Optimization of Osthole as a Pesticide Candidate: Synthesis, Crystal Structures, and Agrochemical Properties of Acrylate Derivatives of Isopropenyl 2,3-Dihydrobenzofurans.

For high-value-added application of osthole derivatives as a pesticide candidate in crop protection, by the use of osthole as a lead compound, a series of novel acrylate derivatives of isopropenyl 2,3-dihydrobenzofurans were prepared by the successive bromination, rearrangement, and esterization reactions. Three-dimensional structures of four compounds were determined by single-crystal X-ray diffraction. The possible mechanism for construction of this new isopropenyl 2,3-dihydrobenzofuran skeleton from the osthole was presented. Against Plutella xylostella Linnaeus, compound 32 (R = PhCH2CH2) displayed 3.5-fold potent insecticidal activity of osthole. Against Tetranychus cinnabarinus Boisduval, compound 40 (LC50: 0.165 mg/mL; R = (CH2)13CH3) showed 8.3-fold pronounced acaricidal activity of osthole (LC50: 1.367 mg/mL); notably, its control effect can be comparable to that of the commercial acaricide spirodiclofen. Additionally, the scanning electron microscopy imaging method demonstrated that compound 40 can destroy the stratum corneum of T. cinnabarinus. Compound 40 can be further explored as a lead acaricidal agent.

Quantitative proteomics analysis reveals the key proteins related to semen quality in Niangya yaks.

BACKGROUND: Proteins related to sperm motility and sperm morphology have an important impact on sperm function such as metabolism, motility and fertilisation etc. An understanding of the key proteins related to semen quality in Niangya yaks would help to provide support for breeding. However, the key proteins that affect semen quality in Niangya yaks remain unclear. METHODS: Herein, we applied tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC‒MS/MS) to analyze the expression levels of sperm proteins in groups of high- and low-quality semen from Niangya yaks. And fifteen differentially expressed proteins (DEPs) were randomly selected for expression level validation by parallel reaction monitoring (PRM). RESULTS: Of the 2,092 quantified proteins, 280 were identified as DEPs in the high-quality group versus the low-quality group. Gene Ontology (GO) analysis revealed that in terms of biological pathways, the DEPs were mainly involved in metabolic processes, cell transformation processes, and single organism metabolic processes. In terms of cell composition, the DEPs were mainly located in the cell membrane, organelle, molecular complex. In terms of molecular functions, the most abundant functions of the DEPs were catalytic activity, binding activity, transport activity, and enzyme regulation activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the DEPs were mainly involved in the cytokine and cytokine receptor interaction, notch signaling pathway, lysine biosynthesis, renal function-related protein and proteasome pathway. From protein-protein interaction (PPI) analysis of DEPs involved in important pathways, 6 related proteins affecting the semen quality of Niangya yaks were identified. And the results of the PRM and TMT analysis were consistent. CONCLUSIONS: The differential sperm proteomic analysis of high- and low-quality semen from Niangya yaks, revealed 6 proteins (PSMC5, PSMD8, PSMB3, HSP90AA1, UGP2 and HSPB1), were mainly concentrated in energy production and metabolism, might play important roles in semen quality, which could serve as candidates for the selection and breeding of Niangya yaks.

Glyphosate exposure deteriorates oocyte meiotic maturation via induction of organelle dysfunctions in pigs.

BACKGROUND: Recently, defects in mammalian oocytes maturation induced by environmental pollution results in the decreasing animal reproduction. Animal exposed to glyphosate is largely unavoidable because glyphosate is one of the most widely used herbicide worldwide due to its high-efficiency and broad-spectrum effects, which causes glyphosate an environmental contaminant found in soil, water and food. During the last few years, the growing and wider use of glyphosate has raised great concerns about its effects of reproductive toxicity. In this study, using porcine models, we investigated effects of glyphosate on organelle functions during oocyte meiosis. RESULTS: The results showed glyphosate exposure disrupted porcine oocyte maturation. Expression levels of cumulus expansion-related genes were interfered, further indicating the meiotic defects. The damaging effects were mediated by destruction of mitochondrial distribution and functions, which induced ROS accumulation and oxidative stress, also indicated by the decreased mRNA expression of related antioxidant enzyme genes. We also found an interference of endoplasmic reticulum (ER) distribution, disturbance of Ca2+ homeostasis, as well as fluctuation of ER stress, showing with the reduced ER stress-related mRNA or protein expression, which could indicate the dysfunction of ER for protein processing and signal transduction in glyphosate-exposed oocytes. Moreover, glyphosate exposure induced the disruption of lysosome function for autophagy, showing with the decrease of LAMP2 expression and autophagy-related genes mRNA expression. Additionally, our data showed the distribution of Golgi apparatus and the functions of ribosome were disturbed after glyphosate exposure, which might affect protein synthesis and transport. CONCLUSIONS: Collectively, our study showed that exposed to glyphosate could affect animal reproduction by compromising the quality of oocytes through its wide toxic effects on organelle functions.

