Concise synthesis of deuterium-labelled proanthocyanidin metabolite 5-(3',4'-dihydroxyphenyl)-γ-valerolactone as an analytical tool.

Deuterated proanthocyanidin metabolite 5-(3',4'-dihydroxyphenyl)-γ-valerolactone has been successfully produced. This metabolite is responsible for several proanthocyanidin protective effects in the field of cancer chemoprevention, skin wrinkle-prevention, and antimicrobials. The synthetic approach applied employs a short reaction sequence and allows the incorporation of four deuterium atoms on non-exchangeable sites, making it an attractive strategy to produce a stable isotopically labeled internal standard for quantitative mass spectrometry isotope dilution-based methods, as demonstrated by developing an LC-MS/MS method to quantify DHPV in urine samples. Overall, this efficient synthesis provides a valuable analytical tool for the study of the metabolic conversion of proanthocyanidins thus helping to investigate the biological effect and establishing the active dose of the key catabolite 5-(3',4'-dihydroxyphenyl)-γ-valerolactone.

Evaluation of in vitro SARS-CoV-2 inactivation by a new quaternary ammonium compound: Bromiphen bromide.

The pneumonia (COVID-19) outbreak caused by the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which unpredictably exploded in late December of 2019 has stressed the importance of being able to control potential pathogens with the aim of limiting their spread. Although vaccines are well known as a powerful tool for ensuring public health and controlling the pandemic, disinfection and hygiene habits remain crucial to prevent infection from spreading and maintain the barrier, especially when the microorganism can persist and survive on textiles, surfaces, and medical devices. During the coronavirus disease pandemic, around half of the disinfectants authorized by the US Environmental Protection Agency contained quaternary ammonium compounds (QACs); their effectiveness had not been proven. Herein, the in vitro SARS-CoV-2 inactivation by p-bromodomiphen bromide, namely bromiphen (BRO), a new, potent, and fast-acting QAC is reported. This study demonstrates that BRO, with a dose as low as 0.02%, can completely inhibit SARS-CoV-2 replication in just 30 s. Its virucidal activity was 10- and 100-fold more robust compared to other commercially available QACs, namely domiphen bromide and benzalkonium chloride. The critical micellar concentration and the molecular lipophilicity potential surface area support the relevance of the lipophilic nature of these molecules for their activity.

A Novel Chromatographic Method to Assess the Binding Ability towards Dicarbonyls.

Human exposure to dicarbonyls occurs via ingestion (e.g., food), inhalation (e.g., electronic cigarettes) and dysregulation of endogenous metabolic pathways (e.g., glycolysis). Dicarbonyls are electrophiles able to induce carbonylation of endogenous substrate. They have been associated with the onset and progression of several human diseases. Several studies have advocated the use of dicarbonyl binders as food preservatives or as drugs aimed at mitigating carbonylation. This study presents the setup of an easy and cheap assay for the screening of selective and potent dicarbonyl binders. The method is based on the incubation of the candidate molecules with a molecular probe. The activity is then determined by measuring the residual concentration of the molecular probe over time by liquid chromatography (LC). However, the naturally occurring dicarbonyls (e.g., glyoxal, methylglyoxal) are not appealing as probes since they are hard to separate and detect using the most popular LC variants. Benzylglyoxal (BGO) was therefore synthesized and tested, proving to be a convenient probe that allows a direct quantification of residual dicarbonyls by reversed phase LC without derivatization. The method was qualified by assessing the binding ability of some molecules known as binders of natural occurring dicarbonyls, obtaining results consistent with literature.

Chemoenzymatic approach towards the synthesis of the antitumor and antileishmanial marine metabolite (+)-Harzialactone A via the stereoselective, biocatalyzed reduction of a prochiral ketone.

As a rich source of biological active compounds, marine natural products have been increasingly screened as candidates for developing new drugs. Among the several marine products and metabolites, (+)-Harzialactone A has drawn considerable attention for its antitumor and antileishmanial activity. In this work a chemoenzymatic approach has been implemented for the preparation of the marine metabolite (+)-Harzialactone A. The synthesis involved a stereoselective, biocatalyzed reduction of the prochiral ketone 4-oxo-5-phenylpentanoic acid or the corresponding esters, all generated by chemical reactions. A collection of different promiscuous oxidoreductases (both wild-type and engineered) and diverse microorganism strains were investigated to mediate the bioconversions. After co-solvent and co-substrate investigation in order to enhance the bioreduction performance, T. molischiana in presence of NADES (choline hydrochloride-glucose) and ADH442 were identified as the most promising biocatalysts, allowing the obtainment of the (S)-enantiomer with excellent ee (97% to > 99% respectively) and good to excellent conversion (88% to 80% respectively). The successful attempt in this study provides a new chemoenzymatic approach for the synthesis of (+)-Harzialactone A.

