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

Abstract

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.

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

“…Typically, the protein structures of inhibitors bound to PPO substantiate that the phenyl moieties and the attached heterocycles are positioned in a hydrophobic pocket below the FAD cofactor whereas the side chains point into a large open pocket . Furthermore, the superposition of a bromopyrazole-based PPO inhibitor bound to the Nicotiana PPO2 ,, and tiafenacil ( 2 ) bound to amaranth PPOx (Figure a) indicated that the phenyl moiety is at the same position and that both the uracil moiety in tiafenacil ( 2 ) and the bromopyrazole headgroup are nicely superposing. , These findings suggested that shape-matching moieties may be easily exchanged by isosteres in PPO inhibitors.…”

“…Due to their broad spectrum of controlled weeds, novel uracil-based PPO inhibitors are attractive starting points for scaffold hopping and investigating isostere motifs with the aim to identify new lead structures to control resistant weeds. To complement recent approaches to replace tiafenacil’s uracil headgroup, , we focused entirely on side-chain variations. From a synthetic chemist’s perspective, the side chain moieties of tiafenacil ( 2 ), epyrifenacil ( 3 ), and isoxazoline ( 4 ) that mimic pyrrole ring C and the hydrophilic carboxylate moiety in protoporphyrinogen IX , can be altered easily to explore their effect on in vivo efficacy and receptor binding (Figure ).…”

Synthesis and Biological Activity Evaluation of Benzoxazinone-Pyrimidinedione Hybrids as Potent Protoporphyrinogen IX Oxidase Inhibitor

“…Trifludimoxazin is the first PPO-inhibiting herbicide with a triazinone motif and is an ultraefficient agent for foliar touch control of grass weeds. , Furthermore, due to its unique enzyme binding properties, trifludimoxazin rapidly acts and is highly active against many PPO-resistant weed biotypes, such as Amaranthus spp . and Ambrosia spp . , The aforementioned three PPO-inhibiting herbicides have a common feature of bearing the benzoxazinone core scaffold, which can be found in several bioactive molecules with anti-inflammatory, bactericidal, insecticidal, and herbicidal properties. , Recently, several novel PPO inhibitors based on the benzoxazinone skeleton have been published (Figure ). For example, Wang’s research publication of compound 1 as the first potent PPO inhibitor with pyrido­[2,3- d ]­pyrimidine-2,4-dione-benzoxazinone hybrids .…”

“…and Ambrosia spp. 33,34 The aforementioned three PPO-inhibiting herbicides have a common feature of bearing the benzoxazinone core scaffold, which can be found in several bioactive molecules with anti-inflammatory, bacter-icidal, insecticidal, and herbicidal properties. 25,35 Recently, several novel PPO inhibitors based on the benzoxazinone skeleton have been published (Figure 2).…”

Design, Synthesis, and Biological Activity Determination of Novel Phenylpyrazole Protoporphyrinogen Oxidase Inhibitor Herbicides Containing Five-Membered Heterocycles

“…24,25 Under the action of molecular oxygen, singlet oxygen is generated, resulting in the peroxidation and degradation of unsaturated fatty acids in the cell membrane, leading to plant cell death and ultimately plant death, which is manifested as leaf albino. 26,27 At present, the protoporphyrinogen oxidase inhibitor herbicides on the market are roughly divided into phenylpyrazole, triazolinone, diphenyl ether, oxadiazole, thiadiazole, pyrimidine dione, oxazolin dione, N-phenylphthalein imide, and others. 28−30 PPO inhibitors have a wide variety of herbicides, which have attracted widespread attention due to their low dosage, strong efficacy, short effective time, and wide herbicide spectrum.…”