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Background: Benzoylureas are the most commonly used chitin synthesis inhibitors. But, the exact target site of benzoylurea insecticides has not been identified. Objective: To study whether benzoylphenylureas analogues with a bipartite model could be designed and synthesized as novel insecticides with improved activities. Methods: Based on the bipartite model of the sulfonylurea receptor binding site and commercial diflubenzuron, a series of novel benzoylureas containing carbamate groups were designed and synthesized via the key intermediate 2,6-difluoro-N-((4-hydroxyphenyl)carbamoyl)benzamide (2). The structures of the target compounds were confirmed by the 1H NMR and high-resolution mass spectrum (HRMS). Results: The results of bioassays indicated that these target compounds possessed good larvicidal activities against a broad spectrum of insects such as oriental armyworm (Mythimna Separata Walker), diamondback moth (Plutella xylostella), and mosquito (Culex pipiens pallens). A compound containing N, N-diisopropyl (3g) exhibited the highest insecticidal activity against oriental armyworm (40% at 10 mg kg-1), which was comparable with that of diflubenzuron. These compounds also had good larvicidal activities against diamondback moth and mosquito; most of these target compounds exhibited comparable larvicidal activities of diamondback moth with diflubenzuron and higher larvicidal activities of mosquito than diflubenzuron. Conclusion: The experimental data above preliminarily proved the rationality of our speculation and design ideology, and BPUs analogues with a bipartite model could improve the interaction with the target.

The diamide insecticides show exceptional activity against

Cancer-associated fibroblasts (CAFs) represent one of the main components in the tumor stroma and play a key role in breast cancer progression. Transforming growth factor-β (TGF-β) has been established to mediate breast cancer metastasis by regulating the epithelial-mesenchymal transition (EMT) and stemness of cancer cells. Caveolin-1 (CAV-1) is a scaffold protein of caveolae that is related to the proliferation and metabolism of cancer cells. It is now well demonstrated that CAV-1 deficiency in the tumor stroma is positively correlated with distant metastasis, but the mechanism remains unclear. Here, we explore whether CAV-1-deficient fibroblasts play an essential role in the EMT and stemness of breast cancer cells (BCCs) through TGF-β signaling. We establish a specific small interfering RNA (siRNA) to inhibit CAV-1 expression in fibroblasts and coculture them with BCCs to investigate the effect of CAV‑1-deficient fibroblasts and the tumor microenvironment on breast cancer progression. This study refreshingly points out that CAV-1 deficiency in fibroblasts enhances TGF-β1 secretion and then activates the TGF-β1/Smad signaling pathway of BCCs, thus promoting the metastasis and stemness of BCCs. Collectively, our findings indicate an unexpected role of CAV-1 deficiency in fibroblasts and the tumor microenvironment as a permissive factor, which is regulated by the TGF-β1 signaling pathway in BCCs.

The design and discovery of novel pesticidal agents according to bioactive natural products is an important aspect of agrochemical innovation. New xanthine derivatives derived from natural xanthine or methylxanthines are rich resources that possess great potential to afford new active pesticidal molecules. Herein novel xanthine derivatives were designed through a strategy of combining the methylxanthine caffeine skeleton with the acrylamide or acrylate motif of cinnamic acid derivatives.A series of novel (E)-3-(1,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)acrylic acid derivatives, caffeine-(E)-acrylamides and caffeine-(E)-acrylates, were synthesized and confirmed via melting points,Compounds I12, I18, I24 and I26 generated from the integration of natural methylxanthine (caffeine) and acrylate moieties could be novel insecticidal leading compounds for further structural optimization. The SAR analysis may bring a new inspiration to the extensive and deep investigations on new xanthine derivatives in the agrochemical area.

Pests are one of the major factors causing crop damage and food security problems worldwide. Based on our previous studies on the discovery of insecticidal leads targeting the ryanodine receptors (RyRs), a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to design and synthesize a series of anthranilic diamides containing a halogenated phenyl 3-trifluoroethoxypyrazole moiety. The preliminary bioassays disclosed that

Diamide compounds such as chlorantraniliprole, a famous anthranilic diamide insecticide targeting the insect ryanodine receptor (RyR), have received continuous attention in pesticide research during the past 15 years owing to their excellent insecticidal potentials. With the aim of discovering new heterocyclic pesticides used for crop protection, based on the structural information of compound M from the reported pharmacophore-based virtual screening for RyR insecticides and diamide compound, a series of new heterocyclic mono-, di-, and tri-amide derivatives containing piperazine moiety have been synthesized in this paper. The new compounds were identified and confirmed by melting point, 1H NMR, 13C NMR and HRMS. Compound M was firstly validated for insecticidal activities, and the new synthesized compounds were all made comprehensive insecticidal evaluations against diamondback moth and oriental armyworm. The bioassay results showed that some of the compounds exhibit favorable insecticidal potentials, particularly some novel piperazine-containing heterocyclic mono-/di-/tri-amide derivatives such as 8g, 14a, 15a, 15g, 15i, 15j, 15k, 15l, and 15m could be used as new insecticidal leading structures for further study (e.g., towards diamondback moth, 15i-15m LC50: 0.0022−0.0081 mg/L). The structure-activity relationships of the compounds discussed in detail provide useful guidance for further design and development of new insecticides.

