Furan fatty acids (FuFAs) are excellent antioxidants but rather unexplored because of their high instability and low contributions to the total lipids of food and biota samples. Therefore, the use of internal standards (IS) is essential for the correct determination of FuFAs in food. However, suitable IS, such as isotope-labeled FuFAs, are currently unavailable, and alternative solutions have to be considered. Since degradation of FuFAs occurs in the furan moiety, the IS must not necessarily carry a carboxyl group. Therefore, one monomethylated (M-11-5) and one dimethylated (D-11-5) 1,4-O-bridged-1,3-diene (oxaDE) were synthesized and applied in the GC/MS analysis of beta-methyl substituted (M-FuFAs) and beta,beta'-dimethyl substituted FuFAs (D-FuFAs). GC/MS measurements verified a similar fragmentation as for FuFA methyl esters (FuFA-MEs), along with favorable low quantification limits (0.8-0.9 pg). Transesterification of two FuFA-EE (9M5, 11D5) along with two oxaDEs (M-11-5, D-11-5) enabled monitoring the recovery of FuFAs and verified the lower stability of D-FuFAs compared to M-FuFAs. Problems caused by unstable reagents in the transesterification step could be identified and solved with the newly introduced IS. The final application of the method to six fish oils enabled the detection of eight FuFAs with amounts up to 1.2 g/100 g fish oil.

An efficient urease-catalyzed approach for the synthesis of highly substituted 6-amino-4 H -pyran-3-carbonitriles based on the formation of three bonds in one step is developed. This unprecedented three-component reaction between one molecule of an aromatic aldehyde and two molecules of an aroylacetonitrile proceeds by employing commercially available urease from jack bean (Canavalia ensiformis) as the catalyst in water at 65 degrees C to deliver the desired 4 H -pyrans in yields of up to 92%. The transformation is proposed to occur via a domino Knoevenagel condensation/1,4-addition/O-cyclization/tautomerization sequence, providing a practical and sustainable approach to 6-amino-4 H-pyran-3-carbonitriles from commercially available substrates. Full and unambiguous structural elucidation of all the products is achieved by means of NMR spectroscopy and X-ray crystal structure analysis.

Introduction: Biological Nitrification Inhibition (BNI) is defined as the plant-mediated control of soil nitrification via the release of nitrification inhibitors. BNI of Brachiaria humidicola (syn. Urochloa humidicola) has been mainly attributed to root-exuded fusicoccane-type diterpenes, e.g., 3-epi-brachialactone. We hypothesized, however, that BNI of B. humidicola is caused by an assemblage of bioactive secondary metabolites.Methods:B. humidicola root exudates were collected hydroponically, and metabolites were isolated by semi-preparative HPLC. Chemical structures were elucidated by HRMS as well as 1D and 2D NMR spectroscopy. Nitrification inhibiting potential of isolated metabolites was evaluated by a Nitrosomonas europaea based bioassay.Results and discussion: Besides previously described brachialactone isomers and derivatives, five phenol and cinnamic acid derivatives were identified in the root exudates of B. humidicola: 2-hydroxy-3-(hydroxymethyl)benzaldehyde, vanillin, umbelliferone and both trans- and cis-2,6-dimethoxycinnamic acid. Notably, vanillin revealed a substantially higher nitrification inhibiting activity than 3-epi-brachialactone (ED50 ∼ 12.5 μg·ml−1, ED80 ∼ 20 μg·ml−1), identifying this phenolic aldehyde as novel nitrification inhibitor (NI). Furthermore, vanillin exudation rates were in the same range as 3-epi-brachialactone (1–4 μg·h−1·g−1 root DM), suggesting a substantial contribution to the overall inhibitory activity of B. humidicola root exudates. In relation to the verification of the encountered effects within soils and considering the exclusion of any detrimental impact on the soil microbiome, the biosynthetic pathway of vanillin via the precursor phenylalanine and the intermediates p-coumaric acid/ferulic acid (precursors of further phenolic NI) might constitute a promising BNI breeding target. This applies not only to Brachiaria spp., but also to crops in general, owing to the highly conserved nature of these metabolites.

