Structural diversity-guided optimization of carbazole derivatives as potential cytotoxic agents.

Carbazole alkaloids, as an important class of natural products, have been widely reported to have extensive biological activities. Based on our previous three-component reaction to construct carbazole scaffolds, we introduced a methylene group to provide a rotatable bond, and designed series of carbazole derivatives with structural diversity including carbazole amide, carbazole hydrazide and carbazole hydrazone. All synthesized carbazole derivatives were evaluated for their in vitro cytotoxic activity against 7901 (gastric adenocarcinoma), A875 (human melanoma) and MARC145 (African green monkey kidney) cell lines. The preliminary results indicated that compound 14a exhibited high inhibitory activities on 7901 and A875 cancer cells with the lowest IC50 of 11.8 ± 1.26 and 9.77 ± 8.32 µM, respectively, which might be the new lead compound for discovery of novel carbazole-type anticancer agents.

Enhanced Insecticidal Effect and Interface Behavior of Nicotine Hydrochloride Solution by a Vesicle Surfactant.

Nicotine hydrochloride (NCT) has a good control effect on hemiptera pests, but its poor interfacial behavior on the hydrophobic leaf leads to few practical applications. In this study, a vesicle solution by the eco-friendly surfactant, sodium diisooctyl succinate sulfonate (AOT), was prepared as the pesticide carrier for NCT. The physical chemical properties of NCT-loaded AOT vesicles (NCT/AOT) were investigated by techniques such as dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM). The results showed that the pesticide loading and encapsulation efficiency of NCT/AOT were 10.6% and 94.8%, respectively. The size of NCT/AOT vesicle was about 177 nm. SAXS and surface tension results indicated that the structure of the NCT/AOT vesicle still existed with low surface tension even after being diluted 200 times. The contact angle of NCT/AOT was always below 30°, which means it could wet the surface of the cabbage leaf well. Consequently, NCT/AOT vesicles could effectively reduce the bounce of pesticide droplets. In vitro release experiments showed that NCT/AOT vesicles had sustained release properties; 60% of NCT in NCT/AOT released after 24 h, and 80% after 48 h. Insecticidal activity assays against aphids revealed that AOT vesicles exhibited insecticidal activity and could have a synergistic insecticidal effect with NCT after the loading of NCT. Thus, the NCT/AOT vesicles significantly improved the insecticidal efficiency of NCT, which has potential application in agricultural production activities.

Discovery of γ-Lactam Alkaloid Derivatives as Potential Fungicidal Agents Targeting Steroid Biosynthesis.

Biological control of plant pathogens is considered as one of the green and effective technologies using beneficial microorganisms or microbial secondary metabolites against plant diseases, and so microbial natural products have played important roles in the research and development of new and green agrochemicals. To explore the potential applications for natural γ-lactam alkaloids and their derivatives, 26 γ-lactams that have flexible substituent patterns were synthesized and characterized, and their in vitro antifungal activities against eight kinds of plant pathogens belonging to oomycetes, basidiomycetes, and deuteromycetes were fully evaluated. In addition, the high potential compounds were further tested using an in vivo assay against Phytophthora blight of pepper to verify a practical application for controlling oomycete diseases. The potential modes of action for compound D1 against Phytophthora capsici were also investigated using microscopic technology (optical microscopy, scanning electron microscopy, and transmission electron microscopy) and label-free quantitative proteomics analysis. The results demonstrated that compound D1 may be a potential novel fungicidal agent against oomycete diseases (EC50 = 4.9748 µg·mL-1 for P. capsici and EC50 = 5.1602 µg·mL-1 for Pythium aphanidermatum) that can act on steroid biosynthesis, which can provide a certain theoretical basis for the development of natural lactam derivatives as potential antifungal agents.

Natural phenolic derivatives based on piperine scaffold as potential antifungal agents.

