Novel Pyrazole Acyl(thio)urea Derivatives Containing a Biphenyl Scaffold as Potential Succinate Dehydrogenase Inhibitors: Design, Synthesis, Fungicidal Activity, and SAR.

As part of a program to discover novel succinate dehydrogenase inhibitor fungicides, a series of new pyrazole acyl(thio)urea compounds containing a diphenyl motif were designed and synthesized. Their structures were confirmed by 1H NMR, HRMS, and single X-ray crystal diffraction analysis. Most of these compounds possessed excellent activity against 10 fungal plant pathogens at 50 µg mL-1, especially against Rhizoctonia solani, Alternaria solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Cercospora arachidicola. Interestingly, compounds 3-(difluoromethyl)-1-methyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9b, EC50 = 0.97 ± 0.18 µg mL-1), 1,3-dimethyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9a, EC50 = 2.63 ± 0.41 µg mL-1), and N-((4'-chloro-[1,1'-biphenyl]-2-yl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4-carboxamide (9g, EC50 = 1.31 ± 0.15 µg mL-1) exhibited activities against S. sclerotiorum that were better than the commercial fungicide bixafen (EC50 = 9.15 ± 0.05 µg mL-1) and similar to the positive control fluxapyroxad (EC50 = 0.71 ± 0.11 µg mL-1). These compounds were not significantly phytotoxic to monocotyledonous and dicotyledonous plants. Structure-activity relationships (SAR) are discussed by substituent effects/molecular docking, and density functional theory analysis indicated that these compounds are succinate dehydrogenase inhibitors.

Discovery of Fungicidal Hydrazide Lead Compounds Derived from Sinapic Acid and Mycophenolic Acid.

Structure optimization based on natural products has become an effective way to develop new green fungicides. In this project, thirty-two novel NPs-derived hydrazide compounds were designed and synthesized by introducing the bioactive hydrazide substructure into sinapic acid and mycophenolic acid. The fungicidal bioassays indicated that the obtained hydrazide compounds showed excellent and selective fungicidal activity against specific pathogens, especially compounds C8, D7, and D8 with EC50 values of 0.63, 0.56, and 0.43 µg mL-1 against M. oryzae, respectively. SAR indicated that the introduction of 4-fluoro, 4-chloro, and 2,4-difluoro groups was conducive to improving the fungicidal activity, while the extension of the hydrazide bridge would affect the selectivity for inhibitory activity. Subsequently, the effects of hydrazide compounds on rice seedling and zebrafish growth were also investigated. The fungicidal mechanism implied that treatment with compound B4 would cause significant changes in metabolites of plasma membrane-related linolenic acid metabolism, arachidonic acid metabolism, and α-linolenic acid metabolism pathways, which further led to the wrinkled hyphae and the blurred plasma membrane and cytoplasm. Finally, the frontier molecular orbitals and charge distribution were calculated to analyze the differences in bioactivity from a structural perspective. These results provide important guidance for the development and practical application of novel fungicides.

Synthesis, crystal structure, herbicidal activity and mode of action of new cyclopropane-1,1-dicarboxylic acid analogues.

A new series of cyclopropane-1,1-dicarboxylic (CPD) acid analogues were designed and synthesized. CPD is an inhibitor of ketol-acid reductoisomerase (KARI), an enzyme of the branched chain amino acid pathway in plants. The structures of CPD analogues were characterized by 1H NMR and HRMS. The structure of N,N'-bis(4-(tert-butyl)phenyl)cyclopropane-1,1-dicarboxamide was further elucidated by X-ray diffraction. The herbicidal activities of these compounds were tested against lettuce (Lactuca sativa) and bentgrass (Agrostis stolonifera). Most of these compounds exhibited low herbicidal activity against both plant species. Among them, N,N'-bis(2-ethylphenyl)cyclopropane-1,1-dicarboxamide displayed moderate activity against bentgrass. Inhibition of KARI activity by the CPD analogues was also assessed experimentally and by molecular docking simulation with results supporting inhibition of KARI as their mode of action. These results provide the basis for design of more effective KARI inhibitors.

