Structure-activity relationships of furanones, dihydropyrrolones and thiophenones as potential quorum sensing inhibitors.

Since their initial isolation from the marine alga Delisea pulchra, bromofuranones have been investigated as potential inhibitors of quorum sensing (QS) in various bacterial strains. QS is an important mechanism by which bacteria co-ordinate their molecular response to the environment. QS is intrinsically linked to bacterial antibiotic resistance. Inspired by nature, chemists have developed a wide variety of synthetic analogs in an effort to elucidate the structure-activity relationships of these compounds, and to ultimately develop novel antimicrobial agents. In this work, we describe advances in this field while paying particular attention to apparent structure-activity relationships. This review is organized according to the main ring systems under investigation, namely furanones, dihydropyrrolones and thiophenones.

Tagetnoic acid, a new lipoxygenase inhibitor peroxy fatty acid from Tagetes minuta growing in Saudi Arabia.

A new peroxy fatty acid, tagetnoic acid (5) [4-((3S,6S)-6-((3E,8E)-octadeca-3,8-dien-1-yl)-3,6-dihydro-1,2-dioxin-3-yl)butanoic acid] and four known metabolites: ecliptal (5-formyl-α-terthiophene) (1), 5-(4-hydroxybut-1-ynyl)-2,2'-bithiophene (2), 22,23-dihydrospinasterone (3), and stigmasterol (4) were separated from the n-hexane fraction of the aerial parts of Tagetes minuta L. (Asteraceae). Their chemical structures were verified using IR, UV, 2D and 1D NMR, and HRMS. Compounds 3-5 displayed potent lipoxygenase inhibitory potential with IC50s 2.26, 1.83, and 1.17 µM, respectively compared to indomethacin (IC50 0.89 µM). Moreover, molecular docking study revealed that the potent activity of 5 is due to H-bonding and hydrophobic interaction. The results of this study suggested that Tagetes minuta dietary consumption would be useful for the individuals at risk of acute and chronic inflammatory disorders.

Thiophenes from Echinops grijsii as a Preliminary Approach To Control Disease Complex of Root-Knot Nematodes and Soil-Borne Fungi: Isolation, Activities, and Structure-Nonphototoxic Activity Relationship Analysis.

Naturally occurring thiophenes possess excellent nematicidal and fungicidal activities. However, thiophenes often have limited application in soil due to their light-dependent toxicity given the living and reproductive condition of soil-borne pathogens. In this study, six new (1-6) and six known thiophenes (7-12) were isolated from Echinops grijsii. Compounds 1-2, 4-5, 8-9, 11 , and 12 showed stronger nematicidal activity against Meloidogyne incognita than commercial nematicide abamectin. 4-10 were demonstrated as nonphototoxic thiophenes. Among these, 4 and 8 were the most potent thiophenes (LC50 values 2.57 and 0.91 µg/mL in light, 1.80 and 0.86 µg/mL in dark, respectively) against M. incognita. SAR revealed that thiophene skeleton was essential for nematicidal activity, while disubstituted groups were helpful for nonphototoxicity. Although an increased number of acetylenes improved activity, it decreased nonphototoxicity. Acyl groups could suppress the effects of light on activity, with the level of inhibitory effects depending on its number and chain length, while chlorine played important roles in promoting activity. Additionally, compounds 1-2, 4-5, 7, 8, and 10 displayed antifungal activity against six soil-borne fungi in various degrees. The discovery of nonphototoxic thiophenes and elucidation of SAR provide important information for the exploitation and utilization of thiophenes in the integrative management regarding disease complexes caused by the combination of root-knot nematode and soil-borne fungi.

Plant Density and Rhizosphere Chemistry: Does Marigold Root Exudate Composition Respond to Intra- and Interspecific Competition?