Insect ryanodine receptors (RyRs) are molecular targets of the anthranilic diamide insecticides. In the present study, a new series of anthranilic diamides containing a cyanophenyl pyrazole moiety were rationally designed by active-fragment assembly and computer-aided design using the 3D structure of

A series of novel anthranilic diamides analogues(9a–9t) containing trifluoroethoxyl pyrazole moiety was designed and synthesized and their insecticidal bioactivities against Mythimna separata(Walker, M. separata) and Plutellaxylostella (P. xylostella) were evaluated. The structures of the title compounds were confirmed by 1H NMR, 13C NMR and HRMS. Preliminary insecticidal activities showed that some of the title compounds possessed good to excellent bioactivities towards M. separata and P. xylostella. Compounds 9c and 9t exhibited 100% mortality rate against M. separate at 0.2 mg/L. For the P. xylostella, the synthesized compounds(9c–9e, 9i and 9o) showed 70%, 80%, 75 %, 65% and 60% insecticidal activities at 1×10−6 mg/L, respectively, higher than that of chlorantraniliprole(0). Based on excellent insecticidal activities, the mode of the action was tested by the calcium-imaging technique, the results of which demonstrated that the novel compounds shared the same target with chlorantraniliprole. The binding pose of the most active compound 9t in RyRs of P. xylostella was predicted by molecular docking, which showed that compound 9t interacted with the residues Glu140(A) and His147(A) via hydrogen bond.

This study investigated the effects of a Lactobacillus paracasei KL1 and Lactobacillus plantarum subsp. plantarum Zhang-LL mixed probiotic on Salmonella-caused pullorosis in chicks. A total of 120 1-day-old Nongda no.3 dwarf chicks were randomly assigned to 4 treatments, with 6 replicates of 5 birds each. The treatments were blank group, Salmonella pullorum–infected group, probiotic treatment group, and probiotic prevention (PP) group. All birds (n = 90) except those in the blank group were infected with S. pullorum on day 4. On day 14, the BW, ADG, mortality, pathology of tissue, cecum colony count, immune organ indices, cecal mucosa secretory IgA, and cytokines were investigated. The results showed that the chicks infected with S. pullorum were depressed and their BW reduced. The PP group had the highest ADG and lowest mortality rate (0%), whereas the S. pullorum–infected group had 37.50% mortality rate and lowest ADG. Pathologic sections showed that the probiotic treatment group had minor lesions but the PP group had no lesions in the ileum, cecum, and liver. Cecal Lactobacillus counts was the highest (P 0.05) in the bursa of Fabricius, whereas in the PP group, all the immune organs were increased (P

In order to find a new variety of ryanodine receptor(RyR) regulator with greater biological activity, a series of anthranilic diamide derivatives possessing pyrrole structure was designed and synthesized in this study. The pyrrole derivatives were evaluated for their insecticidal activity against Mythimna separata and Plutella xylostella. As indicated by the preliminary biological activities, compounds 12h–12j and 12l–12n exhibited a remarkable insecticidal activity against M. separata at 0.25 mg/L. Compared to control chlorantraniliprole, compound 12j exhibited more excellent insecticidal activity at 0.1 mg/L. Meanwhile, compounds 12c, 12h, 12i, 12j, 12l, and 12m were selected to test the insecticidal activity against P. xylostella, which led to the desirable insecticidal activity at 1×10−3 mg/L. Notably, compound 12l demonstrated 47% insecticidal activity at 5×10−6 mg/L over the control. In addition, the biological mechanism of action of compound 12j was investigated by means of insect electrophysiology experiment.

To cope with the global food shortage and insect pest, there is an urgent need to discover new pesticides with novel modes of actions. Ryanodine receptor (RyR) insecticides showed great promise in ...

