Carane-3,4-diol Derivatives as Potential Water-Based Herbicides.

Twelve novel carane-3,4-diol derivatives were designed, synthesized, and evaluated for their herbicidal activities against Lolium multiflorum Lam. and Brassica campestris for the first time. The relationships between the chemical structural factors, including types, the number or the carbon chain length of functional groups, associated with the lipophilicity and the herbicidal activity of the tested compounds were also discussed. The results showed that most of newly synthesized compounds had a dose-dependent, herbicidal activity against the root and shoot growths of Lolium multiflorum Lam. and Brassica campestris. Compared to carane-3,4-diol, most of the target derivatives possessed improved lipophilicity and certain solubilities in representative solvents with different polarities. Particularly, ester derivatives 3a-3b and 3e can be dissolved or dispersed in water, but also displayed higher herbicidal activity against Lolium multiflorum Lam. and Brassica campestris than other ester derivatives. The 50 % inhibitory concentration (IC50) value of compound 3e against shoot growth of Brassica campestris (0.485 mmol/L) was superior to that of commercial herbicide glyphosate (1.14 mmol/L), indicating that the potential application as a water-based herbicide for Brassica campestris control.

Synthesis of Radiolabeled [14C]Rimsulfuron and Stable Isotope Labeled Rimsulfuron-[M + 3] to Support Crop Metabolism Studies for Reregistration.

Rimsulfuron is a sulfonylurea herbicide that controls grass and broadleaf weeds in maize, potatoes, fruits, nuts, and other crops. It can also be used as a burndown herbicide to clear invasive weed species along roadsides and other nonagricultural land. Rimsulfuron acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. As is common practice, rimsulfuron has been subject to periodic reviews by regulatory agencies for reregistration since its introduction into the market in the early 1990s. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this reregistration process for rimsulfuron, a new confined rotational crop study was required to address a data gap requested by the European Food Safety Authority (EFSA). Consequently, the corresponding pyridine and pyrimidine radiolabeled [14C]rimsulfuron and [M + 3] stable isotopes of rimsulfuron were synthesized for this study to support the reregistration process.

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

Synthetic approaches to the 2015-2018 new agrochemicals.

In this review, the synthesis of 33 agrochemicals that received an international standardization organization (ISO) name between January 2015 and December 2018 is described. The aim is to showcase the broad range and scope of reactions, reagents and intermediates used to discover and produce the latest active ingredients addressing the crop protection industry's needs.

Design and synthesis of acrylate and acrylamide substituted pyrimidinediones as potential PPO herbicides.

PPO herbicides emerge to be widely use in the agricultural field and a focus of research to many scientists due to its environmentally-friendly properties. In lieu with this, this study presents acrylate and acrylamide substituted pyrimidinediones as PPO herbicide candidates. Most synthesized compounds exhibits herbicidal activities against both monocot and dicot weeds, especially, compound 5a which showed non-selective superior activity against the commercialized, Saflufenacil. Compound 5a was further tested for residual effect and showed promising results as shorter period is needed to cultivate the next crops. The synthesized acrylate and acrylamide substituted pyrimidinediones, especially, 5a could potentially be utilized in the development of commercial protoporphyrinogen oxidase inhibitors with further tests and studies.

Design, synthesis, and molecular simulation studies of N-phenyltetrahydroquinazolinones as protoporphyrinogen IX oxidase inhibitors.

Discovering new protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors is a promising direction for agrochemical research. Herein, we reported the discovery and in silico structure-guided optimization of N-phenyltetrahydroquinazolinones 1 and 2 as new PPO inhibitors. Most of the obtained compounds 1 and 2 exhibited significantly enhanced Nicotiana tabacum PPO (NtPPO) inhibitory potency than that of flumioxazin. Promisingly, 1-(tert-butoxy)-1-oxopropan-2-yl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)benzoate, 2o, with a Ki value of 4 nM, showed ten folds more enhanced NtPPO-inhibiting potency than flumioxazin. Additionally, compounds 2b and 2i showed a broad spectrum of broadleaf weeds control at 37.5-150 g ai/ha, and selective for wheat at 150 g ai/ha in the post-emergent application. The molecular simulation studies revealed the vital basis between N-phenyltetrahydroquinazolinones and NtPPO. The present work indicated that the N-phenyltetrahydroquinazolinone motif might be a potential scaffold for herbicide discovery.