The development of techniques to non-destructively monitor allelochemical dynamics in soil using polydimethylsiloxane (PDMS) microtubing (silicone tubing microextraction, or STME) provides a means to test important ecological hypotheses regarding the roles of these compounds in plant-plant interactions. The objective of this study was to investigate the impact of intra- and interspecific competition on the exudation of thiophenes by marigolds (Tagetes patula L.). Marigolds were grown at a density of 1, 3 and 5 plants in pots (8.75 × 8.75 cm) containing two STME samplers. An additional treatment included one marigold surrounded by four velvetleaf (Abutilon theophrasti L.) plants. Marigold roots released two primary thiophenes, 3-buten-1-ynyl)-2,2'-bithienyl and α-terthienyl, which are readily absorbed by silicone microtubing. Thiophene exudation was monitored over the period 15-36 days after planting, at 2-5 day intervals. At the end of the study, root and soil samples were also analyzed for thiophene content. Thiophene production per plant increased over time, and thiophene release was strongly correlated with plant size. These results indicate that thiophene release in this study was passively controlled by resource availability. However, poor growth of velvetleaf plants competing with marigold suggests that thiophenes negatively influenced velvetleaf growth. This study, then, provides indirect evidence that thiophene exudation is insensitive to neighbor identity but differentially effective in inhibiting the growth of heterospecific neighbors.

Degradation of sulfolane in aqueous media by integrating activated sludge and advanced oxidation process.

In this study, the performance of an integrated technology, combining biological treatment with advanced oxidation process in sequence, was evaluated for the degradation of sulfolane in aqueous media. In addition, the impact of biological process on AOP was also studied by assessing residual sulfolane, nutrient and total suspended solids (TSS) concentrations. The integration of activated sludge process with UVC/H2O2 resulted in more than 81% of sulfolane degradation in less than 24 h. It was observed that mineralization was much faster in biological system compared to AOP. Mechanistically, the process of degradation is different in the two processes as various by-products were identified during UVC/H2O2 but not during the biological process. The impact of residual sulfolane concentration on UVC/H2O2 was significant beyond a concentration of 30 mg L-1, while below 30 mg L-1 the rate of degradation was independent of sulfolane concentration. Residual nutrients from biological systems did not impact AOP performance. Nevertheless, presence of TSS >44 mg L-1 had a negative impact on the performance of UVC/H2O2 by reducing UV transmittance which led to retardation of sulfolane degradation. The application of UVC/H2O2 after biological treatment was an advantage as UVC/H2O2 could perform dual roles of oxidant and disinfectant.

Removal of low-concentration thiophene by DC corona discharge plasma.

This study focuses on the removal of C4H4S using DC corona discharge plasma. The influences of various factors such as C4H4S concentration (ppm), temperature (°C), O2 concentration (%), and dust concentration (mg/m3) on the conversion of C4H4S were studied. Furthermore, gaseous compositions were determined using Fourier transform infrared (FTIR) spectroscopy. Solid products, which were collected from earth and discharge electrodes, were analyzed using X-ray diffraction (XRD). The results showed that, under the condition of DC corona discharge plasma, C4H4S converted to CO, CO2, S, SO2, and SO42-, and that the conversion rate increased with the increase in specific input energy (SIE). The increase of O2 concentration led to further energy consumption that generated O3, which in turn decreased the conversion rate of C4H4S. The increase in temperature exhibited a positive influence on the conversion of C4H4S when the SIE was less than 268 J/L. However, above this value of SIE, the temperature affected the conversion of C4H4S negatively with the increase in SIE. When dust was introduced, the conversion of C4H4S was significantly improved and the yield of SO2 reduced due to the reaction which took place among C4H4S, SO2 and dust in the electric field. The results showed that the DC corona discharge plasma exhibited considerable potential to remove C4H4S, while dust contributed positively towards the disposal of C4H4S. Graphical abstract In this work, DC corona plasma was used to remove thiophene (C4H4S) from a dust-containing gas stream. The results showed that electron collision, oxidizability of radicals, and existence of O3 were the main causes of C4H4S decomposition. The electron collision effects, contents of radicals, O3, and the conversion rate of C4H4S were enhanced with the increase in SIE (specific input energy). The main products consisted of CO, CO2, SO2, and solid products. The solid products and dust moved to the earth electrode in the electric field.

