In silico validation of hyaluronic acid - drug conjugates based targeted drug delivery for the treatment of COVID-19.

The impact of COVID-19 urges scientists to develop targeted drug delivery to manage Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral infections with a fast recovery rate. The aim of the study is to develop Hyaluronic Acid (HA) drug conjugates of viral drugs to target two important enzymes (Mpro and PLpro) of SARS-CoV-2. Three antiviral drugs, namely Dexamethasone (DEX), Favipiravir (FAV), and Remdesivir (REM), were chosen for HA conjugation due to their reactive functional groups. Free forms of drugs (DEX, FAV, REM) and HA drug conjugates (HA-DEX, HA-FAV, HA-REM, HA-RHA, HA-RHE) were validated against Mpro (PDB ID 6LU7) and PLpro (PDB 7LLZ), which play an essential role in the replication and reproduction of the SARS-CoV-2 virus. The results of the present study revealed that HA-drug conjugates possess higher binding affinity and the best docking score towards the Mpro and PLpro target proteins of SARS-CoV-2 than their free forms of drugs. ADMET screening resulted that HA-drug conjugates exhibited better pharmacokinetic profiles than their pure forms of drugs. Further, molecular dynamic simulation studies, essential dynamics and free energy landscape analyses show that HA antiviral drug conjugates possess good trajectories and energy status, with the PLpro target protein (PDB 7LLZ) of SARS-CoV-2 through long-distance (500 ns) simulation screening. The research work recorded the best drug candidate for Cell-Targeted Drug Delivery (CTDD) for SARS-CoV-2-infected cells through hyaluronic acid conjugates of antiviral drugs.Communicated by Ramaswamy H. Sarma.

Diffusion-ordered NMR spectroscopy in the structural characterization of functionalized carbon nanotubes.

The emerging applications of functionalized carbon nanotubes (CNTs) in various research domains necessitate the use of many different analytical techniques to confirm their structural modifications in a fast and reliable manner. Thus far, NMR spectroscopy has not been among the main tools for characterization of organically modified carbon nanostructures. (1)H analysis is limited because the signals in these derivatives are typically weak and broad, resulting in uncertainties of a few parts per million, and because of the strong interference of residual solvent signals. To overcome these limitations, we investigated the applicability of proton NMR spectroscopy based on gradient-edited diffusion pulse sequences (1D diffusion-ordered spectroscopy, DOSY) in the characterization of CNT derivatives. In general, diffusion NMR experiments allow the separation of NMR signals of different species present in a mixture, according to their own diffusion coefficients, merging spectroscopy information with size analysis. In the present study, a selected set of CNT derivatives was synthesized and analyzed using 1D DOSY experiments by applying strong magnetic field gradients (up to 42.6 G cm(-1)). Colorimetric tests (i.e., Kaiser test) and TGA analysis support the NMR findings, which are related to isolated and/or bundled short SWNTs, on the basis of TEM and AFM characterization. The overall results show that the diffusion-based NMR spectroscopy is a fast and promising approach for the characterization of covalently modified CNT derivatives.

Hydration and self-association of caffeine molecules in aqueous solution: comparative effects of sucrose and beta-cyclodextrin.

The UV-spectra of pure caffeine were measured and two quite differentiated hyper- or hypo-chromic effects were observed as concentration was increased. The first one was explained as due to caffeine-water molecule interaction and the second as originating from dimer formation and staking of caffeine molecules. The effects of sucrose and beta-cyclodextrin on the hydration and the self-association of caffeine were also examined by UV spectroscopy. Sucrose was found to enhance the self-association of caffeine molecules by attracting and structuring water molecules around itself. The caffeine-caffeine hydrophobic interactions were promoted in such hydrophilic environment and so was the stacking. The molecular aggregation leads to reducing the electronic mobility and so is the case for the mesomeric effect in the heterogeneous cycle. This could explain the hypo-chromic phenomenon observed when sucrose concentration was increased. Beta-cyclodextrin shows a distinct behaviour because of its ability to form inclusion complexes with various hydrophobic guest molecules. This ability enhances the solubility of caffeine molecules throughout the inclusion interactions and prevents the caffeine self-association.

