α,α-Dialkylglycines obtained by solid phase Ugi reaction performed over isocyanide functionalized resins

The multicomponent Ugi reaction is a straightforward method that can be used for the synthesis of highly hindered C-tetrasubstituted amino acids by reacting an amine, a ketone or aldehyde, a carboxylic acid and an isocyanide. In the present work, the synthesis of several α,α-dialkylglycines (α,α-diethylglycine, Deg; α,α-dipropylglycine, Dpg; 1-amino-1-cyclohexanecarboxylic acid, Ac₆c) was achieved by solid phase Ugi reaction using resins functionalized with the isocyanide group. Since no resins with these features were available commercially, the functionalization of an aminomethylated resin started by the use of glycine (Gly), β-alanine (β-Ala) and γ-aminobutyric acid (GABA) as spacers. After spacer N-formylation, followed by dehydration, isocyanide functionalised resins were obtained. The resins were then used in solid phase Ugi reaction, using phenylacetic acid as the acid component, 4-methoxybenzylamine as the amine component and different ketones, to afford the desired N-acylated α,α-dialkylglycines in good overall yields (60–80%), after acidolytic cleavage from the resin, thus proving the feasibility of this approach.     

Antioxidant, Anti-inflammatory, and Hypoglycemic Effects of the Leaf Extract from Passiflora nitida Kunth

Diabetes mellitus is a metabolic disease characterized by abnormally high plasma glucose levels, leading to major complications, such as insulin resistance, obesity, hyperlipidemia, and hypertension, also with alterations in the immune and neuronal systems. Brazilian plants have been studied as important sources for new molecules with medicinal properties. The genus Passiflora known as “Maracujá” has been used as a traditional folk medicine for a long time, so an investigation was performed regarding an endemic kind of passion fruit (Passiflora nitida Kunth) from Amazonas, Brazil. Here, we aimed to determine its potential biological activity against metabolic syndrome, oxidative stress, pain, and inflammation. The hydroethanol leaf extract revealed an in vitro α-glucosidase inhibitory activity of 50 % inhibitory concentration (IC₅₀)?=?6.78?±?0.31 μg/mL and an α-amylase inhibition of IC₅₀?=?93.36?±?4.37. In vivo, experiments of different saccharide tolerance resulted in significant glycemia control and, with alloxan-diabetic mice, resulted in a decrease of total cholesterol, a hypoglycemic effect, and an antioxidant activity by thiobarbituric acid-reactive substances measurement. Also, it decreased the carrageenan-induced edema volume and the rate of writhing as a nociceptive response. These results indicate positive effects of P. nitida extract and its potential to inhibit metabolic syndrome.     

Total and inorganic mercury determination in fish tissue by flow injection cold vapour atomic fluorescence spectrometry

A simple and reliable method for Hg determination in fish samples has been developed. Lyophilised fish tissue samples were extracted in a 25% (w/v) tetramethylammonium hydroxide (TMAH) solution; the extracts were then analysed by FI-CVAFS. This method can be used to determine total and inorganic Hg, using the same FI manifold. For total Hg determination, a 0.1% (w/v) KMnO₄ solution was added to the FI manifold at the sample zone, followed by the addition of a 0.5% (w/v) SnCl₂ solution, whereas inorganic Hg was determined by adding a 0.1% (w/v) L-cysteine solution followed by a 1.0% (w/v) SnCl₂ solution to the FI system. The organic fraction was determined as the difference between total and inorganic Hg. Sample preparation, reagent consumption and parameters that can influence the FI-CVAFS performance were also evaluated. The limit of detection for this method is 3.7 ng g^?1 for total Hg and 4.3 ng g^?1 for inorganic Hg. The relative standard deviation for a 1.0 µg L^?1 CH₃Hg standard solution (n = 20) was 1.1%, and 1.3% for a 1.0 µg L^–1 Hg²⁺ standard solution (n = 20). Accuracy was assessed by the analysis of Certified Reference Material (dogfish: DORM-2, NRCC). Recoveries of 99.1% for total Hg and 93.9% inorganic Hg were obtained. Mercury losses were not observed when sample solutions were re-analysed after a seven day period of storage at 4°C.     