Ajothiolanes: 3,4-Dimethylthiolane Natural Products from Garlic ( Allium sativum).

Stereoisomers of 5-(2-allylsulfinyl)-3,4-dimethylthiolane-2-ol, a family of 3,4-dimethylthiolanes of formula C9H16O2S2 we name ajothiolanes, were isolated from garlic ( Allium sativum) macerates and characterized by a variety of analytical and spectroscopic techniques, including ultraperformance liquid chromatography (UPLC), direct analysis in real time-mass spectrometry (DART-MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Ajothiolanes were found to be spectroscopically identical to a family of previously described compounds named garlicnins B1-4 (C9H16O2S2), whose structures we demonstrate have been misassigned. 2D 13C-13C NMR incredible natural abundance double quantum transfer experiments (INADEQUATE) were used to disprove the claim of nine contiguous carbons in these compounds, while X-ray absorption spectroscopy (XAS) along with computational modeling was used to disprove the claim that these compounds were thiolanesulfenic acids. On the basis of the similarity of their NMR spectra to those of the ajothiolanes, we propose that the structures of previously described, biologically active onionins A1-3 (C9H16O2S2), from extracts of onion ( Allium cepa) and Allium fistulosum, and garlicnin A (C12H20O2S4), from garlic extracts, should also be reassigned, in each case as isomeric mixtures of 5-substituted-3,4-dimethylthiolane-2-ols. We conclude that 3,4-dimethylthiolanes may be a common motif in Allium chemistry. Finally, we show that another garlic extract component, garlicnin D (C7H12O2S3), claimed to have an unprecedented structure, is in fact a known compound from garlic with a structure different from that proposed, namely, 2( E)-3-(methylsulfinyl)-2-propenyl 2-propenyl disulfide.

Two new thiophene polyacetylene glycosides from Atractylodes lancea.

Phytochemical investigation on the rhizomes of Atractylodes lancea led to the isolation of two new thiophene polyacetylene glycosides (1 and 2) and six known compounds (3-8). Their structures were elucidated based on the extensive spectroscopic data (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of new compounds were established by calculated and experimental circular dichroism. All the compounds were assessed on the lipopolysaccharide-induced NO production in BV2 cells and compounds 3, 7, and 8 showed moderate inhibitory activities.

Effect of Temperature on Flavor Compounds and Sensory Characteristics of Maillard Reaction Products Derived from Mushroom Hydrolysate.

Maillard reaction products (MRPs) were prepared from mushroom hydrolysate (MH) by heating with d-xylose and l-cysteine at various temperatures (100 °C-140 °C) for 2 h at a pH of 7.4. The sensory characteristics of MH and MRPs were evaluated by panelists and volatile compounds were analyzed by GC/MS. Additionally, partial least squares regression (PLSR) was performed to analyze the correlation between quantitative sensory characteristics and GC/MS data. GC/MS results revealed that higher reaction temperature resulted in more nitrogen and sulfur containing compounds in MRPs while alcohols, ketones and aldehydes were the major flavor compounds obtained in MH. PLSR results showed that 3-phenylfuran and 2-octylfuran were the compounds responsible for the caramel-like flavor; 1-octen-3-ol, (E)-2-octen-1-ol and geranyl acetone were significantly and positively correlated to mushroom-like flavor, whereas, 2-thiophene-carboxaldehyde, 2,5-thiophenedicarboxaldehyde and 3-methylbutanal positively affected MRPs meat-like attribute. Overall, 125 °C was identified as the optimal temperature for preparing MRPs with abundant volatile compounds and favorable sensory characteristics; the concentration of free amino acids and 5'-GMP, which are associated with the umami taste, in MRPs derived under 125 °C were 3 to 4 times higher than those in MH.