Piperine is a natural alkaloid with a wide range of biological functions. Natural phenolic compounds existed in many essential oils (EOs) are plant-derived aroma compounds with broad range of biological activities, however, their actions are slow, and they are typically unstable to light or heat, difficult to extract and so on. In order to find high-potential fungicides derived from piperine, a series of piperine-directed essential oil derivatives were designed and synthesized. The structures of all molecules were confirmed by satisfied spectral data, including 1H NMR, 13C NMR and ESIMS. The target compounds were screened for their potential fungicidal activities against six species of plant pathogen fungi, including Rhizoctonia solani, Fusarium graminearum, Phomopsis adianticola, Alternaria tenuis Nees, Phytophthora capsici and Gloeosporium theae-sinensis. Some of target compounds exhibited moderate and broad-spectrum activity against tested fungi compared to the parental piperine. Further studies have shown that some different concentrations of compounds have significant inhibitory activity against Alternaria tenuis Nees and Phytophthora capsici compared to commercial carbendazim, and compound 2b exhibited particularly significant broad-spectrum fungicidal activity.

Discovery of γ-lactam derivatives containing 1,3-benzodioxole unit as potential anti-phytopathogenic fungus agents.

A series of γ-lactam analogs containing 1,3-benzodioxole moiety were designed, and these derivatives were synthesized from the lead compound of lactam via a structural diversity-oriented synthesis, their structures were confirmed by 1HNMR,13CNMR, ESI-MS spectrum. Their antifungal activities were evaluated against four serious and typically crop-threatening agricultural fungi, including Rhizoctonia solani, Alternaria tenuis Nees, Gloeosporium theae-sinensis, and Fusarium graminearum. Some of these derivatives exhibited activity against Alternaria tenuis Nees higher than that of commercial fungicides carbendazim, such as compounds 7a, 7b, and 7i, compared with the blank control, some of these derivatives showed good antifungal activities against Gloeosporium theae-sinensis and Fusarium graminearum. The systematic study provides evidences for further structural modification and application of lactam analogues as antifungal agents for agriculture.

Heterocyclic lactam derivatives containing piperonyl moiety as potential antifungal agents.

To study the novel functionalized heterocyclic molecules with highly potential biological activity, two series of heterocyclic lactam derivatives containing the piperonyl moiety were designed and synthesized. The newly obtained compounds have been identified on the basis of analytical spectral data, including 1H NMR, 13C NMR, and ESI-MS. The target compounds were evaluated for their potential antifungal activities in vitro against twelve species of the plant pathogen fungi (Sclerotinia sclerotiorum, Rhizoctonia solani, Rap Sclerotinia stemrot, Fusarium graminearum, Phomopsis adianticola, Pestallozzia theae, Pestalotiopsis guepinii, Alternaria tenuis Nees, Monilinia fructicola, Colletotrichum gloeosporioides, Phytophthora capsici, Magnaporthe oryzae). Preliminary bioassays suggested that all prepared compounds I1-14 displayed broad-spectrum and moderate antifungal activities compared with the positive control hymexazol, especially for Sclerotinia sclerotiorum, Rap Sclerotinia stemrot, and Monilinia fructicola. In particular, the inhibition rate of compound I9 exhibited good inhibition activity reached 95.16% against Sclerotinia sclerotiorum, and compounds I5, I12 against Phytophthora capsici were 93.44%, 91.25%. Further studies revealed that compounds I5 (IC50 = 19.13 µM) and I12 (IC50 = 9.12 µM) exhibited obviously antifungal activities against Phytophthora capsici, which were better than that of commercial agricultural fungicide hymexazol (IC50 = 325.45 µM). Therefore, these target compounds could be further studied and explored as a lead skeleton for discovery of novel antifungal agents.

Amino acid-oriented poly-substituted heterocyclic tetramic acid derivatives as potential antifungal agents.