Synthesis, herbicidal activity and soil degradation of novel 5-substituted sulfonylureas as AHAS inhibitors.

BACKGROUND: Chlorsulfuron, metsulfuron-methyl and ethametsulfuron can damage sensitive crops in rotation pattern as a result of their long persistence in soil. To explore novel sulfonylurea (SU) herbicides with favorable soil degradation rates, four series of SUs were synthesized through a structure-based drug design (SBDD) strategy. RESULTS: The target compounds, especially Ia, Id and Ie, exhibited prospective herbicidal activity against dicotyledon oil seed rape (Brassica campestris), amaranth (Amaranthus retroflexus), monocotyledon barnyard grass (Echinochloa crusgalli) and crab grass (Digitaria sanguinalis) at a concentration of 15 a.i. g ha-1 . Additionally, Ia, Id and Ig displayed excellent inhibitory effects against AtAHAS, with Kapp i values of 59.1, 34.5 and 71.8 µm, respectively, which were much lower than that of chlorsulfuron at 149.4 µm. The π-π stack and H-bonds between the Ia conformation and AtAHAS in the molecular docking results confirmed the series of compounds to be conventional AHAS inhibitors. In alkaline soil (pH = 8.46), compounds Ia-Ig revealed various degrees of acceleration in the degradation rate compared with chlorsulfuron. Besides, compound Ia showed considerable wheat and corn safety under postemergence at the concentration of 30, 60 and even 120 a.i. g ha-1 . CONCLUSION: Overall, based on the synthetic procedure, herbicidal activity, soil degradation and crop safety, the Ia sulfonylureas series were chosen to be investigated as prospective AHAS inhibitors. The 5-dimethylamino group on SUs accelerated the degradation rate at different levels in alkaline soils which seems to be controllable in conventional cropping systems in their further application. © 2022 Society of Chemical Industry.

Alkaline Soil Degradation and Crop Safety of 5-Substituted Chlorsulfuron Derivatives.

Sulfonylurea herbicides can lead to serious weed resistance due to their long degradation times and large-scale applications. This is especially true for chlorsulfuron, a widely used acetolactate synthase inhibitor used around the world. Its persistence in soil often affects the growth of crop seedlings in the following crop rotation, and leads to serious environmental pollution all over the world. Our research goal is to obtain chlorsulfuron-derived herbicides with high herbicidal activities, fast degradation times, as well as good crop safety. On account of the slow natural degradation of chlorsulfuron in alkaline soil, based on the previously reported results in acidic soil, the degradation behaviours of 5-substituted chlorsulfuron analogues (L101-L107) were investigated in a soil with pH 8.39. The experimental data indicated that 5-substituted chlorsulfuron compounds could accelerate degradation rates in alkaline soil, and thus, highlighted the potential for rational controllable degradation in soil. The degradation rates of these chlorsulfuron derivatives were accelerated by 1.84-77.22-fold, compared to chlorsulfuron, and exhibited excellent crop safety in wheat and corn (through pre-emergence treatment). In combination with bioassay activities, acidic and alkaline soil degradation, and crop safety, it was concluded that compounds L104 and L107, with ethyl or methyl groups, are potential green sulfonylurea herbicides for pre-emergence treatment on wheat and corn. This paper provides a reference for the further design of new sulfonylurea herbicides with high herbicidal activity, fast, controllable degradation rates, and high crop safety.

Synthesis and Pesticidal Activities of New Quinoxalines.