BACKGROUND:Cleistanthus collinus is a poisonous shrub commonly used for deliberate self-harm in rural south India. Boiled decoction or a paste made from its leaves is used for suicide. Cleistanthoside A and Cleistanthin A are the major toxins identified from this plant. In this study, we disclose the mechanism of Cleistanthin A toxicity and concentrations of the two toxins in different extracts of Cleistanthus collinus.METHODS:The effect of Cleistanthin A was studied on isolated goat leg arteries using two different preparations namely transverse cylinder and longitudinal strip. The influence of Cleistanthin A on peripheral vascular resistance and myocardial contractility was evaluated by rat hind limb and isolated rat heart experiments, respectively. For the quantification of toxins, five different extracts of C. collinus leaves were prepared. The extracts were subjected to analytical HPLC to quantify Cleistanthoside A and Cleistanthin A.RESULTS AND CONCLUSION:Cleistanthin A increased vascular tension in transverse cylinder preparation and increased peak, trough and mean aortic pressures in the rat hind limb preparations. In isolated rat heart experiments, there was an increase in diastolic and mean ventricular pressure with a significant decrease in ventricular pulse pressure. These observations suggest that the hypotension in C. collinus poisoning patients may be due to cardiotoxicity and not due to vasodilation as is currently believed. Quantification of different extracts showed that boiled extracts had higher quantities of Cleistanthoside A whereas crushed leaf extracts yielded significantly higher amounts of Cleistanthin A.

A highly efficient copper(I)-catalyzed approach for the synthesis of 1,1'-bisindoles that is based on the formation of four bonds in one step has been developed. The unprecedented three component reaction between one molecule of a 1,2-bis(2-bromoaryl)hydrazine and two molecules of a 1,3-diketone employing 10 mol% CuI as a catalyst and Cs2CO3 as a base in DMSO at 100 °C for 24 h delivers substituted 1,1'-bisindoles with yields up to 92%. The new method proceeds as a double domino condensation/Ullmann type C-C coupling. It allows an efficient and practical access to substituted 1,1'-bisindoles in one step from easily available starting materials.

Abstract Background Malaria remains the major health problem responsible for many mortality and morbidity in developing countries. Because of the development of resistance by Plasmodium species, searching effective antimalarial agents becomes increasingly important. Pinocembrin is a flavanone previously isolated as the most active antiplasmodial compound from the leaves of Dodonaea angustifolia. For a better understanding of the antiplasmodial activity, the synthesis of pinocembrin and a great number of analogs was undertaken. Methods Chalcones 5a-r were synthesized via Claisen-Schmidt condensation using 2,4-dibenzyloxy-6-hydroxyacetophenone and aromatic aldehydes as substrates under basic conditions. Cyclization of compounds 5a-r to the corresponding dibenzylated pinocembrin analogs 6a-r was achieved using NaOAc in EtOH under reflux. Catalytic hydrogenation using 10% Pd/C as catalyst in an H-Cube Pro was used for debenzylation to deliver 7a-l. The structures of the synthesized compounds were characterized using various physical and spectroscopic methods, including mp, UV, IR, NMR, MS and HRMS. The synthesized dibenzylated flavanones 6a-d, 6i and 7a were evaluated for their in vivo antiplasmodial activities against Plasmodium berghei infected mice. Molecular docking simulation and drug likeness properties of compounds 7a-l were assessed using AutoDock Vina and SwissADME, respectively. Results A series of chalcones 5a-r has been synthesized in yields ranging from 46 to 98%. Treatment of the chalcones 5a-r with NaOAc refluxing in EtOH afforded the dibenzylated pinocembrin analogs 6a-r with yields up to 54%. Deprotection of the dibenzylated pinocembrin analogs delivered the products 7a-l in yields ranging from 78 to 94%. The dibenzylated analogs of pinocembrin displayed percent inhibition of parastaemia in the range between 17.4 and 87.2% at 30 mg/kg body weight. The parastaemia inhibition of 87.2 and 55.6% was obtained on treatment of the infected mice with pinocembrin (7a) and 4’-chloro-5,7-dibenzylpinocembrin (6e), respectively. The mean survival times of those infected mice treated with these two compounds were beyond 14 days indicating that the samples suppressed P. berghei and reduced the overall pathogenic effect of the parasite. The molecular docking analysis of the chloro derivatives of pinocembrin revealed that compounds 7a-l show docking affinities ranging from – 8.1 to – 8.4 kcal/mol while it was -7.2 kcal/mol for chloroquine. Conclusion Pinocembrin (7a) and 4’-chloro-5,7-dibenzyloxyflavanone (6e) displayed good antiplasmodial activity. The in silico docking simulation against P. falciparum dihydrofolate reductase-thymidylate synthase revealed that pinocembrin (7a) and its chloro analogs 7a-l showed better binding affinity compared with chloroquine that was used as a standard drug. This is in agreement with the drug-like properties of compounds 7a-l which fulfill Lipinski's rule of five with zero violations. Therefore, pinocembrin and its chloro analogs could serve as lead compounds for further antiplasmodial drug development.

