Synthesis and Biological Evaluation of Dipeptide-Based Stilbene Derivatives Bearing a Biheterocyclic Moiety as Potential Fungicides.

The escalating demand for crop production, environmental protection, and food safety warrants the development of new fungicides with greater efficiency, environmental friendliness, and innocuous metabolites to fight against destructive phytopathogens. Herein, we report on the synthesis and antifungal activity of dipeptide-based stilbene derivatives bearing a thiophene-substituted 1,3,4-oxadiazole fragment for the first time. In vitro bioassay indicated that the target compounds had remarkable antifungal potency superior to previously reported counterparts without a dipeptidyl group, of which compound 3c exhibited the highest activity against Botrytis cinerea with EC50 values of 106.1 µg/mL. Moreover, the in vivo protective effect of compound 3c (59.1%) against tomato gray mold was more potent than that of carboxin (42.0%). Preliminary investigations on the mode of action showed that compound 3c induced marked hyphal malformations and increased the membrane permeability of B. cinerea as well as inhibiting mycelial respiration. These promising results suggest that this novel type of molecular framework has great potential to be further developed as alternative fungicides.

TAT-modified self-assembled cationic peptide nanoparticles as an efficient antibacterial agent.

The increasing emergence of drug resistant pathogenic bacteria poses a great challenge to clinical therapy and a threat to public health. Cationic peptides have received great attention for their unique antibacterial mechanism and ability to combat drug-resistant bacteria. In this study, we designed a TAT-modified cationic peptide PA-28 which self-assembled into nanoparticles of about 150 nm. These nanoparticles showed strong antimicrobial activities against both gram-positive and gram-negative bacteria, including drug-resistant bacteria. They were more potent than the unassembled counterpart peptide nonalysine (K9). Their antibacterial mechanism of directly destructing bacterial wall/membrane reduces the possibility of developing bacterial resistance. In vivo anti-infective experiments showed that these nanoparticles were able to penetrate the blood-brain barrier to inhibit bacterial growth in infected brains of rats. In addition, these nanoparticles induced low hemolysis below the minimum inhibitory concentration. Therefore, the peptide designed in this study is a promising and efficient antibacterial agent against bacterial infections.

Synthesis, fluorescence properties and theoretical calculations of novel stilbene derivatives based on 1,3,4-oxadiazole bearing anthracene core.

Two novel stilbene derivatives bearing anthracene core based on 1,3,4-oxadiazole were efficiently synthesized and characterized by (1)H-NMR, mass spectrometry and elemental analysis. The optical properties of the title compounds were investigated by UV-vis absorption and fluorescence emission spectra in different solvents. Chemical calculations were performed by density functional theory (DFT) at the (B3LYP)/6-31G* level. The results show the two compounds exhibit strong green fluorescence emission ranged from 489-493 nm, and the fluorescence quantum yield ranged from 0.78-0.92. Their HOMO and LUMO levels are (-5.44 eV, -2.25 eV) and (-5.45 eV, -2.28 eV), respectively. The influence of the solvent on the fluorescence intensities was also discussed.

Synthesis, Bioactivity, and QSAR Study of 3,4-Dichlorophenyl Isoxazole-Substituted Stilbene Derivatives against the Phytopathogenic Fungus Botrytis cinerea.

Gray mold, caused by Botrytis cinerea, is one of the most destructive fungal diseases in crops, responsible for significant economic losses. In search of natural product-based fungicides, we designed and synthesized a series of novel 3,4-dichlorophenyl isoxazole-substituted stilbene derivatives, and their in vivo antifungal activities against B. cinerea were evaluated. The results indicated that some of the target molecules demonstrated remarkable efficiency for the control of tomato gray mold. In particular, compound 5r displayed the highest fungicidal potency with an inhibition rate of 56.11% comparable to that of positive control boscalid (66.96%). Moreover, a hologram quantitative structure-activity relationship (HQSAR) model with good predictive capability was developed to provide in-depth insight into the activity profiles of these compounds. Preliminary mechanism studies suggested that compound 5r might exert its antifungal effect by changing hyphal morphology and increasing the membrane permeability. The present study contributes to the development of natural stilbene derivatives as alternative bioactive agents against B. cinerea.

Synthesis and biological evaluation of stilbene-based peptoid mimics against the phytopathogenic bacterium Xanthomonas citri pv. citri.