Natural products are a source of many novel compounds with biological activity for the discovery of new pesticides and pharmaceuticals. Quinoxaline is a fused N-heterocycle in many natural products and synthetic compounds, and seven novel quinoxaline derivatives were designed and synthesized via three steps. Pesticidal activities of title quinoxaline derivatives were bioassayed. Most of these compounds had herbicidal, fungicidal, and insecticidal activities. The compounds 2-(6-methoxy-2-oxo-3-phenylquinoxalin-1(2H)-yl)acetonitrile (3f) and 1-allyl-6-methoxy-3-phenylquinoxalin-2(1H)-one (3g) were the most active herbicides and fungicides. Mode-of-action studies indicated that 3f is a protoprophyrinogen oxidase-inhibiting herbicide. Compound 3f also possessed broad-spectrum fungicidal activity against the plant pathogen Colletotrichum species. Some of these compounds also had insecticidal activity. Molecular docking and DFT analysis can potentially be used to design more active compounds.

Controllable Soil Degradation Rate of 5-Substituted Sulfonylurea Herbicides as Novel AHAS Inhibitors.

Chlorsulfuron has been applied in wheat fields as a recognized herbicide worldwide, yet it was officially banned in China since 2014 for its soil persistence problem. On the basis of our previous research that 5-dimethylamino distinctively accelerated degradation rate in soils, a modified amino moiety (Ia-c) and monosubstituted amino group (Id-e) were introduced onto the fifth position of the benzene ring in sulfonylurea structures, as well as heterocyclic amino substituents (If-g) to seek a suitable soil degradation rate during such an in situ crop rotation system. Referring to the biological data and ScAHAS inhibition and ScAHAS docking results, they turned out to be AHAS inhibitors with high potent herbicidal activities. The various influence on soil degradation rate along with crop safety indicated that different substituents on the fifth position have exerted an apparent impact. Their united study of structure-activity-safety-degradation relationship has great potential to provide valuable information for further development of eco-friendly agrochemicals.

Design and Synthesis of Novel 4-Hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one Derivatives for Use as Herbicides and Evaluation of Their Mode of Action.

In order to develop a novel herbicide containing the ß-triketone motif, a series of 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one derivatives were designed and synthesized. The bioassay results showed that compound II15 had good pre-emergent herbicidal activity even at a dosage of 187.5 g ha-1. Moreover, compound II15 showed a broader spectrum of weed control when compared with a commercial herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), and displayed good crop safety to Triticum aestivum L. and Zea mays Linn. when applied at 375 g ha-1 under pre-emergence conditions, which indicated its great potential as a herbicide. More importantly, studying the molecular mode of action of compound II15 revealed that the novel triketone structure is a proherbicide of its corresponding phenoxyacetic acid auxin herbicide, which has a herbicidal mechanism similar to that of 2,4-D. The present work indicates that the 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one motif may be a potential lead structure for further development of novel auxin-type herbicides.

Synthesis, insecticidal evaluation and 3D-QSAR study of novel anthranilic diamide derivatives as potential ryanodine receptor modulators.

BACKGROUND: Anthranilic diamide insecticides control lepidopteran pests through selectively binding and activating insect ryanodine receptors. In order to search for potential insecticides targeting the ryanodine receptors, a series of anthranilic diamide analogs including trifluoromethyl, nitro, or chloro groups were designed and synthesized by the principle of bioisosterism and structural optimization. RESULTS: Insecticidal data indicated that some compounds displayed good activity against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). In particular, the larvicidal activity of 6p against P. xylostella was 95% at 0.01 mg L-1 , equivalent to chlorantraniliprole (85%, 0.01 mg L-1 ). The comparative molecular similarity index analysis model obtained indicated that hydrogen bond acceptor and electron-withdrawing groups in the R'3 group are favourable for insecticidal activity against M. separata, which is consistent with the structure-activity relationships. Moreover, the calcium imaging experiment indicated, like chlorantraniliprole, that 6h and 6p are interacting with the ryanodine receptor. CONCLUSION: Introducing trifluoromethyl, nitro, or chloro groups to a specific position in the N-phenylpyrazole could improve or maintain the activity against M. separata and P. xylostella. 6h and 6p could be used as potential lead compounds for ryanodine receptor modulators. © 2018 Society of Chemical Industry.