The Cu(I)-catalyzed reaction between five-, six-, seven-, and eight-membered cyclic 1-bromoallyl tosylates and five- and six-membered cyclic 1,3-dicarbonyls in DMF at 80 °C using Cs2CO3 as a base and 2-picolinic acid as an additive selectively delivers a wide array of bisannulated 4H-pyrans in a single step with yields up to 92%. The transformations are considered to proceed as intermolecular C-allylations/intramolecular O-vinylations. With six-membered cyclic 1-bromoallyl tosylates and acyclic β-ketoesters as substrates, the corresponding 5,6,7,8-tetrahydro-4H-chromene-3-carboxylates are obtained with yields up to 59%.

Abstract The phytochemical study of the CH2Cl2- MeOH (1:1, v/v) extract of the stem bark of Carapa procera DC (Meliaceae) led to the isolation and characterisation of a new natural limonoid 7β-obacunol (6), along with seven known compounds. Their structures were elucidated by spectroscopic means, including 1 D and 2 D NMR, HRESI-MS and by comparison with published data. The cytotoxicity of compounds 1-6 was assessed in vitro by the WST-1 assay on human lung adenocarcinoma A549 and Raw 264.7 mouse macrophage cell lines. Results suggested that obacunone (3) exhibited the most potent cytotoxic effect against A549 and Raw 264.7 cells with respective IC50 values of 25.24 µM and 29.14 µM, while the new natural limonoid 7β-obacunol (6) exhibited 32.75 µM and 39.19 µM, respectively on both cell lines. Therefore, limonoid derivatives might be promising sources of natural bioactive metabolites against cancer. Graphical Abstract

AbstractElektrochemische Synthese – Naturstoffe und deren Synthese – photokatalytische Redoxchemie – Farbstoffe – Nanostrukturen – Wirkstoffe – asymmetrische Katalyse und mehr.

A simple, convenient, transition metal-free one pot synthesis of 3,5-disubstituted-1,2,4-triazoles has been established. The innovation in this reaction is the use of easily available 1,1-diaminoazines as substrates. This method provides the products with wider substrate scope, at an expedited rate, and with relatively better yields in comparison to the reported methods. The reaction mechanism involves an initial intermolecular nucleophilic addition (facilitated by I-2) followed by intramolecular nucleophilic cyclization.

A CuI-catalyzed, hydrazine-free transformation of 2-(2-bromoarylidene)guanylhydrazone hydrochlorides using Cs2CO3 as a base and DMEDA as a ligand at 120 degrees C for 5 h delivers substituted 1H-indazoles with yields up to 75%. The C,N double bond configuration of the substrates was determined by NMR experiments and quantum chemical calculations. The reaction mechanism was studied using quantum chemical calculations. (C) 2021 Elsevier Ltd. All rights reserved.

Cleistanthus collinus leaf extracts are consumed for suicidal purposes in southern India. The boiled decoction is known to be more toxic than the fresh leaf juice. Although several compounds have been isolated and their toxicity tested, controversy remains as to which compounds are responsible for the high level of toxicity of C. collinus. We report herein that cleistanthoside A is the major toxin in the boiled aqueous extract of fresh leaves and causes death in rats in small doses. The toxicity of the boiled extract prepared in the manner described can be attributed entirely to cleistanthoside A. Cleistanthin A could also be isolated from the boiled extract, albeit in trace amounts. As hypotension not responding to vasoconstrictors is the cause of death in patients who have consumed the boiled extract, effects of cleistanthoside A on the determinants of blood pressure, namely, force of cardiac contraction and vascular resistance, were tested in isolated organ experiments. Cleistanthoside A has a direct vasoconstrictor effect; however, it inhibits ventricular contractility. Therefore, the notion that the shock in C. collinus poisoning is of vascular origin must be considered carefully, and the possibility of cardiogenic shock must be studied. We present the crystal structure of cleistanthin A and show the potency of fast NMR methods (NOAH4-BSCN-NUS) in the full spectral assignment of cleistanthoside A as a real-world sample of a natural product. We also compare the results of the NOAH4-BSCN-NUS NMR experiments with conventional NMR methods.

A Highly efficient copper‐catalyzed one‐pot sequential approach has been developed for the synthesis of azole‐fused imidazo[1,2‐a]pyridines with 2‐(2‐bromophenyl)imidazo[1,2‐a]pyridine‐3‐carbaldehydes as substrates. The one‐pot approach involved a sequential imidazole/benzimidazole formation followed by a copper‐catalyzed intramolecular Ullmann type C–N coupling. The method tolerated a variety of functional groups and offered the desired products in good to excellent (50–85 %) yields. The photophysical properties of the compounds synthesized were evaluated by UV/Vis and fluorescence spectroscopy in CH3CN. The π‐expanded azole‐fused imidazo[1,2‐a]pyridines displayed high fluorescence emission with large Stokes shifts and moderate to good quantum yields. A pronounced positive solvatochromism and aggregation caused quenching (ACQ) was observed for 2,3‐bis(4‐methoxyphenyl)‐12‐methylimidazo[1,2‐a]pyrido[2',1':2,3]imidazo[4,5‐c]quinoline.

A transition metal-free, diastereospecific reaction between substituted (Z)-1,2-dibromo-3-phenyl-2-propenes and substituted catechols using Cs2CO3 as a base at 140 degrees C for 18 h delivers exclusively substituted (Z)-2-arylidene-2,3-dihydrobenzo[b][1,4]dioxines in yields up to 89%. Experiments as well as quantum chemical calculations support the assumption that the one pot transformation proceeds as an intermolecular O-allylation/intramolecular O-vinylation. (C) 2020 Elsevier Ltd. All rights reserved.

Biological Nitrification Inhibition (BNI) of Brachiaria humidicola has been mainly attributed to the root-exuded fusicoccane-type diterpene brachialactone. We hypothesized, however, that according to the high diversity of fusicoccanes described for plants and microorganisms, BNI of B. humidicola is caused by an assemblage of bioactive fusicoccanes. B. humidicola root exudates were collected hydroponically and compounds isolated by semi-preparative HPLC. Chemical structures were revealed by spectroscopic techniques, including HRMS as well as 1D and 2D NMR. Nitrification inhibiting (NI) potential of isolated compounds was evaluated by a Nitrosomonas europaea based bioassay. Besides the previously described brachialactone (1), root exudates contained 3-epi-brachialactone (2), the C3-epimer of 1 (m/z 334), as well as 16-hydroxy-3-epi-brachialactone (3) with an additional hydroxyl group at C16 (m/z 350) and 3,18-epoxy-9-hydroxy-4,7-seco-brachialactone (4), which is a ring opened brachialactone derivative with a 3,18 epoxide ring and a hydroxyl group at C9 (m/z 332). The 3-epi-brachialactone (2) showed highest NI activity (ED50 similar to 20 mu g mL(-1), ED80 similar to 40 mu g mL(-1)), followed by compound 4 with intermediate (ED50 similar to 40 mu g mL(-1)) brachialactone (1) with low and compound 3 without activity. In coherence with previous reports on fusicoccanes, stereochemistry at C3 was of high relevance for the biological activity (NI potential) of brachialactones.

