Key Derivatives Research Articles

Stereochemistry of the Kabachnik‐Fields Condensation of Terpenic Amino Oximes with Aldehydes and Dimethyl Phosphite

AbstractThree‐component condensation of aldehydes and dimethyl phosphite with α‐amino oximes derived from (−)‐α‐pinene and (+)‐3‐carene (Kabachnik‐Fields reaction) resulted in amino phosphonates as pairs of diastereomers. Diastereomeric ratio depends on the catalyst used (SnCl2×2H2O, SiO2, Al2O3‐H+) and the heating type (conventional or microwave). The best results were achieved by MW irradiation with simultaneous cooling. Stereochemical assignment of the key derivatives was made by X‐ray diffractometry. According to quantum chemical calculations (DFT PBE0/def2‐TZVPP) and spectroscopic data, the terpenic α‐amino phosphonates should be conformationally inhomogeneous, exhibiting a tendency to form H‐bonded dimers (DFT M06/def2‐SVP, IR). One‐bond spin‐spin coupling 1JP–C was found to be diagnostic for the configuration assignment since the value 1JP–C depends on the dihedral angle between bond C−P and axis of the electron lone pair at the neighboring nitrogen (NMR, DFT PBE0/aug‐cc‐pVTZ−J).

Novel technologies of nitrogen-based compounds

AbstractThis paper discusses the main technological solutions used in the production of key nitrogen derivatives such as nitrobenzene, aniline, ethanolamine, and methylene diphenyl diisocyanate. The technologies presented are not only already functioning technologies, but also the newest installations that are at the testing stage.

Synthesis of novel caffeic acid derivatives and their protective effect against hydrogen peroxide induced oxidative stress via Nrf2 pathway

AimThis study was aimed to synthesize novel caffeic acid derivatives and evaluate their potential applications for the treatment of oxidative stress associated disease. Main methodsCaffeic acid sulfonamide derivatives were synthesized by coupling sulfonamides to the backbone of caffeic acid and fully characterized by melting point test, FT-IR, MS, NMR, UV–vis and n-octanol–water distribution assay. Their free radical scavenging ability was evaluated using DPPH assay and cytotoxicity against A549 cells were determined by MTT assay. The protective effect of these derivatives against hydrogen peroxide (H2O2) induced oxidative injury was assessed in A549 cells from cell viability, production of reactive oxygen species (ROS) and malondialdehyde (MDA), alternation of antioxidase activities, and expressions of Nrf2 and its target genes. Key findingsSix novel caffeic acid sulfonamide derivatives were obtained. The derivatives showed better liphophilicity than the parent caffeic acid. CASMZ, CAST and CASQ exhibited similar DPPH scavenging capability as caffeic acid, while the protection of hydroxyl groups on the benzene ring with acetyl groups caused decrease in radical scavenging activity. No inhibitory effect on the proliferation of A549 cells were observed up to a concentration of 50 μM. Pre-treatment of cells with these derivatives strongly inhibited H2O2 induced decrease of cell viability, reduced the production of ROS and MDA, promoted antioxidase activities, and further upregulated the expression of Nrf2 and its target genes. SignificanceCaffeic acid sulfonamide derivatives were synthesized with simple reactions under mild conditions. They might protect cells from H2O2-induced oxidative injury via Nrf2 pathway.

7-hydroxytropolone is the main metabolite responsible for the fungal antagonism of Pseudomonas donghuensis strain SVBP6.

Pseudomonas donghuensis strain SVBP6, an isolate from an agricultural plot in Argentina, displays a broad-spectrum and diffusible antifungal activity, which requires a functional gacS gene but could not be ascribed yet to known secondary metabolites typical of Pseudomonas biocontrol species. Here, we report that Tn5 mutagenesis allowed the identification of a gene cluster involved in both the fungal antagonism and the production of a soluble tropolonoid compound. The ethyl acetate extract from culture supernatant showed a dose-dependent inhibitory effect against the phytopathogenic fungus Macrophomina phaseolina. The main compound present in the organic extract was identified by spectroscopic and X-ray analyses as 7-hydroxytropolone (7HT). Its structure and tautomerism was confirmed by preparing the two key derivatives 2,3-dimethoxy- and 2,7-dimethoxy-tropone. 7HT, but not 2,3- or 2,7-dimethoxy-tropone, mimicked the fungal inhibitory activity of the ethyl acetate extract from culture supernatant. The activity of 7HT, as well as its production, was barely affected by the presence of up to 50 μM added iron (Fe+2 ). To summarize, P. donghuensis SVBP6 produces 7HT under the positive control of the Gac-Rsm cascade and is the main active metabolite responsible for the broad-spectrum inhibition of different phytopathogenic fungi.

Phytotoxic Activity and Structure-Activity Relationships of Radicinin Derivatives against the Invasive Weed Buffelgrass (Cenchrus ciliaris).

Radicinin (1), is a fungal dihydropyranopyran-4,5-dione isolated together with some analogues, namely 3-epi-radicinin, radicinol, 3-epi-radicinol, and cochliotoxin (2–5), from the culture filtrates of the fungus Cochliobolus australiensis, a foliar pathogen of buffelgrass (Cenchrus ciliaris), an invasive weed in North America. Among the different metabolites 1 showed target-specific activity against the host plant and no toxicity on zebrafish embryos, promoting its potential use to develop a natural bioherbicide formulation to manage buffelgrass. These data and the peculiar structural feature of 1 suggested to carry out a structure-activity relationship study, preparing some key hemisynthetic derivatives and to test their phytotoxicity. In particular, p-bromobenzoyl, 5-azidopentanoyl, stearoyl, mesyl and acetyl esters of radicinin were semisynthesized as well as the monoacetyl ester of 3-epi-radicinin, the diacetyl esters of radicinol and its 3 epimer, and two hexa-hydro derivatives of radicinin. The spectroscopic characterization and the activity by leaf puncture bioassay against buffelgrass of all the derivatives is reported. Most of the compounds showed phytotoxicity but none of them had comparable or higher activity than radicinin. Thus, the presence of an α,β unsaturated carbonyl group at C-4, as well as, the presence of a free secondary hydroxyl group at C-3 and the stereochemistry of the same carbon proved to be the essential feature for activity.

English

The European Union in collaboration with some non-governmental organisation initiated the European Micro Projects Programme (MPP) in south-south States of Nigeria. Basically, the aim of the progamme was to help improve the poor living condition of communities situated in these areas, by the provision of basic infrastructures. One of the key derivatives from the ecological zones/vegetation belts in Niger Delta is the natural resources aside oil and gas reserves, which serve as a means of livelihood for rural community. The objective of this study was to examine the relative effects of density and accessibility of MPP projects on poverty incidence across the vegetational belts of the south-south states in Nigeria. A cross sectional survey of household units was adopted during data collection and resulting data along with other measured parameters were subjected to a combination of descriptive statistics and spatial analytical techniques, to determine if there are relationships between poverty incidence and MPP project distribution along the vegetation belts. The resulting project density within the belts showed that rain forest and fresh water swamp have more concentration within defined output cells. The poverty ranking results for the ecological regions showed that extremely poor respondents are predominant in all the ecological zones with 100% occurrence in mangrove. Moderately poor respondents are more in the low land rain forest and mangrove and coastal vegetation. The highest number of non-poor falls within the derived rainforest and Mangrove forest and coastal vegetation. There is a negative correlation between density of all projects and extreme poverty condition within the belts. It is established that MPP density was not a good predictor of prevalence of poverty. The significant value p > 0.05 showed it is of no statistical significance. Therefore, distributions of considered spatial variables of the MPP schemes and resulting effects have not sufficiently addressed relative poverty conditions amongst rural communities within the area of interest. Infrastructural facilities need be provided in such a manner to address poverty conditions by supporting the rural communities to tap productive ecological resources in these areas. Key words: Infrastructure, spatial distribution, poverty conditions, ecological resources, GIS.

An Overview of Carotenoids, Apocarotenoids, and Vitamin A in Agro-Food, Nutrition, Health, and Disease.

