Detailed Studies on the Methoxylation and Subsequent Dealkylation of -Diethylbenzenesulfonamide Using a Tailor-Made Electrosynthetic Reactor.

Benzenesulfonamides are an outstandingly important family of compounds in organic and medicinal chemistry. Herein, we report detailed studies on the electrochemical mono- and dideethylation of model compound -diethylbenzenesulfonamide. In this context, all parameters of the electrosynthesis were systematically investigated, with a special emphasis on solvent screening and the effect of water on the outcome of the reaction.

Impact of Continuous Glucose Monitoring Versus Blood Glucose Monitoring to Support a Carbohydrate-Restricted Nutrition Intervention in People with Type 2 Diabetes.

Low- and very-low-carbohydrate eating patterns, including ketogenic eating, can reduce glycated hemoglobin (HbA1c) in people with type 2 diabetes (T2D). Continuous glucose monitoring (CGM) has also been shown to improve glycemic outcomes, such as time in range (TIR; % time with glucose 70-180 mg/dL), more than blood glucose monitoring (BGM). CGM-guided nutrition interventions are sparse.

5-Year effects of a novel continuous remote care model with carbohydrate-restricted nutrition therapy including nutritional ketosis in type 2 diabetes: An extension study.

Aims: This study assessed the five-year effects of a continuous care intervention (CCI) delivered via telemedicine, counseling people with type 2 diabetes (T2D) on a very low carbohydrate diet with nutritional ketosis.

Methods: Participants with T2D were enrolled in a 2-year, open-label, non-randomized study comparing CCI and usual care (UC). After 2 years, 194 of the 262 CCI participants were approached for a three-year extension.

Computational Studies on the Diastereospecific Lithium Variant of Oppenauer Oxidation of a Tofisopam Intermediate.

During the synthesis of tofisopam drug substance, an interesting diastereospecific lithium variant of Oppenauer oxidation was observed and investigated by density functional theory (DFT) calculations. The computations revealed energetic differences caused by steric differences between the diastereomers that might provide an explanation for the experimentally formed products. In addition, the trend in the measured NMR shifts was also in line with the computed values, which allowed the assignment of the absolute configuration of the diastereomers.

Studies on the total syntheses of ‑carboline alkaloids orthoscuticellines A and B.

Orthoscuticellines A and B are newly isolated natural -carboline alkaloids from the moss animal . Herein, we report the first targeted total synthesis of orthoscuticelline B and an analogous synthetic method for the preparation of dihydro derivate of orthoscuticelline A. The new synthetic approach is based on commercially available and inexpensive reagents leading to a practical synthesis of the target molecules.

Extending the limitations in the prediction of PAMPA permeability with machine learning algorithms.

Gastrointestinal absorption is a key factor amongst the ADME-related (absorption, distribution, metabolism and excretion) pharmacokinetic properties; therefore, it has a major role in drug discovery and drug safety determinations. The Parallel Artificial Membrane Permeability Assay (PAMPA) can be considered as the most popular and well-known screening assay for the measurement of gastrointestinal absorption. Our study provides quantitative structure-property relationship (QSPR) models based on experimental PAMPA permeability data for almost four hundred diverse molecules, which is a great extension of the applicability of the models in the chemical space.

Soluplus® promotes efficient transport of meloxicam to the central nervous system via nasal administration.

In our present series of experiments, we investigated the nasal applicability of the previously developed Soluplus® - meloxicam polymeric micelle formulation. Utilizing the nasal drug investigations, moderately high mucoadhesion was experienced in nasal conditions which alongside the appropriate physicochemical properties in liquid state, contributed to rapid drug absorption through human RPMI 2650 cell line. Ex vivo studies also confirmed that higher nasal mucosal permeation could be expected with the polymeric micelle nanoformulation compared to a regular MEL suspension.

Reduced COVID-19 severity elicited by weight loss from a medically supervised ketogenic diet in a geographically diverse ambulatory population with type 2 diabetes and obesity.

Objective: To investigate factors associated with COVID-19 severity in ambulatory individuals with type 2 diabetes mellitus (T2DM) and obesity treated with a medically supervised ketogenic diet (MSKD).

Research Design And Methods: In this real-world, retrospective, exploratory analysis, multivariate modelling was used to assess clinical factors associated with hospitalisation for COVID-19 in a geographically diverse outpatient population with T2DM treated virtually.

Results: Leading up to COVID-19 onset, non-hospitalised patients had higher average ketones (0.

New synthesis of a late-stage tetracyclic key intermediate of lumateperone.

New approaches have been tested for the synthesis of lumateperone intermediates. As a result of these efforts, a novel synthesis of the late-stage tetracyclic key intermediate of lumateperone starting from the commercially available quinoxaline is described. The tetracyclic skeleton was constructed by the reaction of 1-trifluoroacetyl-4-aminoquinoxaline with ethyl 4-oxopiperidine-1-carboxylate in a Fischer indole synthesis.

Impact of the COVID-19 Pandemic on the Effectiveness of a Metabolic Health Telemedicine Intervention for Weight Loss: A Propensity Score Matching Analysis.

Background: Coronavirus disease 2019 (COVID-19) pandemic public health measures such as stay-at-home and mandatory work-from-home orders have been associated with obesogenic lifestyle changes, increased risk of weight gain, and their metabolic sequelae. We sought to assess the impact of this pandemic on weight loss from a telemedicine-delivered very-low-carbohydrate intervention targeting nutritional ketosis (NKI).

Methods: A total of 746 patients with a BMI ≥25kg/m, enrolled between January and March 2020 and treated for at least 1 year with the NKI, were classified as pandemic cohort (PC).

Mucoadhesive meloxicam-loaded nanoemulsions: Development, characterization and nasal applicability studies.

Intranasally administered non-steroidal anti-inflammatory drugs (NSAIDs) offer an innovative opportunity in the field of pain management. Combination of the nasal physiological advantages such as the rich vascularization and large absorption area along with novel nanomedical formulations can fulfill all the necessary criteria of an advanced drug delivery system. Nanoemulsions represent a versatile formulation approach suitable for nasal drug delivery by increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery due to their stability, small droplet size and optimal solubilization properties.

Experimental and computational study of BF-catalyzed transformations of -(pivaloylaminomethyl)benzaldehydes: an unexpected difference from TFA catalysis.

Previously, we have studied the trifluoroacetic acid (TFA)-catalyzed rearrangements of unsubstituted and alkoxy-substituted -(pivaloylaminomethyl)benzaldehydes and revealed the formation of rearranged, regioisomeric aldehydes along with dimer-like products ("TFA dimers"). In the present study, related reactions of -(pivaloylaminomethyl)benzaldehydes are described with the difference that boron trifluoride diethyl etherate (BF·OEt) is used as the catalyst. Although in these reactions the formation of the same "TFA dimers" can be observed after a couple of hours reaction time, during further stirring these are transformed into a new dimer-like keto compound ("BF dimer") that gradually becomes the main product.

Development of In Situ Gelling Meloxicam-Human Serum Albumin Nanoparticle Formulation for Nose-to-Brain Application.

The aim of this study was to develop an intranasal in situ thermo-gelling meloxicam-human serum albumin (MEL-HSA) nanoparticulate formulation applying poloxamer 407 (P407), which can be administered in liquid state into the nostril, and to increase the resistance of the formulation against mucociliary clearance by sol-gel transition on the nasal mucosa, as well as to improve drug absorption. Nanoparticle characterization showed that formulations containing 12-15% / P407 met the requirements of intranasal administration. The Z-average (in the range of 180-304 nm), the narrow polydispersity index (PdI, from 0.

The Use of Handheld Ultrasound Devices in Emergency Medicine.

Purpose Of Review: Ultraportable handheld ultrasound (HHU) devices are being rapidly adopted by emergency medicine (EM) physicians. Though knowledge of the breadth of their utility and functionality is still limited compared to cart-based systems, these machines are becoming more common due to ease-of-use, extreme affordability, and improving technology.

Recent Findings: Images obtained with HHU are comparable to those obtained with traditional machines but create unique issues regarding billing and data management.

Recent Advances in the Synthesis of β-Carboline Alkaloids.

β-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates.

Basicity-Tuned Reactivity: -[1,2]-Wittig versus -[1,3]-Wittig Rearrangements of 3,4-Dihydro-2-1,2,3-benzothiadiazine 1,1-Dioxides.

The base-induced (-BuOK) rearrangement reactions of 3,4-dihydro-2-1,2,3-benzothiadiazine 1,1-dioxides result in a ring opening along the N-N bond, followed by ring closure with the formation of new C-N bonds. The position of the newly formed C-N bond can selectively be tuned by the amount of the base, providing access to new, pharmacologically interesting ring systems with high yield. While with 2 equiv of -BuOK 1,2-benzisothiazoles can be obtained in a -[1,2]-Wittig reaction, with 6 equiv of the base 1,2-benzothiazine 1,1-dioxides can be prepared in most cases as the main product, in a -[1,3]-Wittig reaction.

Synthesis of Indolo[2,3-]quinolin-6(7)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C-H Arylation.

The synthesis of variously substituted indolo[2,3-]quinolin-6(7)-ones was developed Pd-catalyzed intramolecular C-H arylation. This method highlights a strategy for preparing indoloquinoline precursors bearing versatile functional groups and provides a new approach for the synthesis of antimalarial isoneocryptolepine analogues. The plausible ring closure mechanism was examined with quantum chemical calculations, where a trigonal bipyramidal concerted metalation-deprotonation transition state is presumable.

Strain-specific strategies of 2'-fucosyllactose, 3-fucosyllactose, and difucosyllactose assimilation by Bifidobacterium longum subsp. infantis Bi-26 and ATCC 15697.

Human milk provides essential nutrients for infant nutrition. A large proportion of human milk is composed of human milk oligosaccharides (HMOs), which are resistant to digestion by the infant. Instead, HMOs act as a bioactive and prebiotic enriching HMO-utilizing bacteria and cause systematic changes in the host.

Rearrangement of -(pivaloylaminomethyl)benzaldehydes: an experimental and computational study.

Treatment of alkoxy-substituted -(pivaloylaminomethyl)benzaldehydes under acidic conditions resulted in the formation of the regioisomeric aldehydes and/or dimer-like products. Detailed NMR studies and single-crystal X-ray measurements supported the structure elucidation of the compounds. DFT calculations were also carried out to clarify the reaction mechanism, and to explain the observed product distributions and structural variances in the dimer-like products.

First total synthesis of β-carboline alkaloid trigonostemine G and its derivatives.

The β-carboline core is the base structure of several biologically active natural and unnatural compounds. Herein, we report the first total synthesis of trigonostemine G, which is a newly isolated natural β-carboline alkaloid from the twigs of . Synthesis of two structurally close derivatives of trigonostemine G is also reported.

Development and Evaluation of Two Potential 5-HT Receptor PET Tracers: [F]ENL09 and [F]ENL10.

The latest addition to the serotonin (5-HT) receptor family is the 5-HT receptor (5-HTR). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HTR available.

A novel tool for structure assignment of hydroxylated metabolites of (arylpiperazinylbutyl)oxindole derivatives based on relative HPLC retention times.

Incubation of oxindole derivatives containing an arylpiperazine pharmacophore in rat liver microsomes in vitro formed several metabolites hydroxylated at various positions of the aromatic rings of the oxindole carbocycle or the arylpiperazine moiety. In order to substitute the sites of metabolic attack on these positional isomers, the exact structure of the molecules had to be identified. As polarities of the compounds depend on the site of hydroxylation, we measured retention times of the metabolites using reversed-phase HPLC.

Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors.

Most of the known inhibitors of D-amino acid oxidase (DAAO) are small polar molecules recognized by the active site of the enzyme. More recently a new class of DAAO inhibitors has been disclosed that interacts with loop 218-224 at the top of the binding pocket. These compounds have a significantly larger size and more beneficial physicochemical properties than most reported DAAO inhibitors, however, their structure-activity relationship is poorly explored.

Evidence of the Exercise-Hypogonadal Male Condition at the 2011 Kona Ironman World Championships.

Purpose: Prior research has illustrated that high volumes of aerobic exercise result in a reduction in basal concentrations of testosterone in men. Those studies were mostly conducted on recreational runners and identified reduced testosterone, but not concentrations low enough to be considered pathological. Therefore, the purpose of this study was to assess the basal concentrations of testosterone and cortisol in elite triathletes, as well as the impact of a World Championship race, on the acute responses of these hormones.

Synthesis of 8-Fluoro-3,4-dihydroisoquinoline and Its Transformation to 1,8-Disubstituted Tetrahydroisoquinolines.

A simple procedure for the synthesis of 8-fluoro-3,4-dihydroisoquinoline is described below, based on a directed -lithiation reaction. This key intermediate was then applied in various transformations. Fluorine⁻amine exchange afforded the corresponding 8-amino-3,4-dihydroisoquinolines, suitable starting compounds for the synthesis of 1-substituted 8-amino-tetrahydroisoquinolines.