BACKGROUND: The emergence of drug-resistant phytopathogenic bacteria and the need for new types of biological disease-control agents have accelerated efforts toward searching for alternative candidates with a low propensity for resistance development. In this study, a new series of stilbene-based peptoid mimics were synthesized, and their biological activities were evaluated against citrus pathogenic bacteria in vitro and in vivo. RESULTS: Antibacterial bioassay results showed that the dicationic peptoid mimics 9a and 9b displayed excellent bioactivity against Xanthomonas citri pv. citri, with the minimum inhibitory concentration values of 25 µM, which were superior to those of commercial copper biocides Delite (200 µM) and Kasumin Bordeaux (100 µM). In vivo bioassay further confirmed their control efficacy against plant bacterial diseases. In addition, the antibacterial mechanism of action elucidated their membrane-disruption effects resulting in the leakage of the bacterial membranes, which was similar to that of antimicrobial peptides. Moreover, the inhibition effect on biofilm formation of peptoid mimics has also been demonstrated. CONCLUSION: Stilbene-based peptoid mimics synthesized in this study showed promising antibacterial activity with a potent membrane-disruptive mechanism. The results suggested that stilbene-based peptoid mimics have the potential as a candidate new type of bactericide for citrus disease protection.

Synthesis and optical properties of two novel stilbene derivatives containing 1,3,4-oxadiazole moiety.

Two novel stilbene derivatives containing 1,3,4-oxadiazole moiety were synthesized and characterized by elemental analyses, (1)H NMR, MS. The photophysical processes of the title compounds were investigated by UV-vis absorption and fluorescence emission spectra in different solutions. The fluorescence quantum yield (Phi) of 1a and 1b in THF is 0.65 and 0.69, respectively. The influence of the solution on the fluorescence intensities was also discussed. Under ultraviolet light excitation, the two compounds exhibit strong blue fluorescence emission. They may serve as potential applications in organic electroluminescent materials.

Synthesis and antifungal activities of novel thiophene-based stilbene derivatives bearing an 1,3,4-oxadiazole unit.

BACKGROUND: Natural stilbenes (especially resveratrol and its derivatives) are well-known phytoalexins that are active against many plant diseases. However, oxidative degradation and low bioavailability limit their exogenous application as fungicides on crops. In this study, a new class of resveratrol-inspired thiophene-based stilbene derivatives bearing an 1,3,4-oxadiazole unit was synthesized and the derivatives' antifungal activities against phytopathogenic fungi were investigated. RESULTS: The results revealed that compounds 5h and 5j exhibited improved antifungal activity against Botrytis cinerea with median effective concentrations (EC50 ) of 168.5 and 155.4 µg mL-1 , respectively, which were superior to the EC50 of resveratrol (263.1 µg mL-1 ). Compound 5j was shown to effectively control disease development in B. cinerea-infected tomatoes in vivo. Notably, considerably abnormal mycelial morphology and increased cell membrane conductivity were observed in the presence of compound 5j. CONCLUSION: A new class of thiophene-containing stilbene derivatives was designed and synthesized. Bioassay results showed that compound 5j exhibited promising antifungal activity, suggesting practical potential for fungal disease control. © 2018 Society of Chemical Industry.

Self-Assembled Nanoparticles of Symmetrical Cationic Peptide Against Citrus Pathogenic Bacteria.

The increasing drug resistance of phytopathogenic bacteria to conventional bactericides has driven the necessity for exploring new alternatives with a lower tendency to develop bacterial resistance. Here, we report a novel cationic symmetrical peptide P5VP5 (Ac- R+ LI R+ K+ V K+ R+ IL R+ -NH2 that enables self-assembly to form nanoparticles with excellent thermal stability. An in vitro assay showed that P5VP5 nanoparticles exhibited excellent antibacterial activity against Xanthomonas axonopodis pv citri with a MIC value of 20 µM. Meanwhile, under an in planta condition, treatment with peptide nanoparticles demonstrated the highest ability to reduce the development of citrus canker lesions in leaves. Moreover, the nanoparticles could destroy the biofilm formation, damage the cell membranes, and affect the cell membrane permeability, ultimately leading to the death of bacteria. Taken together, these nanoparticles are a promising antibacterial agent that can be used to control citrus canker and other plant diseases caused by bacteria.

1-[2-(3,4-Dichloro-phen-yl)-5-(3,4,5-trimethoxy-phen-yl)-2,3-dihydro-1,3,4-oxadiazol-3-yl]ethanone.

The title compound, C(19)H(18)Cl(2)N(2)O(5), was synthesized by the reaction of N'-(3,4-dichloro-benzyl-idene)-3,4,5-trimethoxy-benzo-hydrazide and acetic anhydride. The oxadiazole ring makes dihedral angles of 82.82 (7) and 9.92 (7)° with the 3,4-dichloro-benzene and the 3,4,5-trimethoxy-benzene ring planes, respectively. The crystal structure is stabilized by inter-molecular C-H⋯ O and C-H⋯ N hydrogen bonds. Intra-molecular C-H⋯O and C-H⋯N hydrogen bonds are also present.