Research on Controllable Degradation of Novel Sulfonylurea Herbicides in Acidic and Alkaline Soils.

The degradation issue of sulfonylurea (SU) has become one of the biggest challenges that hamper the development and application of this class of herbicides, especially in the alkaline soils of northern China. On the basis of the previous discovery that some substituents on the fifth position of the benzene ring in Chlorsulfuron could hasten its degradation rate, apparently in acidic soil, this work on Metsulfuron-methyl showed more convincing results. Two novel compounds (I-1 and I-2) were designed and synthesized, and they still retained potent herbicidal activity in tests against both dicotyledons and monocotyledons. The half-lives of degradation (DT50) assay revealed that I-1 showed an accelerated degradation rate in acidic soil (pH 5.59). Moreover, we delighted to find that the degradation rate of I-1 was 9-10-fold faster than that of Metsulfuron-methyl and Chlorsulfuron when in alkaline soil (pH 8.46), which has more practical value. This research suggests that a modified structure that has potent herbicidal activity as well as accelerated degradation rate could be realized and this approach may provide a way to improve the residue problem of SUs in farmlands with alkaline soil.

Modulation of fructo-oligosaccharide during silybin-meditated improvement of nonalcoholic fatty liver / 中国药理学通报

Aim To examine weather fructo-oligosaccharides(FOS) and silybin(Sil) could exhibit synergetic effect on treating obesity-associated non-alcoholic fatty liver disease(NAFLD).Methods Seventy mice were randomly divided into two groups:control group (NCD,fed with normal chow diet),the other sixty mice were fed with high-fat diet (HFD) to establish NAFLD model.Seventy days after the establishment of experimental model,the latter group was then randomly subdivided into six groups:model (HFD),Sil (30mg· kg-1),FOS (2 000 mg · kg-1),Sil (30 mg ·kg-1) combined with FOS of high,medium and low dose respectively.The NCD and HFD group were given 0.5％ CMC,and the other groups were fed with high-fat diet and given 10 mL · kg-1 by gavage daily,then body weight and food intake were recorded.Fasting blood glucose,insulin,homeostasis model of assessment for insulin resistence index (HOMA-IR) and oral glucose tolerance tests(OGTT) were measured after 120 days.All mice were sacrificed after 130 days,and blood and liver were collected.Levels of TC,TG,ALT,AST in serum were detected,and liver index and pathology were also examined.Results FOS (2 000 mg · kg-1) showed obvious synergism for Sil-mediated attenuation of levels of TC,TG,ALT,AST in serum,fasting blood glucose,insulin,HOMA-IR,OGTI curve,liver index and pathology,but FOS (4 000 mg · kg-1) could not bring superiority with a double dose,except for its improvement in body weight of mice with NAFLD.Conclusions In the treatment of NAFLD,FOS exhibits synergetic effect with Sil.This agent might be a potent candidate for obesity and NAFLD prevention,through modulating the composition of gut microbiota.

Indium-Mediated Intramolecular Reaction of N-(2-Iodobenzoyl)azabenzonorbornadienes: A General Access to Dihydrobenzo[c]phenanthridinones.

An efficient synthesis of dihydrobenzo[c]phenanthridinones was achieved by utilizing an indium(0)-mediated intramolecular cyclization reaction under ligand- and base-free conditions. A variety of functional groups were tolerated in the present protocol.

Novel Anthranilic Diamide Scaffolds Containing N-Substituted Phenylpyrazole as Potential Ryanodine Receptor Activators.