The effects of lignin removal and drying on the porosity and enzymatic hydrolysis of sugarcane bagasse

The porosity of lignocellulosic materials is a key feature for the enzymatic hydrolysis of the constituent polysaccharides, being affected by its drying and lignin content. Here we evaluated the influence of both parameters in the porosity of sugarcane bagasse, using raw and chlorite-delignified samples. A fraction of these samples was air dried at room temperature and the remainder one was kept wet. All the samples were subjected to porometry (solute exclusion technique), determination of water retention value and assessment of enzymatic saccharification of polysaccharides. Samples with higher lignin contents had lower porosities and exhibited worse enzymatic conversions of polysaccharides. Mild drying collapsed only the smaller pores, which already were inaccessible to enzymes, and therefore did not affect the efficiencies of saccharification. Our results show that the lignin content plays an important role in the porosity of the material and that its removal improves the enzymatic saccharification of the constituent polysaccharides.     

Synthesis of 3-iodothiophenes via iodocyclization of (Z)-thiobutenynes

A simple synthesis of 3-iodothiophenes was demonstrated using a wide range of (Z)-thioenynes. The key step in the iodocyclofunctionalization was the selective reduction of the triple bond in (Z)-thioenynes by the addition of iodine as an electrophilic agent. The 3-iodothiophenes were obtained in good to excellent yields of 61–92%. The 3-iodothiophenes were used as substrates in Sonogashira cross-coupling reactions to obtain thiophene acetylenes.     

Radioanalytical assessment of environmental contamination around non-remediated uranium mining legacy site and radium mobility

During the past century extensive uranium mining took place in Portugal for radium and uranium production. One such uranium mine was the Boco Mine, in operation during the 1960s and 70s. Mining waste and open pits were left uncovered since mine closure. During the nineties a quarry for sand extraction was operated in the same site and water from a local stream was extensively used in sand sieving. Downstream the mine area, agriculture soil is used for cattle grazing. Water from the stream, water wells, soil, pasture and sheep meat were now analyzed for radionuclides of uranium natural series. The U-series radionuclide ²²⁶Ra was generally the highest in concentrations especially in soil, pasture, and in internal organs of sheep. ²²⁶Ra concentrations were 1,093 ± 96 Bq/kg (dry weight, dw) in soil, 43 ± 3 Bq/kg (dw) in pasture, and 193 ± 84 mBq/kg (wet weight, ww) in muscle tissue of sheep. Other sheep internal organs displayed much higher ²²⁶Ra concentrations, such as the brain and kidneys with 1,850 ± 613 mBq/kg (ww) and 6,043 ± 6,023 mBq/kg (ww), respectively. Results of analyses of tissue samples from sheep grown in a comparison area were 2 to 16 times lower, depending on the organ. Absorbed radiation doses for internal organs were computed and may exceed 5.2 mGy/y in the case of kidneys, near three times higher than in animals from the reference area, but below the threshold for biological effects. Radionuclide transfer in the terrestrial food chain and radiation exposure of the human population is discussed.     

Antiprotozoal and Antibacterial Activity of Ravenelin,a Xanthone Isolated from the Endophytic Fungus Exserohilum rostratum

The natural compound ravenelin was isolated from the biomass extracts of Exserohilum rostratum fungus, and its antimicrobial, antiplasmodial, and trypanocidal activities were evaluated. Ravenelin was isolated by column chromatography and HPLC and identified by NMR and MS. The susceptibility of Gram-positive and Gram-negative bacteria strains to ravenelin was determined by microbroth dilution assay. Cytotoxicity was evaluated in hepatocarcinoma cells (HepG2) and BALB/c peritoneal macrophages by using MTT. SYBR Green I-based assay was used in the asexual stages of Plasmodium falciparum. Trypanocidal activity was tested against the epimastigote and intracellular amastigote forms of Trypanosoma cruzi. Ravenelin was active against Gram-positive bacteria strains, with emphasis on Bacillus subtilis (MIC value of 7.5 µM). Ravenelin’s antiparasitic activities were assessed against both the epimastigote (IC₅₀ value of 5 ± 1 µM) and the intracellular amastigote forms of T. cruzi (IC₅₀ value of 9 ± 2 µM), as well as against P. falciparum (IC₅₀ value of 3.4 ± 0.4 µM). Ravenelin showed low cytotoxic effects on both HepG2 (CC₅₀ > 50 µM) and peritoneal macrophage (CC₅₀ = 185 ± 1 µM) cells with attractive selectivity for the parasites (SI values > 15). These findings indicate that ravenelin is a natural compound with both antibacterial and antiparasitic activities, and considerable selectivity indexes. Therefore, ravenelin is an attractive candidate for hit-to-lead development.     

A Novel Carbon Nitride Nanosheets-based Electrochemical Sensor for Determination of Hydroxychloroquine in Pharmaceutical Formulation and Synthetic Urine Samples

This study introduces modified carbon paste electrodes with carbon nitride nanosheets (CNNS) and outlines their application for the determination of hydroxychloroquine sulfate (HCQ) in tablets and synthetic urine samples. CNNS were synthesized by hydrothermal route (200 °C, 10 h) using melamine and citric acid as their precursors. The carbon nitride nanosheets-based electrode (CNNS/E) presented a linear dynamic range for HCQ (LDR), ranging from 10.0 nmol l⁻¹ to 6.92 μmol l⁻¹, and detection (LOD) and quantification limits (LOQ) of 0.16 nmol l⁻¹ and 0.52 nmol l⁻¹, respectively. LOD and LOQ were calculated by the equations: LOD=3(S_d/b), and LOQ=10(S_d/b). The modified sensor presented excellent relative standard deviations for parameters such as repeatability (2.39 % and 1.87 %) and reproducibility (3.22 % and 2.32 %) in HCQ oxidation peaks (1 and 2). The CNNS/E has not shown significant variations in its anodic signal intensity in the presence of some organic and inorganic substances. It is worth bearing in mind that CNNS/E can be easily manufactured and the sensor has the lowest HCQ detection limits reported so far. The proposed sensor was successfully applied for HCQ determination in tablets and synthetic urine, showing good recovery values and an error of 0.60 % about comparative method in tablet samples, assuring the quality of the method.     

Heterocyclic compounds as antiviral drugs: Synthesis,structure–activity relationship and traditional applications

A virus outbreak challenges the economic, medical, and public health infrastructure worldwide. More than one virus capable of triggering diseases have been identified per year since 1972, which requires the development of new ways of treatment and prevention, however, such processes are not rapid and easy. With the pandemic scenario experienced since early 2020, several drugs with well-known purposes have gained prominence, due to speculation of their use in the treatment against the new coronavirus. Among the main drugs studied, the vast majority contain a heterocyclic structure. In this review, we presented the traditional and efficient synthesis of 15 drugs that have been studied for the COVID-19 treatment, containing in their structure heterocycles like indole, quinoline, pyrimidone, tetrahydrofuran, pyrrolidine, triazole, pyridazine, pyrazole, pyrrolopyrimidine, azetidine, pyrrolotriazine, pyrazine, tetrahydropyran, benzofuran, spiroketal, and thiazole. Furthermore, we have shown the original applications, as well as their structure–activity relationship and what is their situation as a drug candidate against COVID-19. Thus, the objective was to consolidate the main synthetic and pharmacological aspects involving clinically developed heterocycles that at some point were presented as promising against SARS-CoV-2.     

A Bis(pyridine N‐oxide) Analogue of DOTA: Relaxometric Properties of the GdIII Complex and Efficient Sensitization of Visible and NIR‐Emitting Lanthanide(III) Cations Including PrIII and HoIII

We report the synthesis of a cyclen‐based ligand (4,10‐bis[(1‐oxidopyridin‐2‐yl)methyl]‐1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid= L1 ) containing two acetate and two 2‐methylpyridine N‐oxide arms anchored on the nitrogen atoms of the cyclen platform, which has been designed for stable complexation of lanthanide(III) ions in aqueous solution. Relaxometric studies suggest that the thermodynamic stability and kinetic inertness of the Gd^III complex may be sufficient for biological applications. A detailed structural study of the complexes by ¹H NMR spectroscopy and DFT calculations indicates that they adopt an anti‐Δ(λλλλ) conformation in aqueous solution, that is, an anti‐square antiprismatic (anti‐SAP) isomeric form, as demonstrated by analysis of the ¹H NMR paramagnetic shifts induced by Yb^III. The water‐exchange rate of the Gd^III complex is ${k{{298\hfill \atop {\rm ex}\hfill}}}$ =6.7×10⁶ s^?1, about a quarter of that for the mono‐oxidopyridine analogue, but still about 50 % higher than the ${k{{298\hfill \atop {\rm ex}\hfill}}}$ of GdDOTA (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). The 2‐methylpyridine N‐oxide chromophores can be used to sensitize a wide range of Ln^III ions emitting in both the visible (Eu^III and Tb^III) and NIR (Pr^III, Nd^III, Ho^III, Yb^III) spectral regions. The emission quantum yield determined for the Yb^III complex (${Q{{{\rm L}\hfill \atop {\rm Yb}\hfill}}}$ =7.3(1)×10^?3) is among the highest ever reported for complexes of this metal ion in aqueous solution. The sensitization ability of the ligand, together with the spectroscopic and relaxometric properties of its complexes, constitute a useful step forward on the way to efficient dual probes for optical imaging (OI) and MRI.