In order to find new potential pesticide molecules with antifungal activities, we have designed and synthesized a series of amino acid-oriented poly-substituted tetramic acid derivatives, and evaluated their potential antifungal activities against six kinds of plant pathogenic fungus commonly found in agriculture systematically, including Phomopsis adianticola, Fusarium graminearum, Alternaria tenuis Nees, Magnaporthe oryzae, Gloeosporium theae-sinensis, Sclerotinia sclerotiorum. According to the preliminary bioassay studies, all tested molecules, especially compounds I-2, I-5, I-12, I-15, exhibited significant and broad-spectrum anti-fungal effect in vitro compared to the intermediates M-1, M-2, M-3 and hymexazol. What's more, the inhibition rate of compounds I-5, I-6, I-15 against Phomopsis adianticola reached 74.42%, 60.33%, 65.21%, as well as compounds I-3, I-5, I-15 against Sclerotinia sclerotiorum were 65.65%, 74.92%, 61.36%. Further investigation results indicated that compounds I-2, I-5, I-15 presented obviously inhibitory activities against Phomopsis adianticola compared with hymexazol, which might be considered as the basic active framework for further potential fungicides discovery.

Synthesis and Bio-Evaluation of Natural Butenolides-Acrylate Conjugates.

A series of novel 3-aryl-4-hydroxy-2(5H) furanone-acrylate hybrids were designed and synthesized based on the natural butenolides and acrylates scaffolds. The structures of the prepared compounds were characterized by ¹H-NMR, 13C-NMR and electrospray ionization mass spectrometry (ESI-MS), and the bioactivity of the target compounds against twelve phytopathogenic fungi was investigated. The preliminary in vitro antifungal activity screening showed that most of the target compounds had moderate inhibition on various pathogenic fungi at the concentration of 100 mg·L-1, and presented broad-spectrum antifungal activities. Further studies also indicated that compounds 7e and 7k still showed some inhibitory activity against Pestallozzia theae, Sclerotinia sclerotiorum and Gibberella zeae on rape plants at lower concentrations, which could be optimized as a secondary lead for further research.

Heterocyclic pyrrolizinone and indolizinones derived from natural lactam as potential antifungal agents.

With the aim to develop highly potential active heterocyclic compounds, two series of multi-substituted pyrrolizinone and indolizinones derived from lactam were designed, synthesized and evaluated for their potential antifungal activities against six species of the plant pathogen fungi (Fusarium graminearum, Sclerotinia sclerotiorum, Phomopsis adianticola, Gloeosporium theae-sinensis, Alternaria tenuis Nees, Magnaporthe oryzae). The structure of all the newly molecules were confirmed by analytical spectroscopic data, including 1H NMR, 13C NMR and ESI-MS. According to the preliminary studies on bio-evaluation assay, some of the obtained compounds exhibited moderate and broad-spectrum activities against six fungi compared to the intermediates 6a, 6f and the hymexazol. Particularly, the inhibition rate of compounds 7l, 7m and 7t reached 69.25%, 74.76%, 65.38% against Phomopsis adianticola and Magnaporthe oryzae in vitro activity. Furthermore, compounds 7l and 7t displayed obviously inhibition activities against Phomopsis adianticola compared to the hymexazol. Consequently, compounds 7l and 7t with six-membered alkane ring could be used as new motifs for further investigation.

Asymmetric synthesis of novel triazole derivatives and their in vitro antiviral activity and mechanism of action.

In this study, forty-four chiral triazole derivatives have been prepared via asymmetric synthesis, and which has been successfully characterized by typical spectroscopic techniques including 1H NMR, 13C NMR, EI-MS, elemental analysis and optical rotations. Their in vitro antiviral activities against EV71 and CVB3 were fully investigated in cell-based assays. It was observed that 13 synthetic triazole derivatives inhibited the CPE of EV71 on RD cells, with EC50S in the 5.3-15.9 µg/ml range and corresponding SIs of 4.0-27.6, while 17 triazole derivatives showed antiviral activities against CVB3, with EC50S in the 4.7-15.1 µg/ml range and the corresponding SIs of 3.7-14.5. In addition, in some cases, the respective enantiomers showed significantly selective inhibitory effect against EV71, most notably for the enantiomers 9(R) and 10(S), 42(R) and 43(S), which presented an obvious activity difference. The most potential molecules are the compounds 10 and 43 with S-configuration, and which exhibit good SI values compared with the control Ribavirin.

Synthesis and Evaluation of Essential Oil-Derived ß-Methoxyacrylate Derivatives as High Potential Fungicides.

