Protoporphyrinogen Oxidase Inhibitors Research Articles

Molecular Modeling Study and Proposition of Novel Diaryl Ether Derivatives as Protoporphyrinogen Oxidase Inhibitors

Molecular Modeling Study and Proposition of Novel Diaryl Ether Derivatives as Protoporphyrinogen Oxidase Inhibitors

Design, Synthesis of Novel Pyrimidine Derivatives Containing Alkenyl Moieties With Herbicidal Activities

ABSTRACTTo identify lead compounds with potent herbicidal activity, a range of pyrimidine derivatives containing alkenyl groups were designed, synthesized, and characterized using nuclear magnetic resonance (NMR) spectroscopy and high‐resolution mass spectrometry (HRMS). The synthetic pathways for producing these compounds involved substitution reactions, cyclization, hydrolysis, and other processes. The starting materials for each reaction step were readily accessible, facilitating synthesis. The purification of the final product was straightforward, yielding approximately 80%, under mild reaction conditions. Moreover, a pot culture experiment was employed to assess the herbicidal efficacy of the aforementioned compounds. Compounds 6a, 6b, 6h, and 6j demonstrated a significant inhibition against Amaranthus retroflexus, comparable to fomesafen at 150 g a.i./hm2. This suggests that these compounds hold promise as potential lead structures for herbicidal agents. The docking results indicated that the binding energies of compound 6a with protoporphyrinogen oxidase (PPO) were both negative and spontaneous, with numerous interaction active sites. Thus, it is speculated that compound 6a is a PPO inhibitor.

Patterns of herbicide resistance in Raphanus raphanistrum revealed by comprehensive testing and statistical analysis.

Raphanus raphanistrum causes $40 million total revenue losses annually in Western Australia partly due to its historically-documented ability to evolve herbicide resistance to multiple modes of action. In this study, 376 field-sampled populations of R. raphanistrum were tested for resistance to 21 herbicides applied at the recommended label rate. Eight treatments were herbicide mixtures with two, three or four modes of action. A total of 7199 individual resistance tests were conducted across 4 years by screening approximately 104 000 individual seeds and seedlings. The mean survival of individuals within a population for all standalone herbicides was 9%, whereas survival was significantly decreased to 3.5% with a herbicide mixture. Some herbicides such as triasulfuron (herbicide Group 2), 2,4-D (Group 4) or diflufenican (Group 12) were highly impacted by resistance, with frequencies of resistant populations being > 50%. Conversely, there was negligible resistance to glyphosate (Group 9) or protoporphyrinogen oxidase (PPO) inhibitors (tiafenacil, saflufenacil + trifludimoxazin, fomesafen: Group 14), and pre-emergence herbicides (i.e., atrazine or mesotrione: Groups 5 and 27, respectively) remained largely effective. Binary, ternary or quaternary mixtures of Groups 4, 6, 12 and 27 herbicides reduced the frequency of high-level resistant populations to 7.1%, 3.8% or 0%, respectively. The cost-effective control of R. raphanistrum remains a challenge due to herbicide resistance. Raphanus raphanistrum management relies heavily on herbicide uses not yet compromised by resistance, such as pre-emergence herbicides (atrazine, fomesafen, mesotrione), glyphosate, and mixtures of two, three or four modes of action including bromoxynil, diflufenican, MCPA, picolinafen, pyrasulfotole and topramezone. Strategies that integrate effective herbicide use patterns, novel modes of action and efficiently-mechanized non-chemical weed control options (i.e., seed destructors) can completely constrain the selection of herbicide resistance in this highly adaptable species. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Resistance to protoporphyrinogen oxidase inhibitors in giant ragweed (Ambrosia trifida).

