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

Abstract

There are several methods to control weeds, which impose particular challenges for farmers in all parts of the world, although applying small molecular compounds still remains the most efficient technology to date. However, plants can evolve to become resistant toward active ingredients which is also the case for protoporphyrinogen oxidase (PPO) inhibitors, a class of highly effective herbicides in use for more than 50 years. Hence, it is essential to continuously discover and develop new herbicidal PPO inhibitors with enhanced intrinsic activity, an improved resistance profile, enhanced crop safety, favorable physicochemical properties, and a clean toxicological profile. By modifying structural key features from known PPO inhibitors such as tiafenacil, inspired by isostere and mix&match concepts in combination with modeling investigations based on a wild-type Amaranthus crystal structure, we have found new promising lead structures showing strong activity in vitro and in vivo against several notorious dicotyledon and monocotyledon weeds with emerging resistance (e.g., Amaranthus palmeri, Amaranthus tuberculatus, Lolium rigidum, and Alopecurus myosuroides). While several phenyl uracils carrying an isoxazoline motif in their thio-linked side chain showed promising resistance-breaking potential against different Amaranthus species, introducing a thioacrylamide side chain afforded outstanding efficacy against resistant grass weeds.

Design, Synthesis, and Bioactivities of N-Heterocyclic Ureas as Strigolactone Response Antagonists against Parasitic-Weed Seed Germination

“…The utilization of chemical agents may exert deleterious effects on the regular growth patterns of various crop species . The assessment of chemical compounds on the safety of crops serves as a valuable tool for identifying more secure modes of application as well as optimal dosages, which contributes to a decrease in detrimental consequences on the environment and ecosystems, fostering agricultural sustainability and the preservation of valuable resources to a certain extent …”

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

“…Furthermore, sterically more demanding substituents at position R 1 , such as cyclopropyl and iso ‐propyl groups, also were tolerated, albeit with slightly lower efficacy. These promising results prompted us to investigate unprecedented modifications of tiafenacil's thiolactic amide moiety in a dedicated separate study 36 . To further validate our initial in vivo screening results, we selected 15a as direct isostere of tiafenacil 4 which showed strong efficacy in broadleaf weeds.…”

“…The core phenyl group also has been manipulated to create pyridine analogues 34 and the chlorine in position 4 has been substituted with other halogens and cyano‐groups. Alkyl, cycloalkyl, alkenyl and aryl branches alpha to the sulfide in the side‐chain have been investigated along with alkenyl groups, as well as lactam formation 35,36 . Derivatives of the terminal amino acid group such as alkyl branches of oxygen, sulfur and nitrogen atoms also were investigated 33,37 .…”

Design, Synthesis, and Herbicidal Activity of Substituted 3-(Pyridin-2-yl)Phenylamino Derivatives

“…For example, saflufenacil and tiafenacil, developed by BASF and FarmHannong Co., Ltd., respectively, are PPO inhibitors with a broad-spectrum and highly effective herbicidal activity (Figure B). All of these herbicide molecules contain F and Cl atom-substituted phenyl rings …”