N'-(2-Bromo-benzyl-idene)-3,4,5-tri-methoxy-benzohydrazide methanol solvate.

The title compound, C(17)H(17)BrN(2)O(4)·CH(4)O, was synthesized by the condensation of 3,4,5-trimethoxy-benzohydrazide and 2-bromo-benzaldehyde. The two aromatic rings are approximately planar, the dihedral angle being 3.08 (9)°. The mol-ecules are linked by inter-molecular N-H⋯O and O-H⋯O hydrogen bonds into chains along the a axis.

Mesaconitine.

The title compound, (1α,3α,6α,14α,15α,16ß)-3,8,13,14,15-penta-hydr-oxy-1,6,16-trimeth-oxy-4-methoxy-methyl-20-methyl-acon-itan-8,14-diyl 8-acetate 14-benzoate, C(33)H(45)NO(11), a C(19) diterpenoid alkaloid, obtained from the roots of Aconitum kusnezoffii, has been crystallographically characterized in this study. Rings A, B and E have chair conformations, rings C and F display envelope conformations, and ring D adopts a boat conformation. There are inter- and intra-molecular O-H⋯O hydrogen bonds, the latter resulting in the formation of a non-planar seven-membered ring. The inter-molecular inter-actions link the mol-ecules into a two-dimensional network.

N'-(4-Fluoro-benzyl-idene)-3,4,5-trimethoxy-benzohydrazide.

The title compound, C(17)H(17)FN(2)O(4), is of inter-est due to its potential pharmaceutical and agrochemical activity. All three meth-oxy groups are twisted with respect to the attached aromatic ring [C-C-O-C torsion angles = 10.43 (18), 97.38 (14), -19.34 (17)°] and the phenyl ring makes a dihedral angle of 40.6 (2)° with the plane through the remaining atoms in the mol-ecule. Inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into chains running along the c axis.

N'-(2-Chloro-benzyl-idene)-3,4,5-tri-methoxy-benzohydrazide methanol solvate.

In the title compound, C(17)H(17)ClN(2)O(4)·CH(4)O, the dihedral angle between the benzene ring planes is 5.29 (6)°. Inter-molecular N-H⋯O and O-H⋯O hydrogen bonds link the mol-ecules into a chain along the a axis.

Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Oxadiazole-Stilbene Hybrids against Phytopathogenic Fungi.

Natural stilbenes (especially resveratrol) play important roles in plant protection by acting as both constitutive and inducible defenses. However, their exogenous applications on crops as fungicidal agents are challenged by their oxidative degradation and limited availability. In this study, a new class of resveratrol-inspired oxadiazole-stilbene hybrids was synthesized via Wittig-Horner reaction. Bioassay results indicated that some of the compounds exhibited potent fungicidal activity against Botrytis cinerea in vitro. Among these stilbene hybrids, compounds 11 showed promising inhibitory activity with the EC50 value of 144.6 µg/mL, which was superior to that of resveratrol (315.6 µg/mL). Remarkably, the considerably abnormal mycelial morphology was observed in the presence of compound 11. The inhibitory profile was further proposed by homology modeling and molecular docking studies, which showed the possible interaction of resveratrol and oxadiazole-stilbene hybrids with the cytochrome P450-dependent sterol 14α-demethylase from B. cinerea (BcCYP51) for the first time. Taken together, these results would provide new insights into the fungicidal mechanism of stilbenes, as well as an important clue for biology-oriented synthesis of stilbene hybrids with improved bioactivity against plant pathogenic fungi in crop protection.

Synthesis and biological evaluation of novel fluorine-containing stilbene derivatives as fungicidal agents against phytopathogenic fungi.

The rising development of resistance to conventional fungicides is driving the search for new alternative candidates to control plant diseases. In this study, a series of new fluorine-containing stilbene derivatives was synthesized on the basis of our previous quantitative structure-activity relationship analysis results. Bioassays in vivo revealed that the title compounds exhibited potent fungicidal activities against phytopathogenic fungi (Colletotrichum lagenarium and Pseudoperonospora cubensis) from cucumber plants. In comparison to the previous results, the introduction of a fluorine moiety showed improved activities of some compounds against those fungi. Notably, compound 9 exhibited a control efficacy against C. lagenarium (83.4 ± 1.3%) comparable to that of commercial fungicide (82.7 ± 1.7%). For further understanding the possible mode of action of the stilbene against C. lagenarium, the effects on hyphal morphology, electrolyte leakage, and respiration of mycelial cell suspension were studied. Microscopic observation showed considerably deformed mycelial morphology. The conductivity of mycelial suspension increased in the presence of compound 9, whereas no significantly inhibitory effect on respiration was observed. Taken together, the fungicidal mechanism of this stilbene is associated with its membrane disruption effect, resulting in increased membrane permeability. These results provide important clues for mechanistic study and derivatization of stilbenes as alternative sources of fungicidal agents for plant disease control.

