New Thiazolidine-4-One Derivatives as SARS-CoV-2 Main Protease Inhibitors

It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (Mpro) has been deemed a promising drug target vs. COVID-19. Indeed, Mpro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a Mpro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 Mpro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue

Gestione dell'osteoporosi nei pazienti affetti da lesione midollare

L’osteoporosi è una patologia conosciuta e diffusa, ma la sua gestione in un paziente con lesione midollare è poco chiara e frequentemente oggetto di dibattito. Il suo sviluppo, infatti, in un paziente complesso come quello affetto da spinal cord injury (SCI) ha delle caratteristiche particolari e necessita di un’appropriata gestione. Questo report è stato stilato con l’obiettivo di individuare, definire e trattare l’osteoporosi nei pazienti affetti da SCI. La ricerca è stata condotta utilizzando i database elettronici dedicati Medline, Scopus, Pubmed, Google Scholar, inserendo i seguenti termini come testo libero: osteoporosis, SCI, spinal injury combinandoli con gli operatori booleani AND e OR. Come limiti della ricerca sono stati considerati solo gli articoli pubblicati da gennaio 2015 ad oggi e gli articoli più citati. Nella prima parte della trattazione in oggetto abbiamo incluso gli studi che comprendessero dati epidemiologici inerenti i differenti tipi di mielolesione, le principali sedi di insorgenza di osteoporosi in questi pazienti, le cause e i fattori di rischio. Nella seconda parte sono stati inclusi quelli dedicati alle complicanze che possono insorgere; abbiamo poi preso in considerazione gli studi inerenti le varie metodiche di imaging al fine di individuare le metodiche di diagnosi e follow-up migliori. Infine abbiamo incluso gli studi riguardanti i trattamenti disponibili per questa patologia

High resolution 3-T MR imaging in the evaluation of the facial nerve course.

Objectives. To assess the value of 3-Tesla (3-T) MR imaging (MRI) in the evaluation of the course of the intracranial and extra-cranial tracts of the facial nerve. Patients and methods. 83 patients were studied by MRI in order to detect the course of facial nerve; a total of 166 facial nerves were examined. T2-weighted 3D Fast imaging employing steady-state acquisition (FIESTA) and T1-weighted Fast spoiled gradient recalled echo (fast SPRG) sequences were used. Two radiologists (reader A and B), independently, evaluated the course of the tracts of the facial nerve according to a qualitative scale (excellent, good, fair, poor). The Intraclass Correlation Coefficient (ICC) and Pearson correlation coefficient were used to assess the intra-observer and interobserver variability in the nerve course evaluation. Results. Reader A evaluated 35 facial nerves as excellent, 94 as good, 33 as fair and 4 as poor. Reader B rated 31 facial nerves excellent, 89 good, 43 fair and 3 poor. The intraobserver variability was ICC = 0.919 in reader A and ICC = 0.842 in reader B. The interobserver variability (Pearson correlation coefficient) was 0.713 (p ≤ 0.01). Conclusions. According to the preliminary results of our study the use of 3-T MRI with FIESTA and fast SPGR sequences may allow the study of the course of the facial nerve and its branches. The knowledge of the course and of the anatomic relationships of these nerve bundles with surrounding structures, as well as of the anatomical variants, provide useful informations for a prompt neurosurgery and maxillofacial surgical planning

In vitro Antiviral Activity of New Oxazoline Derivatives as Potent Poliovirus Inhibitors

The final stages of polio eradication are proving more difficult than the early phases and the development of effective drugs and treatments is considered a priority, thus the research is ongoing. A screening of our in-house chemical library against poliovirus Sabin strains led to identification of 5 and 6 as hits active at submicromolar concentration. Derivatives of these compounds were synthesized as a preliminary structure-activity relationship study. Among them, 7 and 11 were highly active against poliovirus Sabin 1, 2 and 3. 11 was also very potent against a large panel of wild and vaccine-derived polioviruses. Time of addition experiments suggest that 5 and 7 could be active at an early stage of viral replication, while 11 was active at same concentration at all stages of viral replication. A ligand-based approach was applied to find the common structural features shared by the new compounds and already known poliovirus inhibitors

Phenotypic spectrum in myopathies with tubular aggregates

Lettere En WysbegeerteAfrikaans En NederlandsPlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]

Analytical characterization of an inulin-type fructooligosaccharide from root-tubers of Asphodelus ramosus L

Plant-based systems continue to play a pivotal role in healthcare, and their use has been extensively documented. Asphodelus L. is a genus comprising various herbaceous species, known by the trivial name Asphodelus. These plants have been known since antiquity for both food and therapeutic uses, especially for treating several diseases associated with inflammatory and infectious skin disorders. Phytochemical studies revealed the presence of different constituents, mainly anthraquinones, triterpenoids, phenolic acids, and flavonoids. Although extensive literature has been published on these constituents, a paucity of information has been reported regarding the carbohydrate composition, such as fructans and fructan-like derivatives. The extraction of watersoluble neutral polysaccharides is commonly performed using water extraction, at times assisted by microwaves and ultrasounds. Herein, we reported the investigation of the alkaline extraction of roottubers of Asphodelus ramosus L., analyzing the water-soluble polysaccharides obtained by precipitation from the alkaline extract and its subsequent purification by chromatography. A polysaccharide was isolated by alkaline extraction; the HPTLC study to determine its composition showed fructose as the main monosaccharide. FT-IR analysis showed the presence of an inulin-type structure, and NMR analyses allowed us to conclude that A. ramosus roots contain polysaccharide with an inulin-type fructooligosaccharide with a degree of polymerization of 7-8

Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives

The study presented here aimed at identifying a new class of compounds acting against Leishmania parasites, the causative agent of Leishmaniasis. For this purpose, the thioether derivatives of our in-house library have been evaluated in whole-cell screening assays in order to determine their in vitro activity against Leishmania protozoan. Among them, promising results have been achieved with compound RDS 777 (6-(sec-butoxy)-2-((3-chlorophenyl)thio)pyrimidin-4-amine) (IC50¼29.43 mM), which is able to impair the mechanism of the parasite defence against the reactive oxygen species by inhibiting the trypanothione reductase (TR) with high efficiency (Ki 0.25 ± 0.18 mM). The X-ray structure of L. infantum TR in complex with RDS 777 disclosed the mechanism of action of this compound that binds to the catalytic site and engages in hydrogen bonds the residues more involved in the catalysis, namely Glu466', Cys57 and Cys52, thereby inhibiting the trypanothione binding and avoiding its reduction