Synthesis of Pertyolides A, B, and C: A Synthetic Procedure to C17-Sesquiterpenoids and a Study of Their Phytotoxic Activity.

C17-sesquiterpenoids are a group of natural products that have been recently discovered. These compounds have the peculiarity of lacking the α,ß-methylene butyrolactone system, which is known to be quite relevant for many of the biological activities reported for sesquiterpene lactones. Unfortunately, the biological interest of C17-sesquiterpenoids has not been studied in-depth, mainly due to the poor isolation yields in which they can be obtained from natural sources. Therefore, in order to allow a deeper study of these novel molecules, we have worked out a synthetic pathway that provides C17-sesquiterpenoids in enough quantities from easily accessible sesquiterpene lactones to enable a more thorough investigation of their bioactivities. With this synthesis method, we have successfully synthesized, for the first time, three natural C17-sesquiterpenoids, pertyolides A, B, and C, with good overall yields. Furthermore, we have also evaluated their phytotoxicity against etiolated wheat coleoptiles and corroborated that pertyolides B and C present strong phytotoxic activity.

Fabrication of gelatin microspheres containing ammonium hydrogen carbonate for the tunable release of herbicide.

The major challenge in utilizing pesticides lies in identifying the precise application that would improve the efficiency of these pesticides and decline their environmental and health hazards at the same time. Such application requires the development of specific formulations that enable controlled, stimuli-responsive release of the pesticides. Gelatin is a relatively cheap material characterized by temperature-sensitivity and abundant amino acid groups, which makes it suitable for the storage and controlled release of pesticides. In this study, gelatin microspheres were prepared by emulsion and cross-linking, then they were loaded with 2,4-dichlorophenoxyacetic acid sodium (2,4-D Na) as a model herbicide. To achieve temperature-tunable release of 2,4-D Na from the microspheres, NH4HCO3 was added to the formulations at different concentrations. The prepared formulations were characterized by SEM, FTIR, and size distribution analyzes, and their drug loading capacities were determined. Based on bioassay experiments, the 2,4-D Na-NH4HCO3-loaded gelatin microspheres can effectively control the spread of dicotyledonous weeds. Therefore, the strategy proposed herein can be used to develop novel, effective herbicide formulations.

Synthesis and Biological Activities of Novel (Z)-/(E)-Anisaldehyde-Based Oxime Ester Compounds.

In search of novel natural product-based bioactive molecules, twenty (ten pairs) novel (Z)-/(E)-anisaldehyde-based oxime ester compounds were designed and synthesized by using anisaldehyde as starting material. Structural characterization of the target compounds was carried out by NMR, FT-IR, ESI-MS, and elemental analysis. Their herbicidal and antifungal activities were preliminarily tested. As a result, at 50 µg/mL, compound (E)-5b exhibited excellent to good inhibition rates of 92.3 %, 79.2 %, and 73.9 %, against Rhizoctonia solani, Fusarium oxysporum f. sp. cucumerinum, and Bipolaris maydis, respectively, better than or comparable to that of the positive control chlorothalonil. In addition, at 100 µg/mL, compounds (E)-5b, (E)-5f, (Z)-5f and (E)-5d exhibited excellent to good inhibition rates of 85.8 %, 82.9 %, 78.6 % and 64.2 %, respectively, against the root-growth of rape (B. campestris), much better than that of the positive control flumioxazin. The bioassay result also showed that the synthesized compounds had obvious differences in antifungal and herbicidal activities between (Z)- and (E)-isomers. Preliminary structure-activity relationship was also discussed by theoretical calculation.

Evaluation of Chalcone Derivatives as Photosynthesis and Plant Growth Inhibitors.