A direct and operationally simple method for the regioselective synthesis of 2-aryl-substituted 2H-indazoles is reported. The Pd-catalyzed reaction between easily available 2-bromobenzyl bromides and arylhydrazines employing Cs2CO3 as the base and t-Bu3PHBF4 as the ligand in DMSO at 120 °C in a sealed tube delivers the 2-substituted-2H-indazoles in a single synthetic step with yields up to 79%. The new method is based on a regioselective intermolecular N-benzylation followed by intramolecular N-arylation and oxidation.

Prebiotics are rising in interest in commercial scale productions due to increasing health awareness of consumers. Under bio-economic aspects, sweet and acid whey provide a suitable feed medium for the enzymatic generation of prebiotic lactulose. Since whey has a broad variation in composition, the influence of the feed composition on the concentration of generated lactulose was investigated. The influence of lactose and fructose concentration as well as enzymatic activity of two commercially available β-galactosidases were investigated. The results were evaluated via response surface analysis with a quadratic model containing pairwise interaction terms. The optimal feed composition yielding a theoretical maximal amount of lactulose was determined as 1.28 or 0.74 mol/kg fructose and 0.17 or 0.19 mol/kg lactose with an enzymatic activity of 2.0 or 2.8 μkat/kg for acid (pH 4.4) or sweet (pH 6.6) whey. Furthermore, the major reaction product was isolated and subsequently, the structural identity was elucidated and verified via extensive NMR analysis.

The tautomeric preference of guanylhydrazones towards the azine form induces an unprecedented intramolecular to intermolecular mechanistic switch during the I2-catalyzed oxidative transformation leading to 4,5-disubstituted-3-amino-1,2,4-triazoles in contrast to the reaction of semicarbazones and thiosemicarbazones to form 1,3,4-oxa/thiadiazoles. This intramolecular to intermolecular cyclization shift was established through control experiments and was attributed to the high energy demand (∼22 kcal mol-1) for the azine tautomer to adopt the s-cis conformation which is essential for the intramolecular reaction. An I2 induced protocol for an efficient and straightforward synthesis of 4,5-disubstituted-3-amino-1,2,4-triazoles has been developed via tandem oxidative transformation of guanylhydrazones (in its preferentially existing azine tautomeric form) with distinct advantages such as wide substrate scope, use of substoichiometric amounts of iodine, no requirement of external oxidizing agents, base free reaction conditions, short reaction time and moderate to good yields. The role of silver salt in improving the yield and shortening of reaction time was also highlighted.

A copper-catalyzed approach for the N-acylation of anilines with acetone and acetophenones via C-C bond cleavage is described. Under the developed conditions both CHCl3 and CH2Cl2 were identified as potential C1-source to promote the transformation. The reaction features a site selective C-C bond cleavage to install the amide moieties with high functional-group compatibility and wide substrate scope. The developed method avoids the use of sensitive and narcotic agents. The method also represents an excellent complement to the previous protocols with lower E-factor (13.91 mg/1 mg) than current industrially used method (E-factor 17.54 mg/1 mg). The developed approach has also been extended for the effective preparation of pyridine derivatives and paracetamol in gram scale. The course of the reaction was monitored by H-1 NMR as a preliminary investigation of the reaction mechanism.