Giant ragweed (Ambrosia trifida L.) is one of the most troublesome weed species in corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] cropping systems. Following numerous reports in 2018 of suspected herbicide resistance in several Ambrosia trifida populations from Wisconsin, our objective was to characterize the response of these accessions to acetolactate synthase (ALS), enolpyruvyl shikimate phosphate synthase (EPSPS), and protoporphyrinogen oxidase (PPO) inhibitors applied POST. Four accessions (AT1, AT4, AT6, and AT10) exhibited ≥ 50% plant survival after exposure to the cloransulam 3× rate. Two accessions (AT8 and AT10) and one accession (AT2) exhibited ≥ 50% plant survival after exposure to glyphosate and fomesafen 1× rates, respectively. The AT10 accession exhibited multiple resistance to cloransulam and glyphosate. The AT12 accession was 28.8-fold resistant to fomesafen and 3.7-fold resistant to lactofen. A codon change in PPX2 conferring a R98L substitution was identified as the most likely mechanism conferring PPO-inhibitor resistance. To our knowledge, this is the first confirmed case of PPO-inhibitor resistance in Ambrosia trifida globally and we identified the genetic mutation likely conferring resistance. Proactive and diversified integrated weed management strategies are of paramount importance for sustainable long-term Ambrosia trifida management. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Mapping of flumioxazin tolerance in a snap bean diversity panel leads to the discovery of a master genomic region controlling multiple stress resistance genes.

Effective weed management tools are crucial for maintaining the profitable production of snap bean (Phaseolus vulgaris L.). Preemergence herbicides help the crop to gain a size advantage over the weeds, but the few preemergence herbicides registered in snap bean have poor waterhemp (Amaranthus tuberculatus) control, a major pest in snap bean production. Waterhemp and other difficult-to-control weeds can be managed by flumioxazin, an herbicide that inhibits protoporphyrinogen oxidase (PPO). However, there is limited knowledge about crop tolerance to this herbicide. We aimed to quantify the degree of snap bean tolerance to flumioxazin and explore the underlying mechanisms. We investigated the genetic basis of herbicide tolerance using genome-wide association mapping approach utilizing field-collected data from a snap bean diversity panel, combined with gene expression data of cultivars with contrasting response. The response to a preemergence application of flumioxazin was measured by assessing plant population density and shoot biomass variables. Snap bean tolerance to flumioxazin is associated with a single genomic location in chromosome 02. Tolerance is influenced by several factors, including those that are indirectly affected by seed size/weight and those that directly impact the herbicide's metabolism and protect the cell from reactive oxygen species-induced damage. Transcriptional profiling and co-expression network analysis identified biological pathways likely involved in flumioxazin tolerance, including oxidoreductase processes and programmed cell death. Transcriptional regulation of genes involved in those processes is possibly orchestrated by a transcription factor located in the region identified in the GWAS analysis. Several entries belonging to the Romano class, including Bush Romano 350, Roma II, and Romano Purpiat presented high levels of tolerance in this study. The alleles identified in the diversity panel that condition snap bean tolerance to flumioxazin shed light on a novel mechanism of herbicide tolerance and can be used in crop improvement.

Novel Uracilphenyl sulfonamide-based inhibitors of protoporphyrinogen oxidase: Design, synthesis, and herbicidal activity

Herein, we aimed to develop effective herbicidal compounds by synthesizing 26 novel uracil derivatives containing sulfonamide groups based on the active group splicing principle, with saflufenacil as the reference compound. The structures of the final products were confirmed through 1H NMR, 13C NMR, and HRMS analyses. According to the results, 21 and 19 compounds exhibited outstanding (80 %-100 %) and 60–100 % control efficacies against broadleaf weeds (Zinnia elegans and Abutilon theophrasti) at concentrations of 150 g/hm2 and 37.5 g/hm2, respectively. Notably, compound 2a demonstrated 100 % control efficacy against Zinnia elegans even at the lowest tested concentration of 9.375 g/hm2. On the other hand, the examined compounds exhibited minimal efficacy against other grass weeds, such as Setaria glauca and Echinochloa crusgalli. Furthermore, molecular docking analysis revealed that compound 2a formed hydrogen bonds with Protoporphyrinogen Oxidase (PPO).Studies of the electrostatic potential analysis of the molecular surface showed that the highly active compounds 2a and saflufenacil have similar charge distributions, which may play an important role in the docking of the compounds with their target receptors.These findings offer valuable insights and guidance for developing more effective herbicides, paving the way for future advances in weed control tactics.

Design, Synthesis, and Herbicidal Evaluation of Pyrrolidinone-Containing 2-Phenylpyridine Derivatives as Novel Protoporphyrinogen Oxidase Inhibitors.

