Reactive deep eutectic solvents for EDC-mediated amide synthesis.

The sustainability of amide bond formation is an ever-present topic in the pharmaceutical industry, as it represents the common motif in many clinically approved drugs. Despite many procedures for accomplishing eco-friendly amide synthesis having been developed, this transformation still remains a contemporary challenge. Herein, we report a greener approach for amide synthesis by using Reactive Deep Eutectic Solvents (RDESs) acting as both the reaction medium and reactants. The procedure not only avoids the use of hazardous solvents but also provides operationally simple product recovery with high purity and efficiency, without chromatographic purification. This approach was efficiently applied to the synthesis of a key intermediate in the production of an active pharmaceutical ingredient like atenolol. The green metrics of the gram-scale procedure were compared to the conventional industrial strategy showing an advancement in the greening of amide synthesis.

Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Green Chemistry Principles for Nano- and Micro-Sized Hydrogel Synthesis.

The growing demand for drug carriers and green-technology-based tissue engineering materials has enabled the fabrication of different types of micro- and nano-assemblies. Hydrogels are a type of material that have been extensively investigated in recent decades. Their physical and chemical properties, such as hydrophilicity, resemblance to living systems, swelling ability and modifiability, make them suitable to be exploited for many pharmaceutical and bioengineering applications. This review deals with a brief account of green-manufactured hydrogels, their characteristics, preparations, importance in the field of green biomedical technology and their future perspectives. Only hydrogels based on biopolymers, and primarily on polysaccharides, are considered. Particular attention is given to the processes of extracting such biopolymers from natural sources and the various emerging problems for their processing, such as solubility. Hydrogels are catalogued according to the main biopolymer on which they are based and, for each type, the chemical reactions and the processes that enable their assembly are identified. The economic and environmental sustainability of these processes are commented on. The possibility of large-scale processing in the production of the investigated hydrogels are framed in the context of an economy aimed at waste reduction and resource recycling.

Green solvents for the formation of amide linkages.

The formation of the amide bond is among the most commonly performed transformations in the pharmaceutical industry and the wider chemical industry. The current methods for its installation in organic compounds frequently rely on the use of large amounts of organic solvents, mainly N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), and dichloromethane (DCM), which have been associated with adverse environmental and health concerns over the last decades. This fact led academia and industry to make significant efforts toward the development of synthetic routes with the aim to avoid, reduce or replace the use of hazardous solvents. The present review fits into this framework and discusses the literature existing over the past ten years on strategies for reducing and replacing hazardous solvents, focusing on the use of biobased and neoteric solvents, such as ionic liquids and deep eutectic solvents (ILs and DESs, respectively), and on the reaction media that proved to be greener alternatives for amide bond formation.

Semi-synthesis as a tool for broadening the health applications of bioactive olive secoiridoids: a critical review.

Covering: 2005 up to 2020Olive bioactive secoiridoids are recognized as natural antioxidants with multiple beneficial effects on human health. Nevertheless, the study of their biological activity has also disclosed some critical aspects associated with their application. Firstly, only a few of them can be extracted in large amounts from their natural matrix, namely olive leaves, drupes, oil and olive mill wastewater. Secondly, their application as preventive agents and drugs is limited by their low membrane permeability. Thirdly, the study of their biological fate after administration is complicated by the absence of pure analytical standards. Accordingly, efficient synthetic methods to obtain natural and non-natural bioactive phenol derivatives have been developed. Among them, semi-synthetic protocols represent efficient and economical alternatives to total synthesis, combining efficient extraction protocols with efficient catalytic conversions to achieve reasonable amounts of active molecules. The aim of this review is to summarize the semi-synthetic protocols published in the last fifteen years, covering 2005 up to 2020, which can produce natural olive bioactive phenols scarcely available by extractive procedures, and new biophenol derivatives with enhanced biological activity. Moreover, the semi-synthetic protocols to produce olive bioactive phenol derivatives as analytical standards are also discussed. A critical analysis of the advantages offered by semi-synthesis compared to classical extraction methods or total synthesis protocols is also performed.

Valorization of Tomato Waste as a Source of Carotenoids.