A series of novel phenylpyrazole carboxylic acid derivatives containing fluorine moiety, i.e., diamides 11, simple aryl-bearing amides 12 and acylthioureas 14 were successfully synthesized based on the key fluoro-containing phenylpyrazole acid intermediate. The new compounds were identified and confirmed by melting point, 1H NMR, 13C NMR and elemental analysis or HRMS. The bioassay results indicated that some of the compounds possessed excellent insecticidal activities towards oriental armyworm, diamondback moth and corn borer at low concentrations. For examples, compounds 11a, 11e−g and 14b exhibited remarkable larvicidal activities with LC50 values of 0.13 − 0.39 mg/L and 0.0002 − 0.0014 mg/L against oriental armyworm and diamondback moth, respectively, were comparable with those of the control chlorantraniliprole. Particularly, 11e were found superior to chlorantraniliprole in oriental armyworm tests (LC50: 0.23 mg/L vs. 0.26 mg/L); 11a, 11e, 11f and 14c in diamondback moth tests with LC50 values of 0.0002 mg/L, 0.0002 mg/L, 0.0008 mg/L and 0.0005 mg/L, respectively, were more effective than that of chlorantraniliprole. In addition, 12a also showed a promising insecticidal potential and development/optimization advantage. Compounds 11a, 11e–g, 12a, 14b and 14c could be considered as possible new leading structures for further study. The SAR investigation indicated that the compounds with fluorine motif (e.g., -F, -CF2H, -CF3) held apparently favorable insecticidal potentials, which provided useful guidance for further design/development of new phenylpyrazole-containing agrochemicals.

In order to systematically study the structure-activity relationship of anthranilic diamides and develop insecticides with simple structure and high efficiency, a series of novel anthranilic diamides containing N-H/CH3-1H-pyrazole was designed and synthesized. Their chemical structures were characterized by 1H NMR spectra, high resolution mass spectrometry(HRMS) or 13C NMR spectra. The preliminary bioassay results indicated that all title compounds displayed moderate insecticidal activity against oriental armyworm(Mythimna separata) at 200 mg/L and fungicidal activities against six kinds of fungi at 50 mg/L, especially compound 5i showed 50% insecticidal activity at 25 mg/L. In addition, some compounds exhibited certain antitumor activities. It was demonstrated that the introduction of CH3 group into pyrazole ring was superior to H for the insecticidal activity.

Referring to the structural information of the “hit” compound A from the reported pharmacophore-based virtual screening, a series of novel thienylpyridyl- and thioether/sulfoxide/sulfone-containing acetamide derivatives have been designed and synthesized. The structures of new compounds were confirmed by 1H NMR, 13C NMR and HRMS. The single-crystal structure of A was firstly reported. All the new synthesized compounds were evaluated for insecticidal activities on Mythimna separata Walker and Plutella xylostella L. Through a step-by-step structural optimization, the high insecticidal agents, especially towards Plutella xylostella L., have been found, and thienylpyridyl- and sulfone/thioether-containing acetamides Iq, Io, Ib and A, which are comparable with the control insecticides cartap, triflumuron and chlorantraniliprole in the present study, can be used as novel lead structures for new insecticides innovation research. In addition, some of the compounds, e.g., A, Ih, Id, Io and Iq, also exhibited favourable fungicidal activities against Physalospora piricola, Rhizoctonia cerealis and Sclerotinia sclerotiorum and would provide useful guidance for the design and development of new fungicides.

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.

Stem cells are characterized by the capability of self-renewal and multi-differentiation. Normal stem cells, which are important for tissue repair and tissue regeneration, can be divided into embryonic stem cells (ESCs) and somatic stem cells (SSCs) depending on their origin. As a subpopulation of cells within cancer, cancer stem cells (CSCs) are at the root of therapeutic resistance. Tumor-initiating cells (TICs) are necessary for tumor initiation. Caveolin1 (Cav1), a membrane protein located at the caveolae, participates in cell lipid transport, cell migration, cell proliferation, and cell signal transduction. The purpose of this review was to explore the relationship between Cav1 and stem cells.In ESCs, Cav1 is beneficial for self-renewal, proliferation, and migration. In SSCs, Cav1 exhibits positive or/and negative effects on stem cell self-renewal, differentiation, proliferation, migration, and angiogenic capacity. Cav1 deficiency impairs normal stem cell-based tissue repair. In CSCs, Cav1 inhibits or/and promotes CSC self-renewal, differentiation, invasion, migration, tumorigenicity ability, and CSC formation. And suppressing Cav1 promotes chemo-sensitivity in CSCs and TICs.Cav1 shows dual roles in stem cell biology. Targeting the Cav1-stem cell axis would be a new way for tissue repair and cancer drug resistance.

Fluorinated organic compounds represent a growing and important family of commercial chemicals. Introduction of fluorine into active ingredients has become an effective way to develop modern crop protection products. Given the particular properties of fluorine and high efficiency and selectivity of diamide insecticides, we designed and synthesized 27 anthranilic diamides analogues containing fluoro-sustituted phenylpyrazole. A preliminary bioassay indicated that most target compounds exhibited good biological activity against Mythimna separata and Plutella xylostella. Compound IIIf containing a 2,4,6-trifluoro-substituted benzene ring showed 43% insecticidal activity against M. separata at 0.1 mg L-1, while the control chlorantraniliprole was 36%. The activity of IIIe against P. xylostella at 10-5 mg L-1 was 94%, compared with that of the control being 70%. Thus, introduction of fluorine into diamide insecticides was useful for increasing activity. Insect electrophysiology studies showed that the calcium concentration in the nerve cells of third M. separata larvae was elevated by IIIf, which further confirmed that ryanodine receptor (RyR) was its potential target.

To cope with the global food shortage and insect pest, there is an urgent need to discover new pesticides with novel modes of actions. Ryanodine receptor (RyR) insecticides showed great promise in integrated pest management. Herein, we report the synthesis of novel anthranilic diamide derivatives incorporating pyrrole moieties targeting at insect RyRs. The structures were confirmed by

A series of novel anthranilic diamide derivatives containing pyridylpyrazole and iminodithiocarbamate or thiosemicarbazone motifs were synthesized via multi-step reactions. The structures of seven title compounds (methyl 2-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3- methylbenzylidene)hydrazinecarbodithioate 7 and 3-bromo-N-(2-((2-substitutedcarbamothioylhydrazono)methyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide 8a-8f) were confirmed by melting points, IR, 1H NMR, 13C NMR, and HRMS. The bioassays showed that some of the compounds exhibited modest insecticidal activities against oriental armyworm (Mythimna separata Walker), particularly, compound 8b (3-bromo-N-(4-chloro-2-methyl-6-((2-(methylcarbamothioyl)hydrazono)methyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide) held 100% and 30% larvicidal activity at the concentration of 25 mg/L and 10 mg/L, respectively. In addition, several compounds displayed favorable fungicidal activities against Alternaria solani Sorauer and Physalospora piricola at 50 μg/mL, and were comparable with the controls Chlorothalonil and Triadimefon. The results in this paper will provide important information for further research and development of sulfur-containing heterocyclic agrochemicals.

A series of novel anthranilic diamides derivatives (7a–s) containing halogen, trifluoromethyl group and cyano group were designed, synthesized, and characterized by melting point, 1H NMR, 13C NMR and elemental analyses. The bioactivity revealed that most of them showed moderate to excellent activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella). Above all, the larvicidal activity of 7o against oriental armyworm was 100% and 40% at 0.25 and 0.1 mg L−1, comparable to that of the standard chlorantraniliprole (100%, 0.25 mg L−1 and 20%, 0.1 mg L−1). What is more, 7o against diamondback moth displayed 90% insecticidal activity at 0.01 mg L−1, superior to chlorantraniliprole (45%, 0.01 mg L−1). The experiments 7o on the American cockroach (Periplaneta Americana) heart beating rates (Dorsal vessel) and contractile force were compared with chlorantraniliprole. In addition, 7o could affect the calcium homeostasis in the central neurons of the third larvae of oriental armyworm, which revealed that the ryanodine receptor is the potential target of 7o. The density functional theory (DFT) calculation results revealed the amide bridge, the benzene ring of anthraniloyl moiety and pyrazole ring might play an important role in the insecticidal activity through hydrophobic interactions and π-π conjugations.

An efficient, convenient short synthetic procedure for the synthesis of the intricate 5A5B6C-ring fusion topologies of tricyclic spiranoid β-hydroxybutyrolactones through lactonization of the key intermediate trans-α-hydroxyindenones with malonates is described. All the compounds synthesized exhibited environmentally benign characteristics, moderate fungicidal, nematocidal, and anti-TMV activities.

