Recent advancement in the search of innovative antiprotozoal agents targeting trypanothione metabolism

Leishmania and Trypanosoma parasites are responsible for the challenging neglected tropical diseases leishmaniases, Chagas disease, and human African trypanosomiasis, which account for up to 40,000 deaths annually mainly in developing countries. Current chemotherapy relies on drugs with significant limitations in efficacy and safety, prompting the urgent need to explore innovative approaches to improve the drug discovery pipeline. The unique trypanothione-based redox pathway, which is absent in human hosts, is vital for all trypanosomatids and offers valuable opportunities to guide the rational development of specific, broad-spectrum and innovative anti-trypanosomatid agents. Major efforts focused on the key metabolic enzymes trypanothione synthetase-amidase and trypanothione reductase, whose inhibition should affect the entire pathway and, finally, parasite survival. Herein, we will report and comment on the most recent studies in the search for enzyme inhibitors, underlining the promising opportunities that have emerged so far to drive the exploration of future successful therapeutic approaches

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Argentina

CADASIL is the most common cause of hereditary stroke and vascular dementia. Published information about this disease in South America is scant. We describe clinical and demographic characteristics of 13 patients (10 families) with CADASIL from Argentina.Methods Medical records, diagnostic tests and family history of patients with CADASIL were reviewed.Results Thirteen patients with CADASIL (10 families) were included. All patients had European ancestry. Initial presentation was stroke in most patients (n = 11). Stroke patients later developed cognitive complaints (n = 9), migraine with aura (n = 1), apathy (n = 4) and depression (n = 6). External capsule and temporal lobe involvement on MRI were characteristic imaging findings. Two patients died after intracerebral hemorrhage.Conclusion This is the first report of non-related patients with CADASIL in South America addressing ancestry. Since European ancestry is not highly prevalent in all South American countries, there may be variable incidence of CADASIL within this region

Discovery of N-aryl-naphthylamines as in vitro inhibitors of the interaction between HIV integrase and the cofactor LEDGF/p75

Abstract A series of N-aryl-naphthylamines, exemplified by the structures 11-16, were chosen for an in-house library screening to assay their ability to disrupt the interaction between the LEDGF cofactor and the HIV integrase. Structure modification led also to design and synthesize new compounds 17a-f. Compounds 11e,h,k,n, 13b, and 14 showed good activity in AlphaScreen assay. The most active compound 11e (IC50 Combining double low line 2.5 μM) was selected for molecular modeling studies and showed a binding mode similar to the one of the known LEDGIN 8

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

Comparison of different methods for the extraction of cannabinoids from cannabis

Cannabis oils, namely concentrated cannabis extracts, are getting plenty of attention because of their therapeutic potential for treatment of patients with cancer, HIV, multiple sclerosis and several other pathologies. Here we propose the use of ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) as alternative methods to the current protocols followed by pharmacists, the only authorized to manipulate standardized Cannabis. A third method, consisting of the use of Tween 20 as surfactant, was considered. Our best extraction methodology for commercial hemp extraction was applied to medicinal cannabis. Here we report the results obtained for ‘Eletta campana’, ‘Carmagnola selezionata’, Bediol ® , FM2 ® and Bedrocan ®

Discovery of N-aryl-naphthylamines as in vitro inhibitors of the interaction between HIV integrase and the cofactor LEDGF/p75

A series of N-aryl-naphthylamines, exemplified by the structures 11-16, were chosen for an in-house library screening to assay their ability to disrupt the interaction between the LEDGF cofactor and the HIV integrase. Structure modification led also to design and synthesize new compounds 17a-f. Compounds 11e,h,k,n, 13b, and 14 showed good activity in AlphaScreen assay. The most active compound 11e (IC50 Combining double low line 2.5 μM) was selected for molecular modeling studies and showed a binding mode similar to the one of the known LEDGIN

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]

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

Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase

Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids. Several derivatives were synthesized and tested against RNase H and viral replication and found active at micromolar concentrations. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, and Mg2+titration experiments demonstrated that our compounds coordinate the Mg2+cofactor and interact with amino acids of the RNase H domain that are highly conserved among naïve and treatment-experienced patients. In general, the new inhibitors influenced also the polymerase activity of RT but were selective against RNase H vs the IN enzyme