We report the evaluation of chalcone derivatives as photosystem II (PSII) and plant growth inhibitors. Chalcone derivatives were evaluated as PSII inhibitors through Chl a fluorescence measurement. (E)-Chalcone (6a) and (E)-3-(4-bromophenyl)-1-(4-fluorophenyl)prop-2-en-1-one (6j) showed the best results, reducing the performance index on absorption basis parameter (PIabs ) by 70 %. Additionally, the decrease of TR0 /RC and ET0 /RC parameters indicates that the chalcone derivatives limited the number of active PSII reaction centers and the amount of trapped energy within them. Compounds 6a and 6j both act as post-emergent herbicides at 50 µM, reducing the root biomass of the Ipomoea grandifolia weed by 72 % and 83 %, respectively, corroborating the fluorescence results. The selectivity against weeds as compared to valuable crops by compounds 6a and 6j were evaluated employing Zea mays and Phaseolus vulgaris plants. In these, our newly synthesized compounds showed no effects on biomass accumulation of roots and aerial parts when compared to the control, providing valuable evidence for the role of these compounds as selective inhibitors of the growth of undesired weeds.

Synthesis and Identification of Epoxy Derivatives of 5-Methylhexahydroisoindole-1,3-dione and Biological Evaluation.

Cyclic imides belong to a well-known class of organic compounds with various biological activities, promoting a great interest in compounds with this functional group. Due to the structural complexity of some molecules and their spectra, it is necessary to use several spectrometric methods associated with auxiliary tools, such as the theoretical calculation for the structural elucidation of complex structures. In this work, the synthesis of epoxy derivatives of 5-methylhexahydroisoindole-1,3-diones was carried out in five steps. Diels-Alder reaction of isoprene and maleic anhydride followed by reaction with m-anisidine afforded the amide (2). Esterification of amide (2) with methanol in the presence of sulfuric acid provided the ester (3) that cyclized in situ to give imides 4 and 4-ent. Epoxidation of 4 and 4-ent with meta-chloroperbenzoic acid (MCPBA) afforded 5a and 5b. The diastereomers were separated by silica gel flash column chromatography, and their structures were determined by analyses of the spectrometric methods. Their structures were confirmed by matching the calculated 1H and 13C NMR chemical shifts of (5a and 5b) with the experimental data of the diastereomers using MAE, CP3, and DP4 statistical analyses. Biological assays were carried out to evaluate the potential herbicide activity of the imides. Compounds 5a and 5b inhibited root growth of the weed Bidens pilosa by more than 70% at all the concentrations evaluated.

Aminotenuazonic Acid: Isolation, Structure Elucidation, Total Synthesis and Herbicidal Activity of a New Tetramic Acid from Fruiting Bodies of Laccaria Species.

(5S,6S)-Aminotenuazonic acid, a new 3-acyltetramic acid, related to the well-known mycotoxin tenuazonic acid has been isolated from fruiting bodies of Laccaria bicolor. Its structure was mostly established by analysis of its 2D NMR and HR-(+)-ESI-MS spectra. A total synthesis starting from N-Boc-l-isoleucine gave (5S,6S)-aminotenuazonic acid in 8 % yield over nine steps (67 % de). The key steps of the total synthesis are a light-initiated Hofmann-Löffler-Freytag radical chain reaction and a Dieckmann cyclisation. The relative and absolute configurations of the natural product were determined by comparison of its NMR and CD spectra with those of the corresponding enantiopure synthetic compounds. Metabolic profiling of crude extracts of different mushrooms showed that aminotenuazonic acid is present in all four of the investigated Laccaria species. Aminotenuazonic acid shows phytotoxic activities against the root and shoot growth of Lepidium sativum, Pinus sylvestris and Arabidopsis thaliana comparable to those of tenuazonic acid.

Synthesis and evaluation of indole derivatives as photosynthesis and plant growth inhibitors.