High Value-Added Application of Natural Plant Products in Crop Protection: Honokiol Monoester/Diester Derivatives Containing the Novel Core Scaffold of Benzodihydrofuran and Their Agricultural Bioactivities and Control Effects.

To discover new potential botanical insecticides from plant secondary metabolites, a series of new honokiol-type monoester/diester derivatives containing the core scaffold of benzodihydrofuran were synthesized by structural modification of honokiol. Against Mythimna separata Walker, 2-hydroxymethy-5-(2'-(para-chlorobenzoyloxy)-5'-(1″,2″-epoxypropanyl))phenyl-2,3-dihydrobenzofuran (5) and 2-(2″-chloropyridin-5″-ylcarbonyloxy)methylene-5-(2'-(2″-chloropyridin-5″-ylcarbonyloxy)-5'-(1″,2″-epoxypropanyl))phenyl-2,3-dihydrobenzofuran (37) displayed >2.1-fold promising insecticidal activity of the precursor honokiol. Against Aphis citricola Van der Goot, 2-hydroxymethy-5-(2'-(tridecylcarbonyloxy)-5'-(1″,2″-epoxypropanyl))phenyl-2,3-dihydrobenzofuran (21) (LD50: 0.049 µg/nymph) and 2-(para-fluorobenzylcarbonyloxy)methylene-5-(2'-(para-fluorobenzylcarbonyloxy)-5'-(1″,2″-epoxypropanyl))phenyl-2,3-dihydrobenzofuran (31) (LD50: 0.040 µg/nymph) showed 3.5- and 4.3-folds potent aphicidal activity of honokiol (LD50: 0.171 µg/nymph), respectively. Interestingly, 2-(tridecylcarbonyloxy)methylene-5-(2'-(tridecylcarbonyloxy)-5'-(1″,2″-epoxypropanyl))phenyl-2,3-dihydrobenzofuran (46) (LC50: 0.186 mg/mL) and 2-(dodecylcarbonyloxy)methylene-5-(2'-(dodecylcarbonyloxy)-5'-(1″,2″-epoxypropanyl))phenyl-2,3-dihydrobenzofuran (53) (LC50: 0.159 mg/mL: >6.4-fold of honokiol (LC50: 1.024 mg/mL)) exhibited promising acaricidal activity and control efficiency against Tetranychus cinnabarinus Boisduval. Structure-activity relationships indicated that a specific length of the aliphatic chain is necessary for the agricultural activities of honokiol monoester/diester derivatives, especially for the acaricidal activity of diester derivatives.

Osthole: Synthesis, Structural Modifications, and Biological Properties.

Osthole, a naturally occurring coumarin-type compound, is isolated from the Chinese herbal medicine Cnidium monnieri (L.) and exhibits a broad range of biological properties. In this review, the total synthesis and structural modifications of osthole and its analogs are described. Additionally, the progress on bioactivities of osthole and its analogs has been outlined since 2016. Moreover, the structure-activity relationships and mechanisms of action of osthole and its derivatives are discussed. These can provide references for future design, development, and application of osthole and its analogs as drugs or pesticides in the fields of medicine and agriculture.

iTRAQ-based proteomic analysis of sperm reveals candidate proteins that affect the quality of spermatozoa from boars on plateaus.