In this work, a series of pyrrolidinone-containing 2-phenylpyridine derivatives were synthesized and evaluated as novel protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors for herbicide development. At 150 g ai/ha, compounds 4d, 4f, and 4l can inhibit the grassy weeds of Echinochloa crus-galli (EC), Digitaria sanguinalis (DS), and Lolium perenne (LP) with a range of 60 to 90%. Remarkably, at 9.375 g ai/ha, these compounds showed 100% inhibition effects against broadleaf weeds of Amaranthus retroflexus (AR) and Abutilon theophrasti (AT), which were comparable to the performance of the commercial herbicides flumioxazin (FLU) and saflufenacil (SAF) and better than that of acifluorfen (ACI). Molecular docking analyses revealed significant hydrogen bonding and π-π stacking interactions between compounds 4d and 4l with Arg98, Asn67, and Phe392, respectively. Additionally, representative compounds were chosen for in vivo assessment of PPO inhibitory activity, with compounds 4d, 4f, and 4l demonstrating excellent inhibitory effects. Notably, compounds 4d and 4l induced the accumulation of reactive oxygen species (ROS) and a reduction in the chlorophyll (Chl) content. Consequently, compounds 4d, 4f, and 4l are promising lead candidates for the development of novel PPO herbicides.

Discovery of Pyridyl-Benzothiazol Hybrids as Novel Protoporphyrinogen Oxidase Inhibitors via Scaffold Hopping.

In order to discover novel protoporphyrinogen oxidase (PPO) inhibitors with excellent herbicidal activity, a series of structurally novel 6-(pyridin-2-yl) benzothiazole derivatives were designed based on the scaffold hopping strategy. The in vitro experiments demonstrated that the newly synthesized compounds exhibited noteworthy inhibitory activity against Arabidopsis thaliana PPO (AtPPO), with IC50 values ranging from 0.06 to 1.36 μM. Preliminary postemergence herbicidal activity tests and crop safety studies indicated that some of our compounds exhibited excellent herbicidal activity and crop safety. For instance, compound (rac)-7as exhibited superior herbicidal activities to commercially available flumioxazin (FLU) and saflufenacil (SAF) at all the tested concentrations and showed effective herbicidal activities even at a dosage as low as 18.75 g ai/ha. Meanwhile, compound (rac)-7as showed good crop safety for wheat at a dosage as high as 150 g of ai/ha. Although the absolute configuration of compound 7as has no obvious effect on its herbicidal activity, compound (R)-7as showed a slightly higher crop safety than compound (S)-7as. Molecular simulation studies of Nicotiana tabacum PPO (NtPPO) and our candidate compounds showed that the benzothiazole moiety of compounds (R)-7as or (S)-7as formed multiple π-π stacking interactions with FAD, and the pyridine ring generated π-π stacking with Phe-392. Our finding proved that the pyridyl-benzothiazol hybrids are promising scaffolds for the development of PPO-inhibiting herbicides.

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

To discover protoporphyrinogen oxidase (PPO) inhibitors with robust herbicidal activity and crop safety, three types of substituted 3-(pyridin-2-yl)phenylamino derivatives bearing amide, urea, or thiourea as side chain were designed via structure splicing strategy. Postemergence herbicidal activity assessment of 33 newly prepared compounds revealed that many of our compounds such as 6a, 7b, and 8d exhibited superior herbicidal activities against broadleaf and monocotyledon weeds to commercial acifluorfen. In particular, compound 8d exhibited excellent herbicidal activities and high crop safety at a dosage range of 37.5-150 g ai/ha. PPO inhibitory studies supported our compounds as typical PPO inhibitors. Molecular docking studies revealed that compound 8d provided effective interactions with Nicotiana tabacum PPO (NtPPO) via diverse interaction models, such as π-π stacking and hydrogen bonds. Molecular dynamics (MD) simulation studies and degradation studies were also conducted to gain insight into the inhibitory mechanism. Our study indicates that compound 8d may be a candidate molecule for the development of novel herbicides.