Fast-accumulating scientific evidence from many studies has revealed that fruits and vegetables are the main source of bioactive compounds; in most cases, wastes and byproducts generated by the food processing industry present similar or a higher content of antioxidant compounds. In recent years, the ever-growing amount of agricultural and food wastes has raised serious concerns from an environmental point of view. Therefore, there is an increasing interest in finding new ways for their processing toward safely upgrading these wastes for recovering high-value-added products with a sustainable approach. Among food waste, the abundance of bioactive compounds in byproducts derived from tomato suggests possibility of utilizing them as a low-cost source of antioxidants as functional ingredients. This contribution gives an overview of latest studies on the extraction methods of carotenoids from tomato waste, along with an evaluation of their antioxidant activity, as well as their industrial applications.

Bleeding events in COVID-19: the other side of the coin?

We present three cases of patients affected by severe SARS-CoV-2-related pneumonia treated with a low molecular weight heparin for prevention or treatment of pulmonary embolism, who presented a major bleed, in particular an ileopsoas haematoma that caused severe anaemia; in one case it was fatal. In the recent outbreak of novel coronavirus infection, significantly abnormal coagulation parameters in SARS-CoV-2 infection occur very often, but complications in the opposite direction such as bleeding diathesis are very rare. In these cases, there are different levels of gravity: for one patient the major bleed required the anticoagulant therapy to be stopped until bleeding stabilized, one patient needed interventional radiology and one patient died.

Synthesis, Biological and In Silico Evaluation of Pure Nucleobase-Containing Spiro (Indane-Isoxazolidine) Derivatives as Potential Inhibitors of MDM2-p53 Interaction.

Nucleobase-containing isoxazolidines spiro-bonded to an indane core have been synthesized in very good yields by regio- and diastereoselective 1,3-dipolar cycloaddition starting from indanyl nitrones and N-vinylnucleobases by using environmentally benign microwave technology. The contemporary presence of various structural groups that are individually active scaffolds of different typology of drugs, has directed us to speculate that these compounds may act as inhibitors of MDM2-p53 interaction. Therefore, both computational calculations and antiproliferative screening against A549 human lung adenocarcinoma cells and human SH-SY5Y neuroblastoma cells were carried out to support this hypothesis.

Green Synthesis of Privileged Benzimidazole Scaffolds Using Active Deep Eutectic Solvent.

The exploitation and use of alternative synthetic methods, in the face of classical procedures that do not conform to the ethics of green chemistry, represent an ever-present problem in the pharmaceutical industry. The procedures for the synthesis of benzimidazoles have become a focus in synthetic organic chemistry, as they are building blocks of strong interest for the development of compounds with pharmacological activity. Various benzimidazole derivatives exhibit important activities such as antimicrobial, antiviral, anti-inflammatory, and analgesic activities, and some of the already synthesized compounds have found very strong applications in medicine praxis. Here we report a selective and sustainable method for the synthesis of 1,2-disubstituted or 2-substituted benzimidazoles, starting from o-phenylenediamine in the presence of different aldehydes. The use of deep eutectic solvent (DES), both as reaction medium and reagent without any external solvent, provides advantages in terms of yields as well as in the work up procedure of the reaction.

Biorenewable Deep Eutectic Solvent for Selective and Scalable Conversion of Furfural into Cyclopentenone Derivatives.

The development of novel synthetic routes to produce bioactive compounds starting from renewable sources has become an important research area in organic and medicinal chemistry. Here, we present a low-cost procedure for the tunable and selective conversion of biomass-produced furfural to cyclopentenone derivatives using a mixture of choline chloride and urea as a biorenewable deep eutectic solvent (DES). The proposed medium is a nontoxic, biodegradable, and could be reused up to four times without any unfavorable effect on the reaction yield. The process is tunable, clean, cheap, simple and scalable and meets most of the criteria; therefore, it can be considered as an environmental sustainable process in a natural reaction medium.

Hemostatic gauze based on chitosan and hydroquinone: preparation, characterization and blood coagulation evaluation.

