the globe, the application of small molecular compounds is still the most effective technology to date. Plants can evolve to become resistant to PPO‐inhibitors, a class of herbicides in commercial use since the 1960s. It is therefore essential to continuously develop new herbicides based on this mode‐of‐action with enhanced intrinsic activity, an improved resistance profile and favourable physicochemical properties. Based on an Amaranthus PPO crystal structure and subsequent modelling studies, halogen‐substituted pyrazoles have been investigated as isosteres of uracil‐based PPO‐inhibitors. RESULTS By combining structural features from the commercial PPO‐inhibitors tiafenacil and pyraflufen‐ethyl and by investigating receptor‐binding properties, we identified new promising pyrazole‐based lead structures showing strong activity in vitro and in vivo against economically important weeds of the Amaranthus genus: A. retroflexus, and resistant A. palmeri and A. tuberculatus. CONCLUSION The present work covers a series of novel PPO‐inhibiting compounds that contain a pyrazole ring and a substituted thioacetic acid sidechain attached to the core phenyl group. These compounds show good receptor fit in line with excellent herbicidal activity against weeds that plague corn and rice crops with low application rates. This, in combination with promising selectivity in corn, have the potential to mitigate and affect weeds that have become resistant to some of the current market standards. Remarkably, some of the novel PPO‐inhibitors outlined herein show efficacies against economically important weeds that were superior to recently commercialized and structurally related tiafenacil. © 2023 Society of Chemical Industry. The SAR‐study outlined herein is inspired by molecular modelling studies based on a wild‐type Amaranthus tuberculatus PPO‐crystal structure and has afforded a series of novel PPO‐inhibiting compounds that contain pyrazole moieties such as uracil. These compounds show promising herbicidal activity against important weeds in warm season crops.