Phytochemical constituents and antioxidant activity of Echinops albicaulis.

Two thiophenes; 5-(3-buten-1-ynyl)-2,2'-bithiophene (2) and α-tertthienyl (9), two alkaloids; echinopsine (10) and echinorine (11), three flavonoids; genkwanin (5), apigenin (6), and rutin (7), two triterpenoids; lupeol acetate (1) and lupeol linoleate (4), together with 2,6,10-trimethyldodeca-2,6,10-triene (4) and ß-sitosterol glucoside (8) were isolated from the aerial parts of Echinops albicaulis. Antioxidant, antimicrobial and antiprotozoal activities were evaluated. E. albicaulis aqueous methanolic extract (50, 10, and 1 mg/mL) showed significant antioxidant activity comparable to the potent antioxidant, N-acetyl cysteine, moreover, the aqueous methanolic extract (1 mg/mL) significantly reduced intracellular reactive oxygen species in active cell cultures of human peripheral blood mononuclear cells under oxidative stress more than the reference antioxidant N-acetyl cysteine. None of the isolated compounds showed antimicrobial or antiprotozoal activities at concentration up to 20 µg/mL.

Thiotagetin B and tagetannins A and B, new acetylenic thiophene and digalloyl glucose derivatives from Tagetes minuta and evaluation of their in vitro antioxidative and anti-inflammatory activity.

The three new metabolites: thiotagetin B (2) [(Z)-1″-([2,2'-bithiophen]-5-yl)-8″-chloro-6″,11″-dimethylundeca-6″,10″-dien-2″-yn-9″-one], tagetannin A (9) [3,4-bis-(galloyl-3,5-dimethyl ether)-(α/ß)-d-glucopyranose], and tagetannin B (10) [2,3-bis-(galloyl-3,5-dimethyl ether)-(α/ß)-d-glucopyranose], along with ecliptal (5-formyl-α-terthiophene) (1), 5-(4-hydroxybut-1-ynyl)-2,2'-bithiophene (3), scopoletin (4), p-hydroxybenzoic acid (5), protocatechuic acid methyl ester (6), gallic acid (7), and patuletin 7-O-ß-d-glucoside (8) were isolated from the aerial parts of Tagetes minuta L. (Asteraceae). Their structures were verified by extensive spectroscopic analyses as well as by comparison with literature data. The isolated compounds were evaluated for their antioxidant and anti-inflammatory activities using DPPH and enzyme-linked immunosorbent assays, respectively. Compounds 5-10 possessed the highest antioxidant potential with a scavenging activity (SCA)≈74 to 93% of DPPH radicals. Moreover, 5-10 displayed significant anti-inflammatory potential, while 4 showed moderate activity. Compounds 5-10 exhibited significant decreases in NFκB p65, TNF-α, and IL-6 levels at all tested concentrations.

New cyclic sulfides extracted from Allium sativum: garlicnins P, J2, and Q.

Two atypical cyclic-type sulfides, garlicnin P (1) and garlicnin J2 (2), and one thiabicyclic-type sulfide, garlicnin Q (3), were isolated from the acetone extracts of garlic, Allium sativum, bulbs cultivated in the Kumamoto city area, and their structures characterized. Their production pathways are also discussed.

New cyclic sulfides, garlicnins I2, M, N, and O, from Allium sativum.

One atypical thiolane-type sulfide, garlicnin I2 (1), two 3,4-dimethylthiolane-type sulfides, garlicnins M (2) and N (3), and one thiabicyclic-type sulfide, garlicnin O (4), were isolated from the acetone extracts of Chinese garlic bulbs, Allium sativum and their structures were characterized. Hypothetical pathways for the production of the respective sulfides were discussed.

New terpenoids and thiophene derivatives from the aerial parts of Artemisia sieversiana.