To discover potent insecticides targeting ryanodine receptors (RyRs), a series of novel anthranilic diamides analogues (12a-12u) containing N-substituted phenylpyrazole were designed and synthesized. These compounds were characterized by (1)H NMR, (13)C NMR, and HRMS, and the structure of compound 12u was confirmed by X-ray diffraction. Their insecticidal activities indicated that these compounds displayed moderate to excellent activities. In particular, 12i showed 100 and 37% larvicidal activities against oriental armyworm (Mythimna separata) at 0.25 and 0.05 mg L(-1), equivalent to that of chlorantraniliprole (100%, 0.25 mg L(-1); and 33%, 0.05 mg L(-1)). The activity of 12i against diamondback moth (Plutella xylostella) was 95% at 0.05 mg L(-1), whereas the control was 100% at 0.05 mg L(-1). The calcium-imaging technique experiment results showed that the effects of 12i on the intracellular calcium ion concentration ([Ca(2+)]i) in neurons were concentration-dependent. After the central neurons of Helicoverpa armigera were dyed by loading with fluo-5N and treated with 12i, the free calcium released in endoplasmic reticulum indicated the target of compound 12i is RyRs or IP3Rs. The activation of RyRs by natural ryanodine completely blocked the calcium release induced by 12i, which indicated that RyRs in the central neurons of H. armigera third-instar larvae is the possible target of compound 12i.

Discovery of (2-benzoylethen-1-ol)-containing 1,2-benzothiazine derivatives as novel 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibiting-based herbicide lead compounds.

A series of (2-benzoylethen-1-ol)-containing benzothiazine derivatives was synthesized, and their herbicidal activities were first evaluated. The bioassay results indicated that some of 3-benzoyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide derivatives displayed good herbicidal activity in greenhouse testing, especially, compound 4w had good pre-emergent herbicidal activities against Brassica campestris, Amaranthus retroflexus and Echinochloa crusgalli even at a dosage of 187.5 g ha(-1). More importantly, compound 4w displayed significant inhibitory activity against Arabidopsis thaliana HPPD and was identified as the most potent candidate with IC50 value of 0.48 µM, which is better than the commercial herbicide sulctrione (IC50=0.53 µM) and comparable with the commercial herbicide mesotrione (IC50=0.25 µM). The structure-activity relationships was studied and provided some useful information for improving herbicidal activity. The present work indicated that (2-benzoylethen-1-ol)-containing 1,2-benzothiazine motif could be a potential lead structure for further development of novel HPPD inhibiting-based herbicides.

Synthesis, fungicidal activity and structure-activity relationships of 3-benzoyl-4-hydroxylcoumarin derivatives.

BACKGROUND: To develop a coumarin-based fungicide, a series of 3-benzoyl-4-hydroxylcoumarin derivatives were synthesised and their fungicidal activities were evaluated against typical fungi occurring in Chinese agroecosystems. RESULTS: Target compounds were characterised through (1) H NMR, (13) C NMR and high-resolution mass spectrometry. The crystal structure of compound III-21 was determined through X-ray diffraction. Bioassay results indicated that most of the target compounds showed good growth inhibition against all of the fungi tested in vitro. EC50 of the target compounds against Physalospora piricola, Rhizoctonia cerealis, Sclerotinia sclerotiorum and Botrytis cinerea indicated that most of the target compounds displayed comparable activity with that of carbindazim and chlorothalonil in vitro. Among these compounds, the analogue 3-(2-bromo-4-chlorobenzoyl)-4-hydroxylcoumarin (III-21) displayed the optimum growth inhibition against R. cerealis (87.5%) and B. cinerea (82.7%) in vivo at 200 µg mL(-1) concentration; thus, this analogue is a potential inhibitor of pathogenic fungi and a new major compound for further optimisation. The results of analysing the structure-activity relationships demonstrated that changes in substituents on benzene ring A of 3-benzoyl-4-hydroxylcoumarin caused different fungicidal activities and provided original information on the preferential conformation to maintain high activities. CONCLUSION: The present work demonstrated that 3-benzoyl-4-hydroxylcoumarin derivatives can be used as possible major compounds to develop novel fungicides. © 2015 Society of Chemical Industry.