Carotenoids are fascinating compounds that can be converted into many others, including retinoids that also play key roles in many processes. Although carotenoids are largely known in the context of food science, nutrition, and health as natural colorants and precursors of vitamin A (VA), evidence has accumulated that even those that cannot be converted to VA may be involved in health-promoting biological actions. It is not surprising that carotenoids (most notably lutein) are among the bioactives for which the need to establish recommended dietary intakes have been recently discussed. In this review, the importance of carotenoids (including apocarotenoids) and key derivatives (retinoids with VA activity) in agro-food with relevance to health is summarized. Furthermore, the European Network to Advance Carotenoid Research and Applications in Agro-Food and Health (EUROCAROTEN) is introduced. EUROCAROTEN originated from the Ibero-American Network for the Study of Carotenoids as Functional Food Ingredients (IBERCAROT).

A regional ASTER GDEM error model for the Chinese Loess Plateau

ABSTRACTAccuracy of the global ASTER GDEM (Advanced Space-borne Thermal Emission and Reflection Radiometer Global Digital Elevation Model) version 2 (v2) elevation data product is highly variable regionally, as are its empirical correlations with landscape variables. This paper investigates GDEM error along a 49-site geomorphologic gradient within the core region of the Chinese Loess Plateau, notable for its heterogeneous terrain. The error is modelled using its associations with MODIS (Moderate Resolution Imaging Spectroradiometer) composite forest cover percentage, GlobeLand30 land cover, and key elevation derivatives, including two indices, terrain roughness index (TRI) and topographic position index (TPI), not previously evaluated in GDEM accuracy studies. Overall root mean squared error (RMSE) is 20.33 m, in excess of the GDEM v2 accuracy specifications, while RMSE at each site varies substantially, from 10.67 m for a low relief area to 21.84 m for the most rugged site. Strong associations between covariates, especially slope, aspect, TRI, and forest cover are identified. A regression model using these variables is developed to formally characterize and predict GDEM error. External validation with independent checkpoints across all sites demonstrates that this model can reduce mean error by about 4 m.

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma.

Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.

In-vitro and in-vivo antimalarial activity of caffeic acid and some of its derivatives

To explore the in-vitro and in-vivo antimalarial potential of caffeic acid and derivatives. Two common phenolic acids (caffeic acid and chlorogenic acid) were evaluated for in-vitro and in-vivo antiplasmodial activity in comparison with some semi-synthetic derivatives that were synthesized. An in-vitro assay based on plasmodial lactate dehydrogenase activity, and the classical in-vivo 5-day suppressive test from Peters on an artemisinin-resistant Plasmodium berghei strain was used. Parasitic stage sensitivity to ethyl caffeate was determined in this work. Phenolic acid esters derivatives showed better antiplasmodial activity than corresponding phenolic acids. The derivative with the highest in-vitro activity being caffeic acid ethyl ester, exhibiting an IC50 =21.9±9.4μm. Ethyl caffeate and methyl caffeate were then evaluated for antimalarial activity invivo and ethyl caffeate showed a growth inhibition of 55% at 100mg/kg. Finally, it seems that ethyl caffeate blocks the growth of young parasitic forms. Our study provides evidence for an antimalarial potential of caffeic acid derivatives which are common in several medicinal plants traditionally used against malaria. It also demonstrates the possibility to use such derivatives in the treatment of malaria.

(+)-epi-Epoformin, a Phytotoxic Fungal Cyclohexenepoxide: Structure Activity Relationships.

(+)-epi-Epoformin (1), is a fungal cyclohexene epoxide isolated together with diplopimarane and sphaeropsidins A and C, a nor-ent-pimarane and two pimaranes, from the culture filtrates of Diplodia quercivora, a fungal pathogen for cork oak in Sardinia, Italy. Compound 1 possesses a plethora of biological activities, including antifungal, zootoxic and phytotoxic activity. The last activity and the peculiar structural feature of 1 suggested to carry out a structure activity relationship study, preparing eight key hemisynthetic derivatives and the phytotoxicity was assayed. The complete spectroscopic characterization and the activity in the etiolated wheat coleoptile bioassay of all the compounds is reported. Most of the compounds inhibited growth and some of them had comparable or higher activity than the natural product and the reference herbicide Logran. As regards the structure-activity relationship, the carbonyl proved to be essential for their activity of 1, as well as the conjugated double bond, while the epoxide could be altered with no significant loss.

Flavonoids from Trollius europaeus flowers and evaluation of their biological activity.