Indole derivatives were synthetized based on the Fischer indole methodology using different phenyl hydrazine hydrochlorides and either cyclohexanone or 2-butanone. The pre- and post-emergent herbicidal activities were evaluated against Ipomoea grandifolia. A carbazole, 6-chloro-2,3,4,9-tetrahydro-1H-carbazole (3b), decreased the PIabs parameter by 32% and increased the cross-section related parameters, indicating the inactivation of the reaction center on photosystem II. Compound 3b acts as a post-emergent herbicide prototype since dry biomass was reduced by 50%, corroborating the fluorescence results. Comparing instead with a germination experiment, 2,3,4,9-tetrahydro-1H-carbazole (3a) was found to be the most effective agent, inhibiting seed germination by 22% and decreasing root length by 50%. The tetrahydrocarbazoles showed better results than indole derivatives potentially due to the presence of methylene groups at structures, which increase the compounds' lipophilicity and may facilitate their access to the plant. In addition, electron withdrawing groups on the aromatic ring were found to correlate with increased herbicide activity. Further optimization of this series towards the development of herbicides is ongoing.

Design, synthesis and algicides activities of thiourea derivatives as the novel scaffold aldolase inhibitors.

By using a new Fragment-Based Virtual Screen strategy, two series of novel FBA-II inhibitors (thiourea derivatives) were de novo discovered based on the active site of fructose-1, 6-bisphosphate aldolase from Cyanobacterial (CyFBA). In comparison, most of the N-(2-benzoylhydrazine-1-carbonothioyl) benzamide derivatives (L14∼L22) exhibit higher CyFBA-II inhibitory activities compared to N-(phenylcarbamothioyl) benzamide derivatives (L1∼L13). Especially, compound L14 not only shows higher CyFBA-II activity (Ki = 0.65 µM), but also exhibits most potent in vivo activity against Synechocystis sp. PCC 6803 (EC50 = 0.09 ppm), higher (7-fold) than that of our previous inhibitor (EC50 = 0.6 ppm). The binding modes of compound L14 and CyFBA-II were further elucidated by jointly using DOX computational protocol, MM-PBSA and site-directed mutagenesis assays. The positive results suggest that strategy adopted in this study was promising to rapidly discovery the potent inhibitors with novel scaffolds. The satisfactory algicide activities suggest that the thiourea derivatives is very likely to be a promising lead for the development of novel specific algicides to solve Cyanobacterial harmful algal blooms (CHABs).

Synthesis and Herbicidal Activity Against Buffelgrass (Cenchrus ciliaris) of (±)-3-deoxyradicinin.

A novel synthetic strategy for obtainment of (±)-3-deoxyradicinin (2) is reported. This synthetic methodology is more efficient than those previously reported in the literature and also shows higher versatility towards the introduction of different side-chains at both C-7 and C-2. The obtained compound (±)-2 shows phytotoxicity against the grass-weed buffelgrass comparable to that of the natural phytotoxin radicinin (1). Therefore, (±)-2 can constitute a more practical synthetic alternative to 1 as bioherbicide for buffelgrass control.

Synthesis of the Core Framework of the Cornexistins by Intramolecular Nozaki-Hiyama-Kishi Coupling.

A new and direct approach to the construction of the core framework of the herbicidal natural products cornexistin and hydroxycornexistin has been developed. Formation of the nine-membered carbocycle found in the natural products has been accomplished by an intramolecular Nozaki-Hiyama-Kishi reaction between a vinylic iodide and an aldehyde. Good yields of carbocyclic products were obtained from the reaction, but diastereomeric mixtures of allylic alcohols were produced. The cyclisation reaction was successful irrespective of the relative configuration of the stereogenic centres in the cyclisation precursor.

Design and Synthesis of N-phenyl Phthalimides as Potent Protoporphyrinogen Oxidase Inhibitors.