Obesity and Type 2 Diabetes: Adiposopathy as a Triggering Factor and Therapeutic Options.

Obesity and type 2 diabetes (T2DM) are major public health concerns associated with serious morbidity and increased mortality. Both obesity and T2DM are strongly associated with adiposopathy, a term that describes the pathophysiological changes of the adipose tissue. In this review, we have highlighted adipose tissue dysfunction as a major factor in the etiology of these conditions since it promotes chronic inflammation, dysregulated glucose homeostasis, and impaired adipogenesis, leading to the accumulation of ectopic fat and insulin resistance. This dysfunctional state can be effectively ameliorated by the loss of at least 15% of body weight, that is correlated with better glycemic control, decreased likelihood of cardiometabolic disease, and an improvement in overall quality of life. Weight loss can be achieved through lifestyle modifications (healthy diet, regular physical activity) and pharmacotherapy. In this review, we summarized different effective management strategies to address weight loss, such as bariatric surgery and several classes of drugs, namely metformin, GLP-1 receptor agonists, amylin analogs, and SGLT2 inhibitors. These drugs act by targeting various mechanisms involved in the pathophysiology of obesity and T2DM, and they have been shown to induce significant weight loss and improve glycemic control in obese individuals with T2DM.

Discovery of a Potent and Highly Selective Dipeptidyl Peptidase IV and Carbonic Anhydrase Inhibitor as "Antidiabesity" Agents Based on Repurposing and Morphing of WB-4101.

The management of patients with type 2 diabetes mellitus (T2DM) is shifting from cardio-centric to weight-centric or, even better, adipose-centric treatments. Considering the downsides of multidrug therapies and the relevance of dipeptidyl peptidase IV (DPP IV) and carbonic anhydrases (CAs II and V) in T2DM and in the weight loss, we report a new class of multitarget ligands targeting the mentioned enzymes. We started from the known α1-AR inhibitor WB-4101, which was progressively modified through a tailored morphing strategy to optimize the potency of DPP IV and CAs while losing the adrenergic activity. The obtained compound 12 shows a satisfactory DPP IV inhibition with a good selectivity CA profile (DPP IV IC50: 0.0490 µM; CA II Ki 0.2615 µM; CA VA Ki 0.0941 µM; CA VB Ki 0.0428 µM). Furthermore, its DPP IV inhibitory activity in Caco-2 and its acceptable pre-ADME/Tox profile indicate it as a lead compound in this novel class of multitarget ligands.

Cyclo(His-Pro) Exerts Protective Carbonyl Quenching Effects through Its Open Histidine Containing Dipeptides.

Cyclo(His-Pro) (CHP) is a cyclic dipeptide which is endowed with favorable pharmacokinetic properties combined with a variety of biological activities. CHP is found in a number of protein-rich foods and dietary supplements. While being stable at physiological pH, CHP can open yielding two symmetric dipeptides (His-Pro, Pro-His), the formation of which might be particularly relevant from dietary CHP due to the gastric acidic environment. The antioxidant and protective CHP properties were repeatedly reported although the non-enzymatic mechanisms were scantly investigated. The CHP detoxifying activity towards α,ß unsaturated carbonyls was never investigated in detail, although its open dipeptides might be effective as already observed for histidine containing dipeptides. Hence, this study investigated the scavenging properties of TRH, CHP and its open derivatives towards 4-hydroxy-2-nonenal. The obtained results revealed that Pro-His possesses a marked activity and is more reactive than l-carnosine. As investigated by DFT calculations, the enhanced reactivity can be ascribed to the greater electrophilicity of the involved iminium intermediate. These findings emphasize that the primary amine (as seen in l-carnosine) can be replaced by secondary amines with beneficial effects on the quenching mechanisms. Serum stability of the tested peptides was also evaluated, showing that Pro-His is characterized by a greater stability than l-carnosine. Docking simulations suggested that its hydrolysis can be catalyzed by serum carnosinase. Altogether, the reported results evidence that the antioxidant CHP properties can be also due to the detoxifying activity of its open dipeptides, which might be thus responsible for the beneficial effects induced by CHP containing food.

Candida albicans Biofilm Inhibition by Two Vaccinium macrocarpon (Cranberry) Urinary Metabolites: 5-(3',4'-DihydroxyPhenyl)-γ-Valerolactone and 4-Hydroxybenzoic Acid.

Candida spp. are pathobionts, as they can switch from commensals to pathogens, responsible for a variety of pathological processes. Adhesion to surfaces, morphological switch and biofilm-forming ability are the recognized virulence factors promoting yeast virulence. Sessile lifestyle also favors fungal persistence and antifungal tolerance. In this study, we investigated, in vitro, the efficacy of two urinary cranberry metabolites, 5-(3',4'-dihydroxy phenyl)-γ-valerolactone (VAL) and 4-hydroxybenzoic acid (4-HBA), in inhibiting C. albicans adhesion and biofilm formation. Both the reference strain SC5314 and clinical isolates were used. We evaluated biomass reduction, by confocal microscopy and crystal violet assay, and the possible mechanisms mediating their inhibitory effects. Both VAL and 4-HBA were able to interfere with the yeast adhesion, by modulating the expression of key genes, HWP1 and ALS3. A significant dose-dependent reduction in biofilm biomass and metabolic activity was also recorded. Our data showed that the two cranberry metabolites VAL and 4-HBA could pave the way for drug development, for targeting the very early phases of biofilm formation and for preventing genitourinary Candida infections.

Back to Basics: Choosing the Appropriate Surface Disinfectant.

From viruses to bacteria, our lives are filled with exposure to germs. In built environments, exposure to infectious microorganisms and their byproducts is clearly linked to human health. In the last year, public health emergency surrounding the COVID-19 pandemic stressed the importance of having good biosafety measures and practices. To prevent infection from spreading and to maintain the barrier, disinfection and hygiene habits are crucial, especially when the microorganism can persist and survive on surfaces. Contaminated surfaces are called fomites and on them, microorganisms can survive even for months. As a consequence, fomites serve as a second reservoir and transfer pathogens between hosts. The knowledge of microorganisms, type of surface, and antimicrobial agent is fundamental to develop the best approach to sanitize fomites and to obtain good disinfection levels. Hence, this review has the purpose to briefly describe the organisms, the kind of risk associated with them, and the main classes of antimicrobials for surfaces, to help choose the right approach to prevent exposure to pathogens.

Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs.

Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90-95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed.

Profiling Vaccinium macrocarpon components and metabolites in human urine and the urine ex-vivo effect on Candida albicans adhesion and biofilm-formation.

The aim of this work was to profile, by using an HPLC-MS/MS method, cranberry compounds and metabolites found in human urine after ingestion of a highly standardized cranberry extract (Anthocran®). Two different strategies were adopted for the data analysis: a targeted and an untargeted approach. These strategies allowed the identification of 42 analytes including cranberry components, known metabolites and metabolites hitherto unreported in the literature, including six valerolactones/valeric acid derivatives whose presence in urine after cranberry consumption has never been described before. Absolute concentrations of 26 over 42 metabolites were obtained by using pure available standards. Urine collected at different time points after the last dosage of Anthocran® were tested on the reference strain C. albicans SC5314, a biofilm-forming strain. Fractions collected after 12 h were found to significantly reduce the adhesion and biofilm formation compared to the control (p < 0.05). A similar effect was then obtained by using Anthocran™ Phytosome™, the lecithin formulation containing 1/3 of standardized cranberry extract and formulated to enhance the absorption of the cranberry components. The urinary profile of cranberry components and metabolites in the urine fractions collected at 1 h, 6 h and 12 h after the last capsule intake were then reproduced by using the pure standards at the concentration ranges found in the urine fraction, and tested on C. albicans. Only the mixture mimicking the urinary fraction collected at 12 h and containing as main components, quercetin and 5-(3',4'-dihydroxyphenyl)-γ-valerolactone was found effective thus confirming the ex-vivo results.

How Reaction Conditions May Influence the Regioselectivity in the Synthesis of 2,3-Dihydro-1,4-benzoxathiine Derivatives.

The exploration of different reaction conditions aiming to obtain both 2,3-dihydro-1,4-benzoxathiine-2-yl derivatives and 2,3-dihydro-1,4-benzoxathiine-3-yl ones is reported. The treatment of 1,2-mercaptophenol with an organic base and a specific 2-bromo acrylate results in a solvent- and substrate-dependent exclusive solvation of O- and S-anions, thus managing the regioselectivity.