This work concerns on the preparation and performance evaluation of a new chitosan hydroquinone based gauze for hemostatic use. Chitosan and hydroquinone were firstly connected by etherification and then linked to the pre-carboxylate gauze. The functionalized material and the chitosan-hydroquinone ether were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy and Differential Scanning Calorimetry (DSC). FT-IR results showed that an esterification occurred on carboxylic group of the gauze. The gauze functionalization degree was also evaluated by volumetric analysis. The ether hydroquinone content was obtained by the Folin test. Moreover, the linkage between hydroquinone and chitosan was confirmed by nuclear magnetic resonance (NMR). The hemostatic activity of functionalized gauze was evaluated by dynamic blood clotting assays. The obtained results showed that the prepared material can shorten the blood clotting time and induce the adhesion and activation of platelets. Finally, swelling characteristic of the new gauze was evaluated to confirm its high capacity to absorb the blood.

Lewis acid catalysed methylation of N-(9H-fluoren-9-yl)methanesulfonyl (Fms) protected lipophilic α-amino acid methyl esters.

This work reports an efficient Lewis acid catalysed N-methylation procedure of lipophilic α-amino acid methyl esters in solution phase. The developed methodology involves the use of the reagent system AlCl3/diazomethane as methylating agent and α-amino acid methyl esters protected on the amino function with the (9H-fluoren-9-yl)methanesulfonyl (Fms) group. The removal of Fms protecting group is achieved under the same conditions to those used for Fmoc removal. Thus the Fms group can be interchangeable with the Fmoc group in the synthesis of N-methylated peptides using standard Fmoc-based strategies. Finally, the absence of racemization during the methylation reaction and the removal of Fms group were demonstrated by synthesising a pair of diastereomeric dipeptides.

Synthesis of D-erythro-sphinganine through serine-derived α-amino epoxides.

A total synthesis of D-erythro-sphinganine [(2S,3R)-2-aminooctadecane-1,3-diol] starting from commercial N-tert-butyloxycarbonyl-L-serine methyl ester is described. The approach is based on the completely stereoselective preparation of an α-amino epoxide obtained by treating a protected L-serinal derivative with dimethylsulfoxonium methylide. The oxirane synthon is obtained with an anti configuration fitting the (2S,3R) stereochemistry of the 2-amino-1,3-diol polar head of D-erythro-sphinganine. The synthetic procedure afforded the target compound in a 68% overall yield based on the initial amount of the starting L-serine material.

Neurofunctional correlates of attention rehabilitation in Parkinson's disease: an explorative study.

The effectiveness of cognitive rehabilitation (CR) in Parkinson's disease (PD) is in its relative infancy, and nowadays there is insufficient information to support evidence-based clinical protocols. This study is aimed at testing a validated therapeutic strategy characterized by intensive computer-based attention-training program tailored to attention deficits. We further investigated the presence of synaptic plasticity by means of functional magnetic resonance imaging (fMRI). Using a randomized controlled study, we enrolled eight PD patients who underwent a CR program (Experimental group) and seven clinically/demographically-matched PD patients who underwent a placebo intervention (Control group). Brain activity was assessed using an 8-min resting state (RS) fMRI acquisition. Independent component analysis and statistical parametric mapping were used to assess the effect of CR on brain function. Significant effects were detected both at a phenotypic and at an intermediate phenotypic level. After CR, the Experimental group, in comparison with the Control group, showed a specific enhanced performance in cognitive performance as assessed by the SDMT and digit span forward. RS fMRI analysis for all networks revealed two significant groups (Experimental vs Control) × time (T0 vs T1) interaction effects on the analysis of the attention (superior parietal cortex) and central executive neural networks (dorsolateral prefrontal cortex). We demonstrated that intensive CR tailored for the impaired abilities impacts neural plasticity and improves some aspects of cognitive deficits of PD patients. The reported neurophysiological and behavioural effects corroborate the benefits of our therapeutic approach, which might have a reliable application in clinical management of cognitive deficits.

Maximal exercise in obese patients with COPD: the role of fat free mass.

BACKGROUND: Obese patients (OB) with COPD may better tolerate exercise as compared to normal weight (NW) COPD patients, even if the reason for this is not yet fully understood. We investigated the interactions between obesity, lung hyperinflation, fat-free mass (FFM) and exercise capacity in COPD. METHODS: Forty-four patients (16 females; age 65 ± 8 yrs) were assessed by resting lung function and body composition and exercised on a cycle-ergometer to exhaustion. RESULTS: Twenty-two OB and 22 NW patients did not differ in age, gender and airflow obstruction degree, but in FFM (p < 0.05). OB had significantly higher values in inspiