Cucurbit[7]uril-Mediated Supramolecular Bactericidal Nanoparticles: Their Assembly Process, Controlled Release, and Safe Treatment of Intractable Plant Bacterial Diseases.

A safe, biocompatible, and stimuli-responsive cucurbit[7]uril-mediated supramolecular bactericidal nanoparticle was fabricated by encapsulating a highly bioactive carbazole-decorated imidazolium salt (A1, EC50 = 0.647 µg/mL against phytopathogen Xanthomonas oryzae pv oryzae) into the host cucurbit[7]uril (CB[7]), thereby leading to self-assembled topographies from microsheets (A1) to nanospheroidal architectures (A1@CB[7]). The assembly behaviors were elucidated by acquired single-crystal structures, 1H NMR, ITC, and X-ray powder diffraction experiments. Complex A1@CB[7] displayed lower phytotoxicity and could efficiently switch on its potent antibacterial ability via introducing a simple competitor 1-adamantanamine hydrochloride (AD). In vivo antibacterial trials against rice bacterial blight revealed that A1@CB[7] could relieve the disease symptoms after being triggered by AD and provide a workable control efficiency of 42.6% at 100 µg/mL, which was superior to bismerthiazol (33.4%). These materials can provide a viable platform for fabricating diverse stimuli-responsive supramolecular bactericides for managing bacterial infections with improved safety.

Synthesis and fungicidal activity of novel pyrazole derivatives containing 5-Phenyl-2-Furan.

Pyrazole constitutes an important heterocyclic family covering a broad range of synthetic as well as natural products that exhibit numerous chemical, biological, agrochemical and pharmacological properties. In order to explore compounds with good fungicidal activity, a series of new pyrazole derivatives containing 5-phenyl-2-furan were designed and synthesized. In vitro and in vivo fungicidal activities were evaluated and the compound ethyl-1-(5-phenylfuran-2-carbonyl)-5-propyl-1H-pyrazole-3-carboxylate (I8) displayed significant fungicidal activity against various fungi, especially against P. infestans. The structures of the novel pyrazole derivatives were confirmed by 1H NMR, 13C NMR, MS, elemental analysis and X-ray single crystal diffraction. Further study showed that compound I8 might act on the synthesis of cell walls from morphological and ultrastructural studies by SEM and TEM. The results also revealed that compound I8 could block the nutritional transportation leading to cells senescence and death. These results suggested that the novel pyrazole derivatives proved to be promising lead compounds.

Synthesis and bioactivity of 3,5-dimethylpyrazole derivatives as potential PDE4 inhibitors.

A series of 3,5-dimethylpyrazole derivatives containing 5-phenyl-2-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. Bioassay results showed that the title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Among the designed compounds, compound If showed the best inhibitory activity against PDE4B with the IC50 value of 1.7 µM, which also showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship (SAR) study and docking results suggested that introduction of the substituent groups to the phenyl ring at the para-position, especially methoxy group, was helpful to enhance inhibitory activity against PDE4B.

Rational design of conformationally constrained oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors.

Improvement of subtype selectivity of an inhibitor's binding activity using the conformational restriction approach has become an effective strategy in drug discovery. In this study, we applied this approach to PDE4 inhibitors and designed a series of novel oxazolidinone-fused 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally restricted analogues of rolipram. The bioassay results demonstrated the oxazolidinone-fused tetrahydroisoquinoline derivatives exhibited moderate to good inhibitory activity against PDE4B and high selectivity for PDE4B/PDE4D. Among these derivatives, compound 12 showed both the strongest inhibition activity (IC50=0.60µM) as well as good selectivity against PDE4B and good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary SAR study showed that restricting the conformation of the catechol moiety in rolipram with the scaffold of oxazolidinone-fused tetrahydroisoquinoline could lead to an increase in selectivity for PDE4B over PDE4D, which was consistent with the observed docking simulation.

Design, synthesis and biological evaluation of 2,4-disubstituted oxazole derivatives as potential PDE4 inhibitors.

In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4µM) and good selectivity against PDE4B. Meanwhile, compound 4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship study showed the 3,5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity. Docking results showed that compound 4c played a key role to form integral hydrogen bonds and a π-π stacking interaction, using hydrazide scaffold (CONN) and pyrazole ring respectively, with PDE4B protein. While the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Compound 4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors.

A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). The primary structure-activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as potential PDE4 inhibitors.

The design, synthesis, and biological evaluation of new phosphodiesterase type 4 (PDE4) inhibitors, which possessed 7-(cyclopentyloxy)-6-methoxy 1,2,3,4-tetrahydroisoquinoline ring, were described. Compound 8 [(7-cyclopentyloxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(4-hydroxy-3-methoxy-phenyl)methanone] showed the best inhibitory activity and good selectivity against PDE4B. The docking results showed that the catechol diether moiety of compound 8 played a key role to form integral hydrogen bonds with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound 8 would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

Trajectory Modulation for Impact Reducing of Lower-Limb Exoskeletons.

Lower-limb exoskeletons have received considerable attention because of their effectiveness in walking assistance and rehabilitation for paraplegic patients. Excessive foot-ground impacts during walking make patients uncomfortable and even lead to injury. In this paper, we propose an optimized knee trajectory modulation (OKTM) for foot-ground impact reduction. The OKTM can reduce the peak of ground reaction force (PGRF) by knee-joint trajectory modulation based on a parameters-optimizing spring-damping system. In addition, a hip trajectory modulation (HTM) is presented to compensate for torso pitch deflections due to the OKTM. Unlike traditional mechanical-device-based methods, the proposed OKTM and HTM require no bulky mechanical structures, and can adaptively adjust parameters to adapt to different impacts. We demonstrated the efficiency of the proposed approach in both simulations and experiments for engineering verifications. Results show that the approach can effectively reduce PGRF.

Fabrication of Host-Guest Complexes between Adamantane-Functionalized 1,3,4-Oxadiazoles and ß-Cyclodextrin with Improved Control Efficiency against Intractable Plant Bacterial Diseases.

Supramolecular chemistry provides huge potentials and opportunities in agricultural pest management. In an attempt to develop highly bioactive, eco-friendly, and biocompatible supramolecular complexes for managing intractable plant bacterial diseases, herein, a type of interesting adamantane-functionalized 1,3,4-oxadiazole was rationally prepared to facilitate the formation of supramolecular complexes via ß-cyclodextrin-adamantane host-guest interactions. Initial antibacterial screening revealed that most of these adamantane-decorated 1,3,4-oxadiazoles were obviously bioactive against three typically destructive phytopathogens. The lowest EC50 values could reach 0.936 (III18), 0.889 (III18), and 2.10 (III19) µg/mL against the corresponding Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac), and Pseudomonas syringae pv. actinidiae (Psa). Next, the representative supramolecular binary complex III18@ß-CD (binding mode 1:1) was successfully fabricated and characterized by 1H nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), high-resolution mass spectrometry (HRMS), dynamic light scattering (DLS), and transmission electron microscopy (TEM). Eventually, correlative water solubility and foliar surface wettability were significantly improved after the formation of host-guest assemblies. In vivo antibacterial evaluation found that the achieved supramolecular complex could distinctly alleviate the disease symptoms and promote the control efficiencies against rice bacterial blight (from 34.6-35.7% (III18) to 40.3-43.6% (III18@ß-CD)) and kiwi canker diseases (from 41.0-42.3% (III18) to 53.9-68.0% (III18@ß-CD)) at 200 µg/mL (active ingredient). The current study can provide a feasible platform and insight for constructing biocompatible supramolecular assemblies for managing destructive bacterial infections in agriculture.

A Relational Adaptive Neural Model for Joint Entity and Relation Extraction.

Relation extraction is a popular subtask in natural language processing (NLP). In the task of entity relation joint extraction, overlapping entities and multi-type relation extraction in overlapping triplets remain a challenging problem. The classification of relations by sharing the same probability space will ignore the correlation information among multiple relations. A relational-adaptive entity relation joint extraction model based on multi-head self-attention and densely connected graph convolution network (which is called MA-DCGCN) is proposed in the paper. In the model, the multi-head attention mechanism is specifically used to assign weights to multiple relation types among entities so as to ensure that the probability space of multiple relation is not mutually exclusive. This mechanism also predicts the strength of the relationship between various relationship types and entity pairs flexibly. The structure information of deeper level in the text graph is extracted by the densely connected graph convolution network, and the interaction information of entity relation is captured. To demonstrate the superior performance of our model, we conducted a variety of experiments on two widely used public datasets, NYT and WebNLG. Extensive results show that our model achieves state-of-the-art performance. Especially, the detection effect of overlapping triplets is significantly improved compared with the several existing mainstream methods.

Hydrogen Peroxide Is Involved in ß-Cyclodextrin-hemin Complex-Induced Lateral Root Formation in Tomato Seedlings.

Although previous results showed that ß-cyclodextrin-hemin complex (ß-CDH) could induce tomato lateral root (LR) formation, the corresponding downstream messengers are still not fully understood. In this report, similar to the inducing effects of exogenously applied hydrogen peroxide (H2O2), we discovered that ß-CDH elicited RBOH1 transcript upregulation, endogenous H2O2 accumulation, and thereafter tomato LR development. Above responses were sensitive to dimethylthiourea (DMTU) and ascorbic acid (AsA), two membrane-permeable scavengers of H2O2, showing that accumulation of H2O2 and LR formation were significantly blocked. The test with diphenyleneiodonium (DPI; the inhibitor of NADPH oxidase) revealed that H2O2 mainly produced by NADPH oxidase, might be involved in LR formation triggered by ß-CDH. qPCR combined with pharmacological and anatomical analyses showed that ß-CDH-modulated several marker genes responsible for LR formation, such as CYCA3;1, CYCA2;1, CYCD3;1, and CDKA1 (four cell cycle regulatory genes), ARF7 and RSI-1 (two auxin signaling genes), LAX3 (an auxin influx carrier), IAA14 (encoding a member of the Aux/IAA protein family), PIN3 and PIN7 (two auxin efflux carriers), isocitrate dehydrogenase [NADP], NADH-cytochrome b5 reductase 1, and L-ascorbate oxidase homolog genes (two reactive oxygen species-associated genes and one LR formation-related gene), were causally related to above H2O2 signaling. Particularly, representative proteins related to H2O2 metabolism and lateral rooting, were specifically induced in ß-CDH-treated tomato seedlings. Overall, the results clearly suggested a vital role of H2O2 in the ß-CDH-induced tomato LR formation, and ß-CDH-elicited H2O2-related target proteins responsible for LR formation might be, at least partially, regulated at transcriptional and translational levels.

Synthesis and Larvicidal Activity of Novel Thenoylhydrazide Derivatives.

A pair of chemical isomeric structures of novel N-tert-butylphenyl thenoylhydrazide compounds I and II were designed and synthesized. Their structures were characterized by MS, IR, (1)H NMR, elemental analysis and X-ray single crystal diffraction. The regioselectivity of the Meerwein arylation reaction and the electrophilic substitution reaction of N-tert-butyl hydrazine were studied by density functional theory (DFT) quantum chemical method. The larvicidal tests revealed that some compounds I had excellent larvicidal activity against Culex pipiens pallens. As the candidates of insect growth regulators (IGRs), the larval growth inhibition and regulation against Culex pipiens pallens were examined for some compounds, especially I1 and I7. Compounds I1 and I7 were further indicated as an ecdysteroid agonist by reporter gene assay on the Spodoptera frugiperda cell line (Sf9 cells). Finally, a molecular docking study of compound I7 was conducted, which was not only beneficial to understand the structure-activity relationship, but also useful for development of new IGRs for the control of mosquitos.

Synthesis and fungicidal activity of novel 2,5-disubstituted-1,3,4- thiadiazole derivatives containing 5-phenyl-2-furan.

A series of 2,5-disubstituted-1,3,4-thiadiazoles were synthesized using Lawesson's reagent by an efficient approach under microwave irradiation in good yields. Their structures were characterized by MS, IR, (1)H NMR, (13)C NMR, and elemental analysis. Their in vitro and in vivo fungicidal activities revealed that the title compounds exhibited considerable activity against five selected fungi, especially to Phytophthora infestans. In order to illustrate the mechanism of title compounds against P. infestans, scanning electron micrographs (SEM) and transmission electron micrographs (TEM) were applied. The morphological and ultrastructural studies demonstrated that compound I18 led to swelling of hyphae, thickening and proliferating multilayer cell walls, excessive septation and accumulation of dense bodies. The bioassay results indicated compound I18 might act on cell wall biosynthesis, and blocked the nutrition transportation and led to cells senescence and death. Meanwhile, compound I18 had broad fungicidal activity against other twenty different kinds of fungi. These results suggested that title compounds were eligible to be development candidates and compound I18 as a promising lead compound was worthy to be further discovery, especially against P. infestans.

Involvement of glutathione in ß-cyclodextrin-hemin complex-induced lateral root formation in tomato seedlings.

ß-cyclodextrin-hemin complex (ß-CDH) was shown to induce lateral root (LR) formation in tomato. However, the molecular mechanism is still elusive. In this report, the role of reduced glutathione (GSH) in the induction of lateral root triggered by ß-CDH was investigated. Similar to the responses of ß-CDH, exogenously applied with 0.1 mΜ GSH not only increased endogenous GSH content determined by spectrophotography and the monochlorobimane (MCB)-dependent fluorescent analysis, but also induced, thereafter, LR formation. Meanwhile, both ß-CDH- and GSH-induced lateral root primordia (LRP) exhibited a similar accelerated anatomic structure. Above inducible responses were blocked significantly when the L-buthionine-(S,R)-sulfoximine (BSO), a potent and specific inhibitor of the enzyme catalyzing the first step of GSH biosynthesis, was separately applied. Upon ß-CDH treatment, the changes of endogenous GSH content determined by spectrophotography and fluorescent analysis were consistent with the transcripts of two GSH synthetic genes, GSH1 and GSH2 encoding γ-glutamyl cysteine synthetase and glutathione synthetase, respectively. Exogenously applied with ß-CDH could rescue N-1-naphthylphthalamic acid (NPA; IAA depletion)-triggered inhibition of LR formation. Further molecular evidence revealed that both ß-CDH and GSH modulated gene expression of cell cycle regulatory genes (CYCA2;1, CYCA3;1, CYCD3;1, and CDKA1) and auxin signaling genes (ARF7 and RSI-1), six marker genes responsible for LR formation. By contrast, above changes were sensitive to the co-treatment with BSO. All together, these results suggest a role for GSH in the regulation of tomato LR development triggered by ß-CDH.