This article describes the flavonoid composition of the flowers of Trollius europaeus and the method of isolation thereof and provides an attempt at investigating the antioxidant activity of the isolated flavonoids and the antityrosinase activity of the extracts from the investigated material. The compositional data were acquired by combining results of nuclear magnetic resonance, ultraviolet spectroscopy, electrospray ionisation-tandem mass spectrometry (ESI-MS/MS) analyses and those of an analysis of the products of acid hydrolysis of the compounds. The antioxidant activity of the extracts was studied using the 2,2'-diphenyl-1-picrylhydrazyl assay and the tyrosinase inhibitory activity - with the use of mushroom tyrosinase. Ten flavonoid derivatives of luteolin and apigenin were isolated from the flowers of T.europaeus and identified. The investigation into the antioxidant activity revealed that orientin 2″-O-α-arabinopyranoside (4) and orientin 2″-O-β glucopyranoside (5) had a significant antioxidant effect. The studies conducted led to the development of a method of isolating flavonoid, potentially antioxidant, compounds from T.europaeus. They allowed to determine which of the investigated flavonoids demonstrated significant antioxidant activity and could be used as natural antioxidants.

Optimization Technology of the LHS-1 Strain for Degrading Gallnut Water Extract and Appraisal of Benzene Ring Derivatives from Fermented Gallnut Water Extract Pyrolysis by Py-GC/MS.

Gallnut water extract (GWE) enriches 80~90% of gallnut tannic acid (TA). In order to study the biodegradation of GWE into gallic acid (GA), the LHS-1 strain, a variant of Aspergillus niger, was chosen to determine the optimal degradation parameters for maximum production of GA by the response surface method. Pyrolysis–gas chromatography–mass spectrometry (Py-GC/MS) was first applied to appraise benzene ring derivatives of fermented GWE (FGWE) pyrolysis by comparison with the pyrolytic products of a tannic acid standard sample (TAS) and GWE. The results showed that optimum conditions were at 31 °C and pH of 5, with a 50-h incubation period and 0.1 g·L−1 of TA as substrate. The maximum yields of GA and tannase were 63~65 mg·mL−1 and 1.17 U·mL−1, respectively. Over 20 kinds of compounds were identified as linear hydrocarbons and benzene ring derivatives based on GA and glucose. The key benzene ring derivatives were 3,4,5-trimethoxybenzoic acid methyl ester, 3-methoxy-1,2-benzenediol, and 4-hydroxy-3,5-dimethoxy-benzoic acid hydrazide.

The Pivotal Neuroinflammatory, Therapeutic and Neuroprotective Role of Alpha-Mangostin

Alpha-mangostin (α-MG), one of the key xanthone derivatives, displays a multiplicity of curative qualities like antiinfective, anti-malarial, anticarcinogenic, antidiabetic actions as well as antioxidant properties. Furthermore, it has proven to have neuroprotective, hepatoprotective, and cardioprotective features, of which the anticarcinogenic action is the most auspicious. Additionally, several in vitro and in vivo analyses confirm that α-MG partakes in the major stages of tumor growth: initiation, promotion, and progression. Nevertheless, α-MG services as an inhibitory agent that modulate various enzymes involved in the metabolic activation and excretion of carcinogens, resistance to oxidative damage, and attenuation of inflammatory response. Numerous studies have also implicated α-MG in central nervous system (CNS) disorders, among which neuroinflammatory disorders and brain cancer are cardinal. Based on these initial studies on α-MG, we reviewed the pivotal role of α-MG in neuroinflammatory disorders. J Neurol Res. 2017;7(4-5):67-79 doi: https://doi.org/10.14740/jnr455w

Synthesis and larvicidal activities of compounds based on coumarin and dibenzothiophene/carbazole

Based on a rationally conceived pharmacophore model to build a dual-target mosquito larvicide, a family of coumarin-dibenzothiophene or -carbazole hybrids with various substituents on phenyl were synthesized in moderate yields. Larvicidal activity of hybrid molecules were evaluated against fourth instar larvae of Aedes aegypti. Most of the synthesized hybrids displayed moderate to high activity and the activities of coumarin-linked carbazole hybrids were better than those of dibenzothiophene hybrids. The structure–activity relationships revealed that coumarin, dibenzothiophene and carbazole were the key pharmacophore and carbazole derivatives consisting of an electron-withdrawing group in the coumarin–carbazole hybrid molecular structure possess better activity than their corresponding parent compound.

Terrazoanthines, 2-Aminoimidazole Alkaloids from the Tropical Eastern Pacific Zoantharian Terrazoanthus onoi.

The first chemical study of the common species Terrazoanthus onoi, present off the coast of Ecuador, led to the identification of a new family of 2-aminoimidazole alkaloids named terrazoanthines A-C (1-3). Homologues 1 and 2 feature an unprecedented 6-(imidazol-5-yl)benzo[d]imidazole. Acyl substitution pattern and complete configurational assignments were deduced from comparison between experimental and theoretical 13C NMR and ECD data, respectively. These compounds may represent key derivatives in the biosynthesis of zoanthoxanthins.

Prediction and Characterization of Alkaline‐Earth (M=Be, Mg, Ca, Sr, and Ba) Metallacyclopentadienes and Relevant Derivatives

AbstractAlkaline‐earth metallacyclopentadienes are an active area of research in synthetic chemistry, notable for their roles as precursors of key cyclopentadiene derivatives. However, experimental characterization is limited due to their challenging synthesis and subsequent isolation. Herein, we report systematic theoretical studies of MC4H4 (M=Be, Mg, Ca, Sr, Ba) rings and experimentally relevant complexes. Benchmarking against CCSD(T) and experiment shows reasonable performance for the B3LYP, BP86, and M06‐2X density functionals in predicting the equilibrium geometries, thermochemistry, and vibrational spectra of these species. NICS indices and extra cyclic resonance energies confirm that the compounds in question possess antiaromatic character. For both the bare MC4H4 rings and larger complexes, the Be‐containing compounds were found to be the most strongly bound species. Such viability is explained via ring strain, electron densities, natural bond orders, and orbital analyses. Given that the second least viable Mg complex has been reported in recent experiments, synthesis and characterization of the other group IIA analogs are anticipated.

Exploring the Reactivity of 2-Trichloromethylbenzoxazoles for Access to Substituted Benzoxazoles.

The reactivity of 2-trichloromethylbenzoxazoles toward various nucleophiles, under metal-free or iron-catalyzed conditions, for the synthesis of substituted benzoxazoles is described. These methods allow for selective substitution at either the 2- or 2'-position of the benzoxazoles using the same starting materials/reagents. This approach allows for the controlled synthesis of a variety of key derivatives from a single 2-trichloromethylbenzoxazole starting material.

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies.

To obtain key sugar derivatives for making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H-t X-OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H-c X-OH) from D-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding -t X- or -c X- and (4) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for D-xylo and D-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. -X-OMe, -X-OiPr, -X-NHMe, Fmoc-X-OH) and key coupling reactions making -Aaa-t X-Aaa- or -Aaa-t X-t X-Aaa- type "inserts". Completed for both stereoisomers of X, including the newly synthesized Fmoc-c X-OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.

Fusaproliferin, Terpestacin and Their Derivatives Display Variable Allelopathic Activity Against Some Ascomycetous Fungi.

Herbivorous mammal dung supports a large variety of fimicolous fungi able to produce different bioactive secondary metabolites to compete with other organisms. Recently, the organic extracts of the Solid State Fermentation (SSF) cultures of Cleistothelebolus nipigonensis and Neogymnomyces virgineus, showing strong antifungal activity, were preliminarily investigated. This manuscript reports the isolation of the main metabolites identified, using spectroscopic and optical methods, as fusaproliferin (1) and terpestacin (2). Furthermore, some key hemisynthetic derivatives were prepared and their antifungal activity was tested against the same fungi previously reported to be affected by the organic extracts obtained from SSF. These metabolites and their derivatives resulted able to reduce the growth of Alternaria brassicicola, Botrytis cinerea and Fusarium graminearum in a variable extent strongly dependent from chemical modifications and test fungi. The hydroxy enolic group at C(17) appeared to be a structural feature important to impart activity. This study represents the first report of these secondary metabolites produced by C.nipigonensis and N.virgineus.