One new highly oxygenated nortriterpene, named sieverlactone (1), one new sesquiterpene, 1ß,10ß-epoxy-8α-acetoxyachillin (2), one new natural product, 5-propinyl-thiophene-2-carboxylic acid (3), and one new thiophene, 3-hydroxy-5-propinyl-2-acetyl-thiophene (4), together with 10 other known compounds (5-14), were isolated from the dried aerial parts of Artemisia sieversiana. Their structures were elucidated by a combination of extensive spectroscopic analysis, including 1D, 2D NMR spectroscopic and mass spectrometric data. Meanwhile, the stereochemistry of 1 and 2 was confirmed by single-crystal X-ray diffraction technique using Cu radiation. All the isolates were evaluated for their anti-neuroinflammatory effects on the lipopolysaccharide-induced nitric oxide production in BV-2 murine microglial cells. Compounds 2, 5, and 6 exhibited the significant activities with IC50 values of 6.5 ±â€¯0.5, 11.9 ±â€¯0.7, and 10.1 ±â€¯0.3 µM, respectively, comparable to the positive control, quercetin, with an IC50 value of 16.3 ±â€¯0.4 µM.

Antimalarial Activity of Acetylenic Thiophenes from Echinops hoehnelii Schweinf.

Malaria is one of the world's most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78.7% at dose of 50, 100, 200 and 400 mg/kg respectively. The dichloromethane fraction displayed chemosuppression of 24.9, 33.5 and 43.0% dose of 100, 200 and 400 mg/kg of body weight. Five acetylenicthiophenes were isolated from the dichloromethane fraction of which 5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene decreased the level of parasitaemia by 43.2% and 50.2% while 5-(penta-1,3-diynyl)-2-(3-chloro-4-acetoxy-but-1-yn)-thiophene suppressed by 18.8% and 32.7% at 50 and 100 mg/kg, respectively. The study confirmed the traditional claim of the plant to treat malaria and could be used as a new lead for the development of antimalarial drugs.

Inhibition of human cytochromes P450 2A6 and 2A13 by flavonoids, acetylenic thiophenes and sesquiterpene lactones from Pluchea indica and Vernonia cinerea.

The human liver cytochrome P450 (CYP) 2A6 and the respiratory CYP2A13 enzymes play role in nicotine metabolism and activation of tobacco-specific nitrosamine carcinogens. Inhibition of both enzymes could offer a strategy for smoking abstinence and decreased risks of respiratory diseases and lung cancer. In this study, activity-guided isolation identified four flavonoids 1-4 (apigenin, luteolin, chrysoeriol, quercetin) from Vernonia cinerea and Pluchea indica, four hirsutinolide-type sesquiterpene lactones 5-8 from V. cinerea, and acetylenic thiophenes 9-11 from P. indica that inhibited CYP2A6- and CYP2A13-mediated coumarin 7-hydroxylation. Flavonoids were most effective in inhibition against CYP2A6 and CYP2A13, followed by thiophenes, and hirsutinolides. Hirsutinolides and thiophenes exhibited mechanism-based inhibition and in irreversible mode against both enzymes. The inactivation kinetic KI values of hirsutinolides against CYP2A6 and CYP2A13 were 5.32-15.4 and 0.92-8.67 µM, respectively, while those of thiophenes were 0.11-1.01 and 0.67-0.97 µM, respectively.

Chiral analysis of ammuxetine enantiomers in dog plasma using online SPE/liquid chromatography with tandem mass spectrometric detection after precolumn chiral derivatization.