Protoporphyrinogen oxidase (PPO) has been identified as one of the most promising targets for herbicide discovery. A series of novel phthalimide derivatives were designed by molecular docking studies targeting the crystal structure of mitochondrial PPO from tobacco (mtPPO, PDB: 1SEZ) by using Flumioxazin as a lead, after which the derivatives were synthesized and characterized, and their herbicidal activities were subsequently evaluated. The herbicidal bioassay results showed that compounds such as 3a (2-(4-bromo-2,6-difluorophenyl) isoindoline-1,3-dione), 3d (methyl 2-(4-chloro-1,3-dioxoisoindolin-2-yl)-5-fluorobenzoate), 3g (4-chloro-2-(5-methylisoxazol-3-yl) isoindoline-1,3-dione), 3j (4-chloro-2-(thiophen-2-ylmethyl) isoindoline-1,3-dione) and 3r (2-(4-bromo-2,6-difluorophenyl)-4-fluoroisoindoline-1,3-dione) had good herbicidal activities; among them, 3a showed excellent herbicidal efficacy against A. retroflexus and B. campestris via the small cup method and via pre-emergence and post-emergence spray treatments. The efficacy was comparable to that of the commercial herbicides Flumioxazin, Atrazine, and Chlortoluron. Further, the enzyme activity assay results suggest that the mode of action of compound 3a involves the inhibition of the PPO enzyme, and 3a showed better inhibitory activity against PPO than did Flumioxazin. These results indicate that our molecular design strategy contributes to the development of novel promising PPO inhibitors.

Herbicidal aryldiones incorporating a 5-methoxy-[1,2,5]triazepane ring.

Novel 2-aryl-cyclic-1,3-diones containing a 5-methoxy-[1,2,5]triazepane unit were explored towards an effective and wheat safe control of grass weeds. Their preparation builds on the ease of synthetic access to 7-membered heterocyclic [1,2,5]triazepane building blocks. Substitution and pattern hopping in the phenyl moiety revealed structure-activity relationships in good agreement with previously disclosed observations amongst the pinoxaden family of acetyl-CoA carboxylase inhibitors. In light of basic physicochemical, enzyme inhibitory and binding site properties, the N-methoxy functionality effectively acts as a bioisostere of the ether group in the seven-membered hydrazine ring.

Design, synthesis and biological evaluation of novel N-nitrophenyl derivatives based on the structure of acetohydroxyacid synthase.

Acetohydroxyacid synthase (AHAS, EC: 2.2.1.6) is a target for the development of novel herbicides. Two series of N-nitrophenyl derivatives, type-A and type-B, were designed and synthesized based on the active site of the AHAS structure. All the structures of newly prepared compounds were thorough characterized by IR, and 1H NMR spectrums. The IC50 values of all synthesized target compounds against AHAS enzyme and EC50 values for herbicidal activity against Brassica campestris L., Amaranthus mangostanus L. and Sorghum sudanense were determined. The bioactive assay results showed that the type-B compounds exhibited highly improved inhibitory activity against the AHAS enzyme and the tested plants comparing to type-A compounds. The IC50 values of most type-B compounds against the AHAS enzyme were between 25-177µM. The EC50 values of several type-B compounds against Sorghum sudanense reached 5.0mg/L. The differences in the biological activity between type-A and type-B compounds were attributed to two structural features - the orthogonal bend at the N-nitro amides group and the common plane structure of another phenyl with chain bridge. With the structure of the target compounds and the IC50 values for AHAS enzyme, a statistically significant CoMFA model with high predict abilities (q2=0.606, r2=0.982, N=4, SEE=0.058, F=280.255) was obtained, and its reliability was verified. The model will provide a theoretical basis for the further structural optimization.

Synthesis and Reactions of α-Hydroxyphosphonates.

This review summarizes the main synthetic routes towards α-hydroxyphosphonates that are known as enzyme inhibitors, herbicides and antioxidants, moreover, a number of representatives express antibacterial or antifungal effect. Special attention is devoted to green chemical aspects. α-Hydroxyphosphonates are also versatile intermediates for other valuable derivatives. O-Alkylation and O-acylation are typical reactions to afford α-alkoxy-, or α-acyloxyphosphonates, respectively. The oxidation of hydroxyphosphonates leads to ketophosphonates. The hydroxy function at the α carbon atom of hydroxyphosphonates may be replaced by a halogen atom. α-Aminophosphonates formed in the nucleophilic substitution reaction of α-hydroxyphosphonates with primary or secondary amines are also potentially bioactive compounds. Another typical reaction is the base-catalyzed rearrangement of α-hydroxy-phosphonates to phosphates. Hydrolysis of the ester function of hydroxyphosphonates leads to the corresponding phosphonic acids.