Synthesis and biological evaluation of novel quinazoline-triazole hybrid compounds with potential use in Alzheimer's disease.

A library of twelve quinazoline-triazole hybrid compounds were designed, synthesized and evaluated as a novel class of acetylcholinesterase inhibitors to treat Alzheimer's disease (AD). The biological assay results demonstrated the ability of several hybrid compounds to inhibit AChE enzyme (IC50 range = 0.2-83.9 µM). To understand the high potential activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of quinazoline-triazole hybrid compounds. As expected, compounds 8a and 9a-b bind to both catalytic anionic site (CAS) and peripheral anionic site (PAS) in the active site of AChE enzyme, which implicates that these compounds could act as dual binding site inhibitors. These compounds were not cytotoxic and they also displayed appropriated physicochemical as well as pharmacokinetic profile to be developed as novel anti-AD drug candidates.

Evaluation of GalNAc-siRNA Conjugate Activity in Pre-clinical Animal Models with Reduced Asialoglycoprotein Receptor Expression.

The hepatocyte-specific asialoglycoprotein receptor (ASGPR) is an ideal candidate for targeted drug delivery to the liver due to its high capacity for substrate clearance from circulation together with its well-conserved expression and function across species. The development of GalNAc-siRNA conjugates, in which a synthetic triantennary N-acetylgalactosamine-based ligand is conjugated to chemically modified siRNA, has enabled efficient, ASGPR-mediated delivery to hepatocytes. To investigate the potential impact of variations in receptor expression on the efficiency of GalNAc-siRNA conjugate delivery, we evaluated the pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates in multiple pre-clinical models with reduced receptor expression. Despite greater than 50% reduction in ASGPR levels, GalNAc conjugate activity was retained, suggesting that the remaining receptor capacity was sufficient to mediate efficient uptake of potent GalNAc-siRNAs at pharmacologically relevant dose levels. Collectively, our data support a broad application of the GalNAc-siRNA technology for hepatic targeting, including disease states where ASGPR expression may be reduced.

Synthesis and cytotoxic evaluation of novel ester-triazole-linked triterpenoid-AZT conjugates.

Betulinic acid and analogous naturally occurring triterpenoid acids were transformed into the corresponding propargyl esters and subsequently deployed as substrates for a click chemistry-mediated coupling with azidothymidine (AZT) en route to novel 1,2,3-triazole-tethered triterpenoid-AZT conjugates. Twelve new hybrids were thus prepared and assessed in terms of their cytotoxic activity, revealing an interesting anticancer activity of five triterpenoid-AZT hybrids on KB and Hep-G2 tumor cell lines.

Role of standardized grape polyphenol preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model.

SCOPE: Metabolic syndrome has become an epidemic and poses tremendous burden on the health system. People with metabolic syndrome are more likely to experience cognitive decline. As obesity and sedentary lifestyles become more common, the development of early prevention strategies is critical. In this study, we explore the potential beneficial effects of a combinatory polyphenol preparation composed of grape seed extract, Concord purple grape juice extract, and resveratrol, referred to as standardized grape polyphenol preparation (SGP), on peripheral as well as brain dysfunction induced by metabolic syndrome. METHODS AND RESULTS: We found dietary fat content had minimal effect on absorption of metabolites of major polyphenols derived from SGP. Using a diet-induced animal model of metabolic syndrome (DIM), we found that brain functional connectivity and synaptic plasticity are compromised in the DIM mice. Treatment with SGP not only prevented peripheral metabolic abnormality but also improved brain synaptic plasticity. CONCLUSION: Our study demonstrated that SGP, comprised of multiple bioavailable and bioactive components targeting a wide range of metabolic syndrome related pathological features, provides greater global protection against peripheral and central nervous system dysfunctions and can be potentially developed as a novel prevention/treatment for improving brain connectivity and synaptic plasticity important for learning and memory.

Vietnamese traditional medicine from a pharmacist's perspective.

Traditional medicine plays an important role in the healthcare system of Vietnam. Vietnamese traditional medicine (VTM) is underpinned by the oriental philosophy and theory of healing. VTM is largely influenced by traditional Chinese medicine, but differs to a certain extent. VTM is largely not evidence-based from a clinical perspective but subclinical research data from the past decades support the traditional use of many herbal VTM drugs. For safe use, knowledge of the occurrence of adverse reactions and herb-drug interactions is necessary. The Vietnamese government supports further development of VTM in a scientific way and integration of VTM with Western medicine. This article first gives an overview of the general aspects of VTM (historical perspective, regulatory aspects, comparison with traditional Chinese medicine, philosophical background, the Vietnamese market situation, quality assurance and formulations), and subsequently focuses on its safe and effective use in Vietnamese clinical pharmacy and medical practice.