Ammuxetine (AMT), a novel chiral antidepressant candidate compound, exhibits better antidepression effects than duloxetine in different animal models. In this article, a chiral derivatization method, combined with online solid phase extraction (online SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), was developed for the chiral separation of AMT enantiomers after administration of racemic AMT to dogs. The derivatization reaction employed 2,3,4,6-tetra-O-acetyl-b-glucopyr-anosyl isothiocyanate (GITC) as a precolumn chiral derivatization reagent. A SPE column Retain PEP Javelin (10 × 2.1 mm) was used to remove proteins and other impurities in plasma samples. The enantiomeric derivatives were separated on a ZORBAX SB-C18 column (50 × 2.1 mm × 3.5 µm) with an isocratic elution procedure. The selected multiple reaction monitoring mode of the positive ion was performed and the parent to the product transitions m/z 681.0/543.1 and m/z 687.4/543.1 were used to measure the derivatives of AMT and duloxetine (internal standard) with electrospray ionization. The method was validated in terms of specificity, linearity, sensitivity, precision, accuracy, matrix effect, and stability. The method was applied to a pharmacokinetics study of AMT racemate in dogs. The results suggested that the pharmacokinetic of AMT enantiomers might be stereoselective in dogs.

Antifungal effect of volatile organic compounds produced by Bacillus amyloliquefaciens CPA-8 against fruit pathogen decays of cherry.

The present work focuses on the antifungal effect of volatile organic compounds (VOCs) produced by Bacillus amyloliquefaciens CPA-8 against Monilinia laxa, M. fructicola and Botrytis cinera, three postharvest fruit pathogens of sweet cherry fruit. VOCs were evaluated with a double petri dish assay against mycelial and colony growth of target pathogens. For this purpose, CPA-8 was grown on different media and cultured for 24 and 48 h at 30 °C before assays. Data showed that mycelial growth inhibition was higher when CPA-8 was grown on Tryptone Soya Agar (TSA) while no differences were generally observed when CPA-8 was cultured for either, 24 and 48 h. Moreover, no effects were observed on colony growth. The main volatile compounds emitted by CPA-8 were identified by solid-phase microextraction (SPME)-gas chromatography as 1,3 pentadiene, acetoin (3-hydroxy-2-butanone) and thiophene. Pure compounds were also tested in vitro on mycelial growth inhibition and their EC50 values against the three pathogens were estimated. Thiophene was the most effective VOC, showing more than 82% suppression of mycelial growth at the highest concentration (1.35 µL/mL headspace) and EC50 values ranging from 0.06 to 6.67 µL/mL headspace. Finally, the effectiveness of thiophene and CPA-8 VOCs was evaluated against artificially inoculated cherry fruits. Among the target pathogens, M. fructicola was clearly controlled by CPA-8 with less than 25% of rotten fruits compared to the control (65% disease incidence) and for all pathogens, less than 37.5% of CPA-8 treated decayed fruits produced spores (disease sporulation). Otherwise, pure thiophene showed no effect against any pathogen on disease incidence and disease sporulation. The results indicated that VOCs produced by B. amyloliquefaciens CPA-8 could develop an additive antifungal effect against postharvest fruit pathogens on stone fruit.

Atypical Cyclic Sulfides, Garlicnins G, I, and J, Extracted from Allium sativum.

Newly characterized, atypical sulfides, garlicnins G (1), I (2), and J (3), were isolated from the acetone extracts of garlic bulbs, Allium sativum. Their production pathways are regarded as different from those of cyclic sulfoxides, 3,4-dimethyltetrahydrothiophene-S-oxide derivatives such as onionins A1-A3, garlicnins B1-B4 and C1-C3.

Thiotagetin A, a new cytotoxic thiophene from Tagetes minuta.

Phytochemical investigation of the n-hexane fraction of the methanolic extract of Tagetes minuta L. (Asteraceae) aerial parts afforded a new thiophene derivative: thiotagetin A (3), together with ß-sitosterol (1) and stigmasterol (2). The structure of the new thiophene was identified by UV, IR, 1D (1H and 13C), 2D (1H-1H COSY, HSQC and HMBC) NMR and HRESIMS spectral data. Compound 3 displayed cytotoxic activity against KB and MCF7 cancer cell lines with ED50 values of 2.03 and 3.88 µg/mL, respectively, compared to adriamycin (0.26 and 0.07 µg/mL, respectively).