Spray interval, application order, and plant height influences control of dicamba-resistant Palmer amaranth

Abstract Palmer amaranth, which is resistant to glyphosate and protoporphyrinogen oxidase inhibitors, remains a threat to cotton and soybean production in Tennessee. This is partly due to the recent evolution of dicamba-resistant Palmer amaranth in western Tennessee, which further complicates weed management. Experiments were conducted in 2021 and 2022 to determine the best timing between sequential applications and the order in which 2,4-D or dicamba should be used with glufosinate to control resistant Palmer amaranth. Palmer amaranth control increased when the interval between postemergence herbicide applications decreased from 21 to 7 d. At the 7-d interval in a dicamba-based system, the order of herbicides did not affect Palmer amaranth control. However, in a 2,4-D-based system, the greatest control was achieved when 2,4-D was applied first, followed by either 2,4-D or glufosinate. While weed height at the time of application had a significant effect on Palmer amaranth control with auxin herbicides, control was still unacceptable in the field at the labeled rates of dicamba or 2,4-D when applied to weeds that were <10 cm tall (48% and 53%, respectively). Neither dicamba nor 2,4-D provided acceptable control of the Palmer amaranth populations evaluated in this study. Sequential applications separated by 7 d provided better weed control than those separated by 21 d. Given that the better 7-d sequential treatments provided less than 90% control and resulted in more than 64,000 surviving Palmer amaranth plants per hectare suggests that relying solely on these herbicides for Palmer amaranth control is not a sustainable weed management strategy.

Common ragweed (Ambrosia artemisiifolia L.) accessions in the Mid-Atlantic region resistant to ALS-, PPO-, and EPSPS-inhibiting herbicides

Abstract Common ragweed is a troublesome weed in many crops. Farmers and crop advisors in the coastal Mid-Atlantic region have reported inadequate control of common ragweed in soybean fields with glyphosate and other herbicide modes of action. To determine whether herbicide resistance was one of the causes of poor herbicide performance, 29 accessions from four states (Delaware, Maryland, New Jersey, and Virginia) where common ragweed plants survived herbicide applications and produced viable seeds were used for greenhouse screening. Common ragweed seedlings from those accessions were treated with multiple rates of cloransulam, fomesafen, or glyphosate, applied individually postemergence (POST). All accessions except one demonstrated resistance to at least one of the herbicides applied at twice the effective rate (2×), 17 accessions were two-way resistant (to glyphosate and cloransulam, or to glyphosate and fomesafen), and three-way resistance was present in eight accessions collected from three different states. Based on the POST study, five accessions were treated preemergence (PRE) with herbicides that inhibit acetolactate synthase (ALS), and two accessions were treated with herbicides that inhibit protoporphyrinogen oxidase (PPO). All accessions treated PRE with the ALS inhibitors chlorimuron or cloransulam demonstrated resistance at the 2× rates. Both accessions treated PRE with the PPO inhibitor sulfentrazone had survivors at the 2× rate. When the same accessions were treated PRE with fomesafen, one had survivors at the 2× rate, and one had survivors at the 1× rate. Results from these tests confirmed common ragweed with three-way resistance to POST herbicides is widespread in the region. In addition, this is the first confirmation that common ragweed accessions in the region are also resistant to ALS- or PPO-inhibiting herbicides when applied PRE.

A systematic review of chemical weed management in peanut (Arachis hypogaea) in the United States: challenges and opportunities

