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.     

Probing the Local Reaction Environment During High Turnover Carbon Dioxide Reduction with Ag-Based Gas Diffusion Electrodes

Discerning the influence of electrochemical reactions on the electrode microenvironment is an unavoidable topic for electrochemical reactions that involve the production of OH⁻ and the consumption of water. That is particularly true for the carbon dioxide reduction reaction (CO₂RR), which together with the competing hydrogen evolution reaction (HER) exert changes in the local OH⁻ and H₂O activity that in turn can possibly affect activity, stability, and selectivity of the CO₂RR. We determine the local OH⁻ and H₂O activity in close proximity to a CO₂-converting Ag-based gas diffusion electrode (GDE) with product analysis using gas chromatography. A Pt nanosensor is positioned in the vicinity of the working GDE using shear-force-based scanning electrochemical microscopy (SECM) approach curves, which allows monitoring changes invoked by reactions proceeding within an otherwise inaccessible porous GDE by potentiodynamic measurements at the Pt-tip nanosensor. We show that high turnover HER/CO₂RR at a GDE lead to modulations of the alkalinity of the local electrolyte, that resemble a 16 m KOH solution, variations that are in turn linked to the reaction selectivity.     

Characterization of Pentaclethra macroloba oil

The Pracaxi oil—(Pentaclethra macroloba) contains high concentrations of fatty acids with emollient action that contribute to skin hydration. The use of this oil is supported by the utilization of natural resources thus enabling regional development and social contribution. The objective of this study was to characterize the P. macroloba oil by thermogravimetry (TG, DTG, and DTA), gas chromatography, Fourier transform infrared spectroscopy (FT-IR), and oxidation stability—Rancimat, aiming at the quality control of plant raw material. Three samples of crude oil sold by Amazon Oil Industry (Ananindeua, Pará, Brazil) were studied. The analysis of these oil samples showed different fatty acids, especially the behenic, oleic, linoleic, and lignoceric acids totalizing approximately 96 % of the grease composition and in smaller percentage arachidic, lauric, myristic, palmitic, and linolenic acids were found. The major acids have wide medicinal use. According to the TG/DTG curve, thermal stability was observed up to 220 °C, indicating a greater mass loss related to the dehydration and elimination of volatile substances. The thermal decomposition process occurred in the range of 430–450° C according to the DTG curve. The absorption spectrum in the infrared region (FT-IR) showed well-defined bands confirming the presence of functional groups present in the oil. Tests in a Rancimat have shown an induction period between 8 and 10 h demonstrating that the samples are in agreement with the standards required by ANP No. 14/2012 which requires at least 6 h of testing.     

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.     

Reglucosylation of the Benzoxazinoid DIMBOA with Inversion of Stereochemical Configuration is a Detoxification Strategy in Lepidopteran Herbivores

Benzoxazinoids are chemical defenses against herbivores and are produced by many members of the grass family. These compounds are stored as stable glucosides in plant cells and require the activity of glucosidases to release the corresponding toxic aglucones. In maize leaves, the most abundant benzoxazinoid is (2R)‐DIMBOA‐Glc, which is converted into the toxic DIMBOA upon herbivory. The ways in which three Spodoptera species metabolize this toxin were investigated. (2S)‐DIMBOA‐Glc, an epimer of the initial plant compound, was observed in the insect frass, and the associated glucosyltransferase activity was detected in the insect gut tissue. The epimeric glucoside produced by the insect was found to be no longer reactive towards plant glucosidases and thus cannot be converted into a toxin. Stereoselective reglucosylation thus represents a detoxification strategy in Spodoptera species that might help to explain their success as agricultural pests on benzoxazinoid‐containing crops.     

Building symmetric polynomials to fit a potential energy surface: application to an A_2B_2 molecule

We present a method to build potential energy surfaces with the correct permutational symmetry of identical atoms. It is explained and applied to an A $_2$ B $_2$ molecular system. This method allows us to use different reference geometries, which are often needed in large molecules.     

Characterization of Biocatalysts Prepared with Thermomyces lanuginosus Lipase and Different Silica Precursors,Dried using Aerogel and Xerogel Techniques

The use of lipases in industrial processes can result in products with high levels of purity and at the same time reduce pollutant generation and improve both selectivity and yields. In this work, lipase from Thermomyces lanuginosus was immobilized using two different techniques. The first involves the hydrolysis/polycondensation of a silica precursor (tetramethoxysilane (TMOS)) at neutral pH and ambient temperature, and the second one uses tetraethoxysilane (TEOS) as the silica precursor, involving the hydrolysis and polycondensation of the alkoxide in appropriate solvents. After immobilization, the enzymatic preparations were dried using the aerogel and xerogel techniques and then characterized in terms of their hydrolytic activities using a titrimetric method with olive oil and by the formation of 2-phenylethyl acetate in a transesterification reaction. The morphological properties of the materials were characterized using scanning electron microscopy, measurements of the surface area and pore size and volume, thermogravimetric analysis, and exploratory differential calorimetry. The results of the work indicate that the use of different silica precursors (TEOS or TMOS) and different drying techniques (aerogel or xerogel) can significantly affect the properties of the resulting biocatalyst. Drying with supercritical CO₂ provided higher enzymatic activities and pore sizes and was therefore preferable to drying, using the xerogel technique. Thermogravimetric analysis and differential scanning calorimetry analyses revealed differences in behavior between the two biocatalyst preparations due to the compounds present.     

Mullite crystallization using fully hydrolyzed silica sol: the gelation temperature influence

Mullite is an aluminosilicate widely used as a structural material for high temperature applications. This paper studies the effect of the gelation temperature on the synthesis of two mullite precursors: polymeric and colloidal silica, using both in fully-hydrolyzed silica sol, derived from sodium silicate. The gels were synthesized using aqueous silicic acid and aluminum nitrate. Ethylene glycol was added into polymeric gels. Two gelation temperatures were used: 80 and 100 °C. In the polymeric precursor, the increasing of the gelation temperature caused an increase in the silica incorporation inside the mullite crystalline lattice at 1,000 °C, and it also generated an increase in the reaction extent at all calcination temperatures. In the colloidal precursors, these effects were more intense than in the polymeric precursors in terms of yield. Colloidal samples calcined at 1,250 °C crystallized cristobalite and alpha alumina in addition to mullite when they were previously gelled at 80 °C. On the other hand, the same sample gelled at 100 °C led to only crystallized mullite. The reaction extent increased by more than 20 % for colloidal samples gelled at 100 °C compared to colloidal samples gelled at 80 °C (calcined at 1,250 °C). This increase was due to the almost total incorporation of alumina and silica in the crystalline lattice of mullite.     

Enzymatic Building-Block Synthesis for Solid-Phase Automated Glycan Assembly

Automated chemical oligosaccharide synthesis is an attractive concept that has been successfully applied to a large number of target structures, but requires excess quantities of suitably protected and activated building blocks. Herein we demonstrate the use of biocatalysis to supply such reagents for automated synthesis. By using the promiscuous NmLgtB-B β1-4 galactosyltransferase from Neisseria meningitidis we demonstrate fast and robust access to the LacNAc motif, common to many cell-surface glycans, starting from either lactose or sucrose as glycosyl donors. The enzymatic product was shown to be successfully incorporated as a complete unit into a tetrasaccharide target by automated assembly.