Synthesis, biological evaluation, and structure-activity relationship study of novel stilbene derivatives as potential fungicidal agents.

A total of 22 novel stilbene derivatives containing the 1,3,4-oxadiazole moiety and trimethoxybenzene were designed and synthesized. Their chemical structures were characterized by (1)H and (13)C nuclear magnetic resonance, infrared, and high-resolution mass spectrometry. Bioassay results revealed that some of the title compounds showed potent in vivo fungicidal activities against three phytopathogenic fungi (Pseudoperonospora cubensis, Colletotrichum lagenarium, and Septoria cucurbitacearum) from cucurbits at 600 µg/mL. Notably, compounds 4b, 4d, 4i, 4k, and 4l exhibited a broad spectrum and remarkably high activities against those fungi, some of which even showed a comparable control efficacy to that of the commercial fungicides. Three-dimensional quantitative structure-activity relationship based on comparative molecular field analysis with good predictive ability (q(2) = 0.516; r(2) = 0.920) was reasonably discussed. For the first time, the present work suggested that the stilbene derivatives containing the 1,3,4-oxadiazole moiety could be developed as potential fungicides for crop protection.

Chemical composition and antibacterial activity of the essential oil from Agathis dammara (Lamb.) Rich fresh leaves.

The essential oil of fresh leaves from Agathis dammara (Lamb.) Rich was extracted using hydro-distillation, and GC-FID and GC-MS were used to analyse the essential oil. Nineteen compounds were identified, among which the major components were limonene (36.81%), ß-bisabolene (33.43%) and ß-myrcene (25.48%). In the antibacterial test, disc diffusion method and micro-well dilution assay proved that the essential oil had significant antibacterial activities. The inhibition zones against Staphylococcus aureus and Pseudomonas aeruginosa were 23.7 and 23 mm, respectively, which demonstrated that the inhibition effects were greater than positive control (10 µg/disc streptomycin). And the lowest MIC value of the essential oil was found against S. aureus (1.25 mg/mL) and Bacillus subtilis (1.25 mg/mL). This is the first report on the antibacterial activities of A. dammara essential oil.

Asymmetric 1,3,4-oxadiazole derivatives containing naphthalene and stilbene units: synthesis, optical and electrochemical properties.

Six novel asymmetric 1,3,4-oxadiazole derivatives containing naphthalene and stilbene units have been efficiently synthesized and characterized by FT-IR, (1)H NMR, (13)C NMR, mass spectrometry and elemental analysis. The UV-vis absorption maximum wavelength, fluorescence excitation wavelength, fluorescence emission wavelength and fluorescence quantum yield were measured in dilute tetrahydrofuran solution. The solvent effect was also studied. The HOMO and LUMO levels of these compounds were calculated by density functional theory (DFT) (B3LYP, 6-31G(*)) method and cyclic voltammetry. They emit bright violet to blue emission with high fluorescence quantum yields (0.23-0.94) and large Stokes shifts (53-102 nm). These compounds possess high HOMO levels (-5.03 to -5.17 eV) and suitable band gaps, indicating that they could be benefit for hole injection. The results show that they have a potential for application in optoelectronic materials.

Synthesis, fluorescence properties and applications of two novel oxadiazole-based stilbene optical brighteners as UV protectants for insect baculovirus.

Two novel symmetrical stilbene optical brighteners based on 1,3,4-oxadiazole bearing sodium sulfonate unit were synthesized. The two target compounds were characterized by NMR and elemental analysis. The photophysical processes of the target compounds were investigated by UV-Vis absorption and fluorescence emission spectra in different solutions. The two optical brighteners were tested as radiation protectants for the Spodoptera litura nuclear polyhedrosis virus (SINPV) against 2nd-instar S. litura larvae. The results indicate that the two compounds exhibit strong blue fluorescence emission, and the fluorescence quantum yield in DMF is 0.86 and 0.75, respectively. The insecticidal effect of SINPV is increased by the addition of the two compounds and especially the compound 3b shows more obvious synergy effect.

Characterization and optical properties of novel unsymmetrical stilbene-based 1,3,4-oxadiazole derivatives.

A series of novel unsymmetrical stilbene-based 1,3,4-oxadiazole derivatives were efficiently synthesized by a four-pots reaction sequence. All of the title compounds were characterized by MS, (1)H-NMR and elemental analysis. UV-Vis absorption and fluorescence emission spectra of the compounds were investigated in dilute chloroform solution; the compounds exhibit strong blue-green fluorescence ranged from 397 to 499 nm and show potential for application in organic optical materials.