AbstractHerbicides are the primary tool for controlling weeds in peanut (Arachis hypogaea L.) and are crucial to sustainable peanut production in the United States. The literature on chemical weed management in peanut in the past 53 yr (1970 to 2022) in the United States was systematically reviewed to highlight the strengths and weaknesses of different herbicides and identify current research gaps in chemical weed management. Residual weed control in peanut is achieved mainly with dimethenamid-P, ethalfluralin, pendimethalin, and S-metolachlor. More recently, the use of the protoporphyrinogen oxidase inhibitor flumioxazin and acetolactate synthase inhibitors, such as diclosulam, for residual weed control in peanut has increased considerably. Postemergence broadleaf weed control in peanut is achieved mainly with acifluorfen, bentazon, diclosulam, imazapic, lactofen, paraquat, and 2,4-DB, while the graminicides clethodim and sethoxydim are the major postemergence grass weed control herbicides in peanut. Although several herbicides are available for weed control in peanut, no single herbicide can provide season-long weed control due to limited application timing, lack of extended residual activity, variability in weed control spectrum, and rotational restrictions. Therefore, effective weed management in peanut often requires herbicide mixtures and/or sequential application of preplant-incorporated, preemergence, and/or postemergence herbicides. However, the available literature showed a substantive range in herbicide efficacy due to variations in environmental conditions and flushes of weed germination across years and locations. Despite the relatively high efficacy of herbicides, the selection of herbicide-resistant weeds is another area of increasing concern. Future research should focus on developing new strategies for preventing or delaying the development of resistance and improving herbicide efficacy within the context of climate change and emerging constraints such as water shortages, rising temperatures, and increasing CO2 concentration.

Synthesis, Herbicidal Activity, Mode of Action, and In Silico Analysis of Novel Pyrido[2,3-d]pyrimidine Compounds.

Natural products are a main source of new chemical entities for use in drug and pesticide discovery. In order to discover lead compounds with high herbicidal activity, a series of new pyrido[2,3-d] pyrimidine derivatives were designed and synthesized using 2-chloronicotinic acid as the starting material. Their structures were characterized with 1H NMR, 13C NMR and HRMS, and the herbicidal activities against dicotyledonous lettuce (Lactuca sativa), field mustard (Brassica campestris), monocotyledonous bentgrass (Agrostis stolonifera) and wheat (Triticum aestivum) were determined. The results indicated that most of the pyrido[2,3-d] pyrimidine derivatives had no marked inhibitory effect on lettuce at 1 mM. However, most of the pyrido[2,3-d] pyrimidine derivatives possessed good activity against bentgrass at 1 mM. Among them, the most active compound, 3-methyl-1-(2,3,4-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2o), was as active as the positive controls, the commercial herbicides clomazone and flumioxazin. Molecular simulation was performed with molecular docking and DFT calculations. The docking studies provided strong evidence that 2o acts as an herbicide by inhibition of protoporphyrinogen oxidase. However, the physiological results indicate that it does not act on this target in vivo, implying that it could be metabolically converted to a compound with a different molecular target.

Cross and multiple herbicide resistance across Ukraine

Goal. Identify resistance to herbicides in weed species on the crops of leading agricultural companies in the regions of Ukraine and identify ways to counteract the emergence of resistant weed biotypes.
 Methods. The research of herbicide effectiveness was carried out in production and vegetation experiments. Control plants were collected on non-arable land. Statistical analysis was performed using StatPlus software from AnalystSoft Inc.
 Results. Field and greenhouse studies in 2014—2023 identified herbicide resistance in highly damaging biotypes of monocotyledonous and dicotyledonous weed species in Ukraine. In 2022—2023, herbicide-resistant ragweed (Ambrosia artemisiifolia L.) affected sunflower crops, the main crop that ensures the profitability of crop production in the country. Imidazolinone resistance in Ambrosia was identified in 2015. In 2023, multiply resistance to herbicides — acetolactate synthase inhibitors and protoporphyrinogen oxidase inhibitors (ALS+PРO) — was identified in A. artemisiifolia in large areas of sunflower in central and southern Ukraine. In previous years, resistant to the action of herbicides — acetolactate synthase inhibitors of the imidazolinone class ‒ imazapyr and imazamox biotypes of monocot Echinochloa crus-galli var. crus-galli (L.) P. Beauv., and dicot Amaranthus retroflexus L., and Chenopodium album L. have been identified. Cross-resistance to herbicides: monocot to sulfonylurea (nicosulfuron), and triazole pyrimidines (penoxsulam); dicots to sulfonylurea foramsulfuron, iodosulfuron-methyl-sodium, thifensulfuron-methyl, tribenuron-methyl; to sulfonylaminocarbonyl triazolinone derivative — thiencarbazone-methyl; to triazole pyrimidine derivatives — florasulam, and flumetsulam were established. The multiple resistance of Echinochloa crus-galli, Amaranthus retroflexus, and Chenopodium album to herbicides of the classes of glycine derivatives — glyphosate, monocot to graminicide pinoxaden, and dicot species to phenoxy carboxylic derivatives — 2.4-D, benzoic acid — dicamba; triketones — topramezone; diphenyl ethers — aclonifen have not been established. It was shown that herbicide compositions under the influence of the ammonium pool can increase the level of controlling resistant weed biotypes effectiveness. In 2018—2021, in rice crop rotations in the South of Kherson region, the emergence and spread of a cereal multiply resistant (ALS + ACC) species, Eragrostis spp. was detected.
 Conclusions. The identification of highly harmful resistant Ambrosia artemisiifolia, Echinochloa crus-galli, Amaranthus retroflexus, Chenopodium album, and Eragrostis spp. in the South and Central part of the «grain belt» of Ukraine shows the limited effectiveness of weed control exclusively with herbicides with one mechanism of action and requires a significant revision of the principles of crop rotation formation and methods of weed control in the state to maintain high levels of profitability and productivity of agrophytocenoses. Solving these issues is urgent in order to preserve Ukraine’s potential as one of the guarantors of world food security.