Essential oils (EOs) are plant-derived aroma compounds with a wide range of biological activity, but their actions are slow, and they are typically unstable to light or heat, difficult to extract and so on. To find highly potential fungicides derived from natural EOs, a series of essential oil-based ß-methoxyacrylate derivatives have been designed and synthesized. The target compounds have been screened for their potential fungicidal activity against eleven species of plant pathogen fungi, including Alternaria alternata, Phomopsis adianticola, Pestalotiopsis theae, Sclerotinia sclerotiorum, etc. Compared with intermediates I, the parent essential oils and azoxystrobin, almost all of essential oil-based ß-methoxyacrylate derivatives exhibited significantly better fungicidal activity. Further investigation revealed that some compounds showed remarkable inhibitory activities against Pestalotiopsis theae, Phomopsis adianticola, Sclerotinia sclerotiorum and Magnapothe grisea at different concentrations in contrast to the commercial product azoxystrobin. Compound II-8 exhibited particularly significant fungicidal activity.

Peptidomimetics Based On Dehydroepiandrosterone Scaffold: Synthesis, Antiproliferation Activity, Structure-Activity Relationship, and Mechanisms.

A series of novel peptidomimetics bearing dehydroepiandrosterone moiety were designed, synthesized, and evaluated for their inhibition activities against cell proliferation. According to the preliminary studies on inhibitory activities, some of the newly prepared compounds indicated significantly inhibition activities against human hepatoma cancer (HepG2), human lung cancer (A549), human melanoma (A875) cell lines compared with the control 5-fluorouracil. Especially, compounds Ii (IC50 < 14 µM) and Ik (IC50 < 13 µM) exhibited obvious inhibition activities against all tested cell lines. The highly potential compound Ik induced apoptosis in HepG2 cells were analyzed by flow cytometry, and the apoptotic effects of compound Ik were further evaluated using Annexin V-FITC/propidium iodide dual staining assay, which revealed these highly potential compounds induced cell death in HepG2 cells at least partly by apoptosis.

Acylthiourea derivatives as colorimetric sensors for anions: Synthesis, characterization and spectral behaviors.

Several acylthioureas have been synthesized to develop colorimetric sensors for detection of biologically important anions. UV-vis titration experiments indicated that the absorbance values have a good linear relationship with concentration of anions when the anions were added in AR-1, AR-4 and AR-6 sensor molecules. The detection limit to AcO(-) and F(-) is 5×10(-6) mol/L when the concentration of receptors are 2×10(-5) mol/L. Especially, compounds AR-1 and AR-4, decorated with strong electron-withdrawing NO2 substituent, showed augmented anion sensing properties, being capable of naked-eye detecting of F(-) and AcO(-) when the water content is lower than 15%. The recognition details of anion sensing were also assessed using (1)H NMR technique and confirmed that the basic anions induced deprotonation of N-H.

Asymmetric syntheses and bio-evaluation of novel chiral esters derived from substituted tetrafluorobenzyl alcohol.

A series of novel chiral esters derived from tetrafluorobenzyl alcohol were designed and prepared via asymmetric synthesis. The target molecules have been identified on the basis of analytical spectra data. All newly synthesized compounds have been screened their potential insecticidal activity against Plutella xylostella compared with those of fenvalerate and d-trans-phenothrin by standard method, and the respective pairs of enantiomers (3-B1-R/S, 3-C1-R/S, 3-D1-R/S) indicated significantly different activities.

Heterocycle-functional gramine analogues: solvent- and catalyst-free synthesis and their inhibition activities against cell proliferation.

A series of novel gramine analogues were designed and synthesized via a convenient three-component reaction, and which were evaluated for their inhibition activities against cell proliferation. Their structures were confirmed by satisfactory spectra analyses mainly including (1)H NMR, and ESI-MS analyses. The preliminary assays indicated that some of the newly synthesized compounds displayed significantly good inhibition activities against human lung cancer (NCI-H460), hepatocellular liver carcinoma (HepG2), gastric cancer (SGC-7901 and BGC-823) cell lines compared with the control 5-Fluorouracil (5-FU), which might be developed as novel lead scaffold for potential anticancer agents.