BACKGROUND: Tibetan pigs (TP) exhibit heritable adaptations to their hypoxic environments as a result of natural selection. However, candidate proteins that affect the sperm quality of boars on plateaus have not yet been clearly investigated. METHODS: In this study, to reveal the candidate proteins that affect the quality of spermatozoa of boars on plateaus, we analyzed the sperm quality using computer-assisted semen analysis (CASA) system and reactive oxygen species (ROS) levels. We also compared the proteomes of sperm proteomes between TP and Yorkshire pigs (YP) raised at high altitudes using the isobaric tags for relative and absolute quantitation (iTRAQ) in combination with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic method, and confirmed the relative expression levels of the four proteins by western blotting. RESULTS: The sperm quality of the TP was superior to that of the YP on plateaus. Of the 1,555 quantified proteins, 318 differentially expressed proteins (DEPs) were identified. Gene ontology (GO) analysis revealed that the DEPs were predominantly associated with the sorbitol metabolic process, removal of superoxide radicals, cellular response to superoxide, response to superoxide and regulation of the mitotic spindle assembly. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were mainly enriched in pathways involved in the regulation of the actin cytoskeleton, glutathione metabolism, oxidative phosphorylation, and estrogen signaling. Based on the protein-protein interaction (PPI) network analysis, we identified 8 candidate proteins (FN1, EGF, HSP90B1, CFL1, GPX4, NDUFA6, VDAC2, and CP) that might play important roles and affect the sperm quality of boars on plateaus. Moreover, the relative expression levels of four proteins (CFL1, EGF, FN1, and GPX4) were confirmed by western blot analysis. CONCLUSIONS: Our study revealed 8 candidate proteins (FN1, EGF, HSP90B1, CFL1, GPX4, NDUFA6, VDAC2, and CP) that affect the sperm quality of boar on plateaus and provide a reference for further studies on improving sperm quality and the molecular breeding of boars on plateaus.

Regioselective hemisynthesis and insecticidal activity of C8-hydrazones/acylhydrazones/sulfonylhydrazones coumarin-type derivatives of osthole.

Osthole, a coumarin-type natural product, is isolated from Chinese traditional herbal medicine Cnidium monnieri. In order to improve the pesticidal activity of osthole, and high value-added application of the plant Cnidium monnieri, a series of new derivatives containing hydrazone/acylhydrazone/sulfonylhydrazone skeletons at the C-8 position of osthole were regioselectively semi-prepared. The steric structure of 3c was determined by the X-ray crystal structure. Against Mythimna separata Walker, benzoylhydrazone 3b (R1 = 4-CH3Ph) showed 1.6 folds potent insecticidal activity of the precursor osthole. Introduction of the acylhydrazones on the 3'-methyl-2'-butylenyl fragment at the C-8 position of osthole can improve the insecticidal activity. These will provide a foundation for future structural modifications of osthole as pesticidal agents.

Construction of oxime ester derivatives of osthole from Cnidium monnieri, and evaluation of their agricultural activities and control efficiency.

BACKGROUND: In order to discover natural-product-based pesticidal candidates, a series of coumarin-like derivatives containing oxime ester fragments at the C-8 position were prepared by structural modification of osthole, a natural plant product isolated from Cnidium monnieri. Their pesticidal activities were evaluated against two typically fruit trees/crop-threatening agricultural pests, Mythimna separata Walker and Tetranychus cinnabarinus Boisduval. RESULTS: Osthole was regioselectively oxidized by selenium dioxide to give the E-isomer, (2'E)-3'-formaldehydylosthole (2). Four key steric structures of 2, (2'E, 4'E)-(o-chloropyrid-3-ylcarbonyl)oximinylosthole (4o), (2'E, 4'E)-(styrylcarbonyl)oximinylosthole (4t), and (2'E, 4'E)-(acetyl)oximinylosthole (4w) were undoubtedly confirmed by X-ray crystallography. Against T. cinnabarinus, it is noteworthy that (2'E, 4'E)-(p-chlorophenylcarbonyl)oximinylosthole (4c) exhibited over three-fold more potent acaricidal activity of the precursor osthole, with especially good control efficiency observed in the glasshouse. Against M. separata, compounds 4c and (2'E, 4'E)-(p-nitrophenylcarbonyl)oximinylosthole (4f) showed the most pronounced growth inhibitory activity. The relationships between their structures and agricultural activities also were studied. CONCLUSION: These results demonstrate that compound 4c could be further structurally modified as pesticidal agents. It will lay the foundation for future application of osthole derivatives as pesticides. © 2020 Society of Chemical Industry.

Correction to: Comparative proteomic analysis of Tibetan pig spermatozoa at high and low altitudes.

Following publication of the original article [1], the authors reported an error in one of the authors' names. In this Correction the incorrect and correct author name are shown. The original publication of this article has been corrected.