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

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitor herbicides have attracted widespread attention in recent years as ideal herbicides due to their high efficiency, low toxicity, and low pollution. In this article, 30 phenylpyrazole derivatives containing five-membered heterocycles were designed and synthesized according to the principle of bioelectronic isoarrangement and active substructure splicing. A series of structural characterizations were performed on the synthesized compounds. The herbicide activity in greenhouse was evaluated to determine their growth inhibition effect on weeds, their IC50 value through in vitro PPO enzyme activity measurement was calculated, and target compounds 2i and 3j that have herbicide effects comparable to pyraflufen-ethyl were selected. Crop safety experiments have shown that when the spraying concentration is 300 g of ai/ha, gramineous crops such as wheat, corn, and rice are more tolerant to compound 2i, with wheat exhibiting high tolerance, which is equivalent to the crop safety of pyraflufen-ethyl. Compound 2i can be used as a candidate herbicide for wheat, corn, and paddy fields, and the results are consistent with the cumulative concentration experiment. Molecular docking results showed that compound 2i interacted with the amino acid residue ARG-98 by forming two hydrogen bonds and interacted with the amino acid residue PHE-392 by forming two π-π stacking interactions, indicating that compound 2i has more excellent herbicidal activity than pyraflufen-ethyl and is expected to become a potential lead compound of phenylpyrazole PPO inhibitor herbicides.

Protoporphyrinogen oxidase inhibitors discovered by Artificial Intelligence platform

Protoporphyrinogen oxidase inhibitors discovered by Artificial Intelligence platform

Design, synthesis and biological activity determination of novel phenylpyrazole protoporphyrinogen oxidase inhibitor herbicides

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is the last common enzyme in the biosynthetic pathway in the synthesis of heme and chlorophyll. The high-frequency use of PPO inhibitor herbicides has led to the gradual exposure of pesticide damage and resistance problems. In order to solve this kind of problem, there is an urgent need to develop new PPO inhibitor herbicides. In this paper, 16 phenylpyrazole derivatives were designed by the principle of active substructure splicing through the electron isosterism of five-membered heterocycles. Greenhouse herbicidal activity experiments and in vitro PPO activity experiments showed that the inhibitory effect of compound 9 on weed growth was comparable to that of pyraflufen-ethyl. Crop safety experiments and cumulative concentration experiments in crops showed that when the spraying concentration was 300 g ai/ha, wheat, corn, rice and other cereal crops were more tolerant to compound 9, among which wheat showed high tolerance, which was comparable to the crop safety of pyraflufen-ethyl. Herbicidal spectrum experiments showed that compound 9 had inhibitory activity against most weeds. Molecular docking results showed that compound 9 formed one hydrogen bond interaction with amino acid residue ARG-98 and two π-π stacking interactions with amino acid residue PHE-392, indicating that compound 9 had better herbicidal activity than pyraflufen-ethyl. It shows that compound 9 is expected to be a lead compound of phenylpyrazole PPO inhibitor herbicide and used as a herbicide in wheat field.

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 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.