Novel salicylic acid-oriented thiourea-type receptors as colorimetric chemosensor: synthesis, characterizations and selective naked-eye recognition properties.

Based on the salicylic acid backbone, three highly sensitive and selective colorimetric chemosensors with an acylthiourea binding unit have been designed, synthesized and characterized. These chemosensors have been utilized for selective recognition of fluoride anions in dry DMSO solution by typical spectroscopic titration techniques. Furthermore, the obtained chemosensors AR1-3 have shown naked-eye sensitivity for detection of biologically important fluoride ion over other anions in solution.

N-nitrourea derivatives as novel potential fungicides against Rhizoctonia solani: synthesis, antifungal activities, and 3D-QSAR.

A series of N-nitrourea derivatives bearing various aryl substituents were conveniently obtained via three steps including nitration, carbamic chlorination, and aminolysis reactions. The structures of all newly synthesized compounds were characterized and confirmed by IR, ¹H-NMR, MS, and elemental analysis. The preliminary bioassays indicate that five compounds possess sufficient fungicidal activity against Rhizoctonia solani. Structure-activity relationship (SAR) is also discussed based on the experimental data, and the further quantitative structure-activity relationship (QSAR) was analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).

Adsorptive separation and photocatalytic degradation of methylene blue dye on titanate nanotube powders prepared by hydrothermal process using metal Ti particles as a precursor.

Titanate nanotube powders (TNTPs) with the twofold removal ability, i.e. adsorptive separation and photocatalytic degradation, are synthesized under hydrothermal conditions using metal Ti particles as a precursor in the concentrated alkaline solution, and their morphology, structure, adsorptive and photocatalytic properties are investigated. Under hydrothermal conditions, the titanate nanotubes (TNTs) with pore diameter of 3-4nm are produced on the surface of metal Ti particles, and stacked together to form three-dimensional (3D) network with porous structure. The TNTPs synthesized in the autoclave at 130°C for 24h exhibits a maximum adsorption capability of about 197mg g(-1) in the neutral methylene blue (MB) solution (40mg L(-1)) within 90min, the adsorption process can be described by pseudo second-order kinetics model. Especially, in comparison with the adsorptive and the photocatalytic processes are performed in turn, about 50min can be saved through synchronously utilizing the double removal ability of TNTPs when the removal ratio of MB approaches 95% in MB solution (40mg L(-1)) at a solid-liquid (S/L) ratio of 1:8 under ultraviolet (UV) light irradiation. These 3D TNTPs with the twofold removal properties and easier separation ability for recycling use show promising prospect for the treatment of dye pollutants from wastewaters in future industrial application.

Determination of stereoselective interaction between enantiomers of chiral gamma-aryl-1H-1,2,4-triazole derivatives and Penicillium digitatum.

A series of chiral gamma-aryl-1H-1,2,4-triazole derivatives has been synthesized and the respective analogues have been tested for their inhibitory activities against Penicillium digitatum (P. digitatum). In vitro experiments were indicative of a strong inhibitory effect of all of the compounds on P. digitatum, and seven of the compounds 5 exhibited better inhibition than the commercial fungicides triadimefon and triadimenol. The respective pairs of enantiomers showed significantly different inhibitory activities, most notably in the case of 5g-R and 5g-S, for which a 230-fold difference was observed. These observations suggest that P. digitatum discriminates the enantiomers and that the R enantiomer better fits the active site of cytochrome P450.

Chiral gamma-aryl-1H-1,2,4-triazole derivatives as highly potential antifungal agents: Design, synthesis, structure, and in vitro fungicidal activities.

A novel series of chiral gamma-aryl-1H-1,2,4-triazole derivatives as highly potential antifungal agents have been designed and synthesized conveniently by using the chiral auxiliary as a controlling reagent. All of the compounds exhibit moderate to high ee values reaching up to 99%, and the preliminary bioassay results demonstrated that most of the target compounds take on a significantly wide spectrum activity against Fusarium oxysporium, Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria, and Colletotrichum gossypii species.