Comparative proteomic analysis of Tibetan pig spermatozoa at high and low altitudes.

BACKGROUND: To illuminate the mechanisms underlying the high-altitude tolerance of Tibetan pig spermatozoa, proteomes of spermatozoa from Tibetan pigs raised in high and low altitudes were compared using a tandem mass tag (TMT)-labeled quantitative proteomics approach. RESULTS: A total of 77 differentially expressed proteins (DEPs) were identified. Gene Ontology (GO) analysis revealed DEPs that were predominantly associated with the actin cytoskeleton, the tricarboxylic acid (TCA) cycle, and adenosine triphosphate (ATP) metabolism, and were from 12 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Three subnetworks were significantly enriched and 10 centric proteins were identified by protein-protein interaction (PPI) network analysis. Relative expression levels of the proteins (ATP5H, CYCS, MYH9 and FN1) were confirmed using Western blotting. CONCLUSIONS: Our study is the first to use a tandem mass tag (TMT) approach to analyze Tibetan pig spermatozoa, and provides a foundation to understand the mechanisms underlying the reproductive adaptations of Tibetan pigs to high-altitude environments.

Discovery of Novel Triazole-Containing Pyrazole Ester Derivatives as Potential Antibacterial Agents.

To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were evaluated as potential topoisomerase II inhibitors. Compound 4d exhibited the most potent antibacterial activity with Minimum inhibitory concentration (MIC) alues of 4 µg/mL, 2 µg/mL, 4 µg/mL, and 0.5 µg/mL against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella gallinarum, respectively. The in vivo enzyme inhibition assay 4d displayed the most potent topoisomerase II (IC50 = 13.5 µg/mL) and topoisomerase IV (IC50 = 24.2 µg/mL) inhibitory activity. Molecular docking was performed to position compound 4d into the topoisomerase II active site to determine the probable binding conformation. In summary, compound 4d may serve as potential topoisomerase II inhibitor.

Design, synthesis and biological evaluation of novel flavone Mannich base derivatives as potential antibacterial agents.

A series of novel Mannich base derivatives of flavone containing benzylamine moiety was synthesized using the Mannich reaction. The results of antifungal activity are not ideal, but its antifungal effect has a certain increase compared to flavonoids. After that, four bacteria were used to test antibacterial experiments of these compounds; compound 5g (MIC = 0.5, 0.125 mg/L) showed significant inhibitory activity against Staphylococcus aureus and Salmonella gallinarum compared with novobiocin (MIC = 2, 0.25 mg/L). Compound 5s exhibited broad spectrum antibacterial activity (MIC = 1, 0.5, 2, 0.05 mg/L) against four bacteria. The selected compounds 5g and 5s exhibit potent inhibition against Topo II and Topo IV with IC50 values (0.25-16 mg/L). Molecular docking model showed that the compounds 5g and 5s can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial antibacterial agents.

Design, synthesis, and antifungal activity of novel cinnamon-pyrazole carboxamide derivatives.

Hit, Lead & Candidate Discovery To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon-pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide (5III-d) and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide (5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and 5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC50 values ranging from 19.4 to 28.7 µM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.

Novel coumarin-pyrazole carboxamide derivatives as potential topoisomerase II inhibitors: Design, synthesis and antibacterial activity.

The identification of novel Topoisomerase II (Topo II) inhibitors is one of the most attractive directions in the field of bactericide research and development. In our ongoing efforts to pursue the class of inhibitors, six series of 70 novel coumarin-pyrazole carboxamide derivatives were designed and synthesized. As a result of the evaluation against four destructive bacteria, including Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8III-k (MIC = 0.25 mg/L) showed considerable inhibitory activity than ciprofloxacin (MIC = 0.5 mg/L) against Escherichia coli and 8V-c (MIC = 0.05 mg/L) exhibited excellent antibacterial activity than ciprofloxacin (MIC = 0.25 mg/L) against Salmonella. The selected compounds (8III-k, 8V-c and 8V-k) exhibit potent inhibition against Topo II and Topo IV with IC50 values (9.4-25 mg/L). Molecular docking model showed that the compounds 8V-c and 8V-k can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial Topo II inhibiting bactericides.

Design, Synthesis and Biological Evaluation of Novel Pyrazole Sulfonamide Derivatives as Potential AHAS Inhibitors.