Low carrier volume herbicide trials and UAAS support management efforts of giant salvinia (Salvinia molesta): a case study

AbstractExpanding the current aquatic herbicide portfolio, reducing total spray volumes, or remotely delivering herbicide using novel spray technologies could improve management opportunities targeting invasive aquatic plants, where options are more limited. However, research on giant salvinia (Salvinia molesta Mitchell) response to foliar herbicide applications at carrier volumes ≤140 L ha−1 is incomplete. Likewise, no data exist documenting S. molesta control with unoccupied aerial application systems (UAAS). Following the recent >100-ha incursion of S. molesta in Gapway Swamp, NC, a case study was developed to provide guidance for ongoing management efforts. In total, three field trials evaluated registered aquatic and experimental herbicides using a 140 L ha−1 carrier volume. Select foliar applications from UAAS were also evaluated. Results at 8 wk after treatment (WAT) indicated the experimental protoporphyrinogen oxidase inhibitor, PPO-699-01 (424 g ai ha−1), in combination with endothall dipotassium salt (2,370 g ae ha−1) provided 78% visual control, whereas control when PPO-699-01 (212 g ai ha−1) was applied alone was lower at 35%. Evaluations also showed diquat (3,136 g ai ha−1) alone, glyphosate (4,539 g ae ha−1) alone, and metsulfuron-methyl (42 g ai ha−1) alone achieved 86% to 94% visual plant control at 8 WAT. Sequential foliar applications of diquat, flumioxazin (210 g ai ha−1), and carfentrazone (67 g ai ha−1) at 6 wk following exposure to in-water fluridone treatments were no longer efficacious by 6 WAT due to plant regrowth. Carfentrazone applications made from a backpack sprayer displayed greater control than applications made with UAAS deploying identical carrier volumes at 2 WAT; however, neither application method provided effective control at 8 WAT. Additional field validation is needed to further guide management direction of S. molesta control using low carrier volume foliar applications.

Enhanced Herbicide Metabolism and Target-Site Mutations Confer Multiple Resistance to Fomesafen and Nicosulfuron in Amaranthus retroflexus L.

Amaranthus retroflexus L. is a highly competitive broadleaf weed of corn-soybean rotation in northeastern China. In recent years, the herbicide(s) resistance evolution has been threatening its effective management in crop fields. One resistant A. retroflexus (HW-01) population that survived the protoporphyrinogen oxidase (PPO) inhibitor fomesafen and acetolactate synthase (ALS) inhibitor nicosulfuron applied at their field-recommended rate was collected from a soybean field in Wudalianchi City, Heilongjiang Province. This study aimed to investigate the resistance mechanisms of fomesafen and nicosulfuron and determine the resistance profile of HW-01 to other herbicides. Whole plant dose-response bioassays revealed that HW-01 had evolved resistance to fomesafen (50.7-fold) and nicosulfuron (5.2-fold). Gene sequencing showed that the HW-01 population has a mutation in PPX2 (Arg-128-Gly) and a rare mutation in ALS (Ala-205-Val, eight/twenty mutations/total plants). In vitro enzyme activity assays showed that ALS extracted from the HW-01 plants was less sensitive to nicosulfuron (3.2-fold) than ST-1 plants. Pre-treatment with the cytochrome P450 inhibitors malathion, piperonyl butoxide (PBO), 3-amino-1,2,4-triazole (amitrole), and the GSTs inhibitor 4-chloro-7-nitrobenzofurazan (NBD-Cl) significantly increased fomesafen and nicosulfuron sensitivity in the HW-01 population compared with that of the sensitive (S) population ST-1. Moreover, the rapid fomesafen and nicosulfuron metabolism in the HW-01 plants was also confirmed via HPLC-MS/MS analysis. Furthermore, the HW-01 population showed multiple resistance (MR) to PPO, ALS, and PSII inhibitors, with resistance index (RI) values ranging from 3.8 to 9.6. This study confirmed MR to PPO-, ALS-, and PSII-inhibiting herbicides in the A. retroflexus population HW-01, as well as confirming that the cytochrome P450- and GST-based herbicide metabolic along with TSR mechanisms contribute to their multiple resistance to fomesafen and nicosulfuron.