Background In recent years, pyridylpyrazole derivatives, such as pyridylpyrazole-containing anthranilic diamide have attracted much attention by virtue of their useful insecticidal properties and unique action mode. Moreover, some pyridylpyrazole-containing compounds have also been found to possess significant fungicidal activities. With the aim of discovering new bioactive agrochemicals for crop protection, a series of poly-heterocyclic compounds containing pyridylpyrazole and aziridine, or β-lactam, or thiazolinone moieties were synthesized. Results A series of pyridylpyrazole-containing poly-heterocyclic compounds were obtained, and confirmed through IR, 1 H NMR, 13 C NMR, HRMS and elemental analysis. The crystalline structure of 4-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-3-chloro-1-mesitylazetidin-2-one (compound 13f) was determined to further illustrate a trans- configuration of the β-lactam motif. In addition, bioassays showed that most of these new compounds exhibited modest insecticidal activity towards Mythimna separate Walker at 200 µg mL-1 . Some of the compounds displayed excellent fungicidal activity towards some plant fungi, including Cercospora arachidicola (13j: EC50 = 14.5 µg mL-1 ), Physalospora piricola (12d and 13d: EC50 = 10.5 and 9.70 µg mL-1 ), Alternaria solani Sorauer (13j: EC50 = 7.29 µg mL-1 ), Puccinia sorghi Schw. (13d: control efficacy 99.0 ± 2.1% at 200 µg mL-1 ) and Erysiphe graminis (14d: control efficacy 95.0 ± 1.4% at 200 µg mL-1 ). Conclusion Compounds 12b-12e, 13a, 13d, 13f, 13j, 13 k and 14d could be considered potential fungicidal lead compounds to do further structural optimization. The structure-activity relationship analysis in this study brings some new understanding to the biological activities of N-pyridylpyrazole-containing compounds, and provides important information for the research and development of novel agricultural fungicides with poly-heterocyclic structures. © 2017 Society of Chemical Industry.

Salmonella pullorum is a highly pathogenic bacteria in poultry industry. However, antibiotics were restricted in many countries because of the increasing risk of antibiotic resistance, Therefore, an environmental friendly and effective alternative strives to be developed. This study investigated the benefit of a probiotic-fermented herbal blend on the growth performance and gut microbiota of newborn broilers infected with S. pullorum. A total of 120 one-day-old dwarf male chicks were randomly allotted to 4 treatment groups, each including 5 replicates of 6 chicks: negative control (NC), positive control (PC), herbal blend (HB), and probiotic-fermented herbal blend (PF). All birds (n = 90), except for those in the NC, were infected with S. pullorum (1.69 × 108 CFU) on day 1. On day 11, body weight (BW), mortality, tissue pathology, cecal colony counts, immune organ indices, cecal mucosa secretory immunoglobulin A (sIgA) concentrations, and cecal cytokine mRNA expression levels were investigated. No mortality was observed after the PF treatment, and less pathological condition was in the ileum, cecum, and liver of HB and PF. BW, average daily gain and average daily feed intake were significant higher in the HB group compared to the PC and were the highest in the PF (P < 0.05). HB treatment significantly increased cecal populations of Lactobacilli, and decreased cecal populations of Escherichia coli and Salmonella, but results were more pronounced in the PF group (P < 0.05). Both HB and PF treatments increased cecal mucosa sIgA compared with the PC (P < 0.05). Tumor necrosis factor alpha and interferon gamma were lowest (P < 0.05) and interleukin 4 was the highest (P < 0.05) in PF, which exhibited similar levels to the NC group. PF treatment significantly improved the development of the thymus and bursa in S. pullorum-infected chicks. In conclusion, PF treatment prevented death, improved growth performance, regulated intestinal flora and enhanced immune ability of in S. pullorum-infected with chicks.

Spray droplet size is an important factor affecting spray drift, which is directly related to the spray effect and efficiency by unmanned aerial vehicle. Effect of adjuvants on the droplet size of emamectin benzoate dilute emulsion was systematically investigated by measuring droplet size, dynamic surface tension, and rheology. The results showed that droplet size was independent of dynamic surface tension and viscosity, but was related to the viscoelastic property and strain. For the emulsions with N, N-dimethyldodecylamine-N-oxid (OA), polyalkoxylated butyl ether (LQ) and poly (vinyl alcohol) (PVA), the viscous modulus (G′′) were higher than elastic modulus (G′) under the crossover frequency, indicating that the emulsions were the viscous liquid. Furthermore, the diluted emulsions with OA and LQ had small drop, while that with PVA had big drop. These leaded to the breakup of the liquid sheet at lower deformation and the small spray droplet formation. While emulsions containing Guar gum 2-hydroxy-3-(trimethylammonio) propyl ether chloride (Gum Cl) and Sil800 (silicone adjuvant) exhibited a weak elastic behavior, and had the large droplet size. In addition, compared to the emulsions with OA, LQ and PVA, the dilute emulsions with Gum Cl and Sil800 had the large drop diameter, and G′ had a rapid decrease at bigger strain. This suggested the dilute emulsions with Gum Cl and Sil800 had a high stability during atomization. The study would provide a useful guide for selecting drift control adjuvants and raising pesticide efficiency.