Acetohydroxy acid synthase (AHAS; EC 2.2.1.6, also referred to as acetolactate synthase, ALS) has been considered as an attractive target for the design of herbicides. In this work, an optimized pyrazole sulfonamide base scaffold was designed and introduced to derive novel potential AHAS inhibitors by introducing a pyrazole ring in flucarbazone. The results of in vivo herbicidal activity evaluation indicates compound 3b has the most potent activity with rape root length inhibition values of 81% at 100 mg/L, and exhibited the best inhibitory ability against Arabidopsis thaliana AHAS. With molecular docking, compound 3b insert into Arabidopsis thaliana AHAS stably by an H-bond with Arg377 and cation-π interactions with Arg377, Trp574, Tyr579. This study suggests that compound 3b may serve as a potential AHAS inhibitor which can be used as a novel herbicides and provides valuable clues for the further design and optimization of AHAS inhibitors.

Correction: Intermolecular interactions boost aggregation induced emission in carbazole Schiff base derivatives.

Correction for 'Intermolecular interactions boost aggregation induced emission in carbazole Schiff base derivatives' by Xiaoping Gan, et al., Org. Biomol. Chem., 2017, 15, 256-264.

Design, synthesis and biological evaluation of novel nicotinamide derivatives bearing a substituted pyrazole moiety as potential SDH inhibitors.

BACKGROUND: Succinate dehydrogenase (SDH) plays an important role in the Krebs cycle, which is considered as an attractive target for development of succinate dehydrogenase inhibitors (SDHIs) based on antifungal agents. Thus, in order to discover novel molecules with high antifungal activities, SDH as the target for a series of novel nicotinamide derivatives bearing substituted pyrazole moieties were designed and synthesised via a one-pot reaction. RESULTS: The biological assay data showed that compound 3 l displayed the most potent antifungal activity with EC50 values of 33.5 and 21.4 µm against Helminthosporium maydis and Rhizoctonia cerealis, respectively. Moreover, 3 l exhibited the best inhibitory ability against SDH enzymes. The results of docking simulation showed that 3 l was deeply embedded into the SDH binding pocket, and the binding model was stabilised by a cation-π interaction with Arg 43, Tyr 58 and an H-bond with Trp 173. CONCLUSION: The study suggests that the pyrazole nicotinamide derivative 3 l may serve as a potential SDHI that can be used as a novel antifungal agent, and provides valuable clues for the further design and optimisation of SDH inhibitors. © 2016 Society of Chemical Industry.

Intermolecular interactions boost aggregation induced emission in carbazole Schiff base derivatives.

Six D-π-A model compounds (compounds 1-6) were conveniently synthesized and characterized by 1H NMR, 13C NMR, MS and single crystal X-ray diffraction. One photon absorption and emission properties were studied by using a series of UV-visible and fluorescence spectra and theoretical calculations were applied to investigate the structure-property relationships, which showed that all six compounds possessed an obvious intramolecular charge transfer process which could be attributed to their optical properties. We simultaneously investigated their fluorescence emission performance in water/acetonitrile mixtures and found that they all have outstanding aggregation induced emission properties. Scanning electron microscopy testing illustrated that orderly aggregation was the main reason for their aggregation induced emission properties. Cytotoxicity tests indicated that all these compounds had good biocompatibility for living cells, and bio-imaging studies highlighted the potential application of the six compounds in one-photon fluorescence microscopy imaging domains.

Design, Synthesis and Biological Evaluation of α-Aminophosphonate Derivatives Containing a Pyrazole Moiety.

Acetylcholinesterase (AChE) is a key enzyme which present in the central nervous system of living organisms. Organophosphorus pesticides (OPs) that serve as insecticides are AChE inhibitors which have been used widely in agriculture. A series of novel OPs containing pyrazole moiety have been designed and synthesized. The biological evaluation indicated compound 4e appeared 81% larvicidal activity against Plutella xylostella at the concentration of 0.1 mg/L and the inhibition of AChE by compound 4e was distinctly enhanced with the increasing doses. Molecular docking of compound 4e into the three dimensional X-ray structure of the Drosophila melanogaster AChE (DmAChE, PDB code: 1QO9) was carried out utilizating the Discovery Studio (DS), the binding model revealed that the title structure was tightly embedded in the binding sites of DmAChE. Therefore, we suggest that compound 4e may serve as a novel AChE inhibitor that can be utilized as a new insecticidal drug.

Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK.

Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26µM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.