Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation

Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's drugs (DMAADs) following the multifactorial nature of AD, we have recently developed multifunctional compounds. We herein describe the design, synthesis, molecular modeling and biological evaluation of a new series of donepezil-related compounds possessing metal chelating properties, and being capable of targeting different enzymatic systems related to AD (cholinesterases, ChEs, and monoamine oxidase A, MAO-A). Among this set of analogues compound 5f showed excellent ChEs inhibition potency and a selective MAO-A inhibition (vs MAO-B) coupled to strong complexing properties for zinc and copper ions, both known to be involved in the progression of AD. Moreover, 5f exhibited moderate antioxidant properties as found by in vitro assessment. This compound represents a novel donepezil–hydroxyquinoline hybrid with DMAAD profile paving the way to the development of a novel class of drugs potentially able to treat AD

LA SIEROLOGIA TIPO-SPECIFICA PER HERPES SYMPLEX TIPO 2 NELLA GESTIONE DEI PAZIENTI HIV POSITIVI

none8noVedi allegato.Pauri, P.; Balercia, M.; Barchiesi, F.; Butini, L.; Costantini, A.; Del Gobbo, R.; Marinelli, K.; Tomassini, T.Pauri, P.; Balercia, M.; Barchiesi, Francesco; Butini, L.; Costantini, Andrea; Del Gobbo, R.; Marinelli, K.; Tomassini, T

Traceability and authentication in agri-food production: A multivariate approach to the characterization of the Italian food excellence elephant garlic (Allium ampeloprasum L.), a vasoactive nutraceutical

A research platform for food authentication was set up by combining stable isotope ratio analysis, metabolomics by gas and liquid mass-spectrometry and NMR investigations, chemometric analyses for food excellences. This multi-analytical approach was tested on samples of elephant garlic (Allium ampeloprasum L.), a species belonging to the same genus of common garlic (Allium ampeloprasum L.), mainly produced in southern Tuscany-(Allium ampeloprasum). The isotopic composition allowed the product to be geographically characterized. Flavonoids, like (+)-catechin, cinnamic acids, quercetin glycosides were identified. The samples showed also a significant amount of dipeptides, sulphur-containing metabolites and glutathione, the latter of which could be considered a molecular marker of the analyzed elephant garlic. For nutraceutical profiling to reach quality labels, extracts were investigated in specific biological assays, displaying interesting vasorelaxant properties in rat aorta by mediating nitric oxide release from the endothelium and exhibited positive inotropic and negative chronotropic effects in rat perfused heart

Azetidin-2-one-based small molecules as dual hHDAC6/HDAC8 inhibitors: Investigation of their mechanism of action and impact of dual inhibition profile on cell viability

The search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HDAC8 is an epigenetic eraser, unique HDAC-class I member that displays some aminoacidic similarity to HDAC6. New polypharmacological agents for cancer treatment, based on a dual hHDAC6/hHDAC8 inhibition profile were developed. The dual inhibitor design investigated the diphenyl-azetidin-2-one scaffold, typified in three different structural families, that, combined to a slender benzyl linker (6c, 6i, and 6j), displays nanomolar inhibition potency against hHDAC6 and hHDAC8 isoforms. Notably, their selective action was also corroborated by measuring their low inhibitory potency towards hHDAC1 and hHDAC10. Selectivity of these compounds was further demonstrated in human cell-based western blots experiments, by testing the acetylation of the non-histone substrates alpha-tubulin and SMC3. Furthermore, the compounds reduced the proliferation of colorectal HCT116 and leukemia U937 cells, after 48 h of treatment. The toxicity of the compounds was evaluated in rat perfused heart and in zebrafish embryos. In this latter model we also validated the efficacy of the dual hHDAC6/hHDAC8 inhibitors against their common target acetylated-alpha tubulin. Finally, the metabolic stability was verified in rat, mouse, and human liver microsomes

Molecular analysis of hepatitis B virus (HBV) in an HIV co-infected patient with reactivation of occult HBV infection following discontinuation of lamivudine-including antiretroviral therapy

Abstract Background Occult hepatitis B virus (HBV) infection (OBI) is characterized by HBV DNA persistence even though the pattern of serological markers indicates an otherwise resolved HBV infection. Although OBI is usually clinically silent, immunocompromised patients may experience reactivation of the liver disease. Case presentation We report the case of an individual with human immunodeficiency virus (HIV) infection and anti-HBV core antibody positivity, who experienced severe HBV reactivation after discontinuation of lamivudine-including antiretroviral therapy (ART). HBV sequencing analysis showed a hepatitis B surface antigen escape mutant whose presence in an earlier sample excluded reinfection. Molecular sequencing showed some differences between two isolates collected at a 9-year interval, indicating HBV evolution. Resumption of ART containing an emtricitabine/tenofovir combination allowed control of plasma HBV DNA, which fell to undetectable levels. Conclusion This case stresses the ability of HBV to evolve continuously, even during occult infection, and the effectiveness of ART in controlling OBI reactivation in HIV-infected individuals.</p