Herbicide activity of extracts from Ailanthus altissima (Simaroubaceae).

The purpose of the present study was to isolate and characterize ailanthone-rich materials from the bark of the deciduous tree Ailanthus altissima (Mill.) Swingle and to assess their herbicide activity on selected herbaceous species. Ailanthone-rich fractions were obtained from A. altissima bark by extraction with dichloromethane and ethyl acetate and subsequent purification of these crude extracts, and of the remaining water mixture after solvent extraction, by means of gel permeation chromatography. A number of fractions were isolated and characterized for ailanthone content. A dichloromethane fraction was shown to contain 92% w/w of ailanthone, as demonstrated by HPLC and NMR analysis. A significant pre-emergence herbicide activity was found for most of the extracts which was directly correlated to ailanthone concentration. A remarkable combined pre- and post-emergence herbicide activity was found for a specific fraction. These results indicate that the bark of A. altissima may represent an interesting source for the production of natural herbicides for use in agriculture.

Two-dimensional diffusion-ordered NMR spectroscopy as a tool for monitoring functionalized carbon nanotube purification and composition.

Functionalized carbon nanotube (CNT) derivatives are currently under thorough investigation in different biomedical investigations. In this field of research, the composition of sample either in terms of covalently attached or physisorbed moieties can greatly affect the observed results and hamper the comparison between different studies. Therefore, the availability of a fast and reliable analytical technique to assess both the type of interaction (covalent vs noncovalent) and the composition of CNT conjugates is of great importance. Here we describe that the two-dimensional diffusion-ordered (DOSY) NMR spectroscopy is extremely useful to discriminate between conjugated and unconjugated polyethylene glycol groups in samples obtained by condensation with oxidized single-walled carbon nanotubes (SWNTs). This fast and nondestructive technique allows us to follow the removal of unconjugated polyethylene glycol chains during the purification. In particular, DOSY analysis reveal that about 1/3 (wt %) of the polyethylene glycol used for the condensation remained physisorbed to functionalized SWNTs after dialysis. Complete elimination of physisorbed polyethylene glycol was achieved using diafiltration.

Synthesis and characterization of novel cardanol based benzoxazines.

Benzoxazines are a class of phenolic compounds extensively studied in polymer science because of their properties as fiber reinforcements, fire-retardants and curing agents. In this article is described a solvent-less process, based on a Mannich reaction involving a primary amine and an aldehyde, for the preparation of new benzoxazines deriving from cardanol (a well known phenol obtained as a renewable organic resource and harmful by-product of the cashew industry). Particular attention is given to the synthesis and chemical characterization (both by 1H NMR spectroscopy and HPLC), while the thermal polymerization process has been monitored by differential scanning calorimetry.

Synthesis of 6-amino-6-deoxyhyaluronan as an intermediate for conjugation with carboxylate-containing compounds: application to hyaluronan-camptothecin conjugates.

A novel methodology for making drug conjugates using hyaluronan as a carrier was developed. This strategy involves a completely regioselective two-step synthesis of 6-amino-6-deoxyhyaluronan, which is then easily functionalized with drugs through a suitable linker. The case of hyaluronan-camptothecin conjugates is described, making use of a simple succinate linker. The antitumor activity of new hyaluronan derivatives prepared is at present under evaluation.

Synthesis of 6-O-methotrexylhyaluronan as a drug delivery system.

Selective halogenation of hyaluronan and partial halogen substitution by methotrexate led to 6-chloro-6-deoxy-6-O-methotrexylhyaluronan, a potential antitumor drug. The remaining halogen could be further substituted by a second organic carboxylate, leading to mixed esters. 6-O-Acetyl-6-O-methotrexylhyaluronan and 6-O-butyryl-6-O-methotrexylhyaluronan were thus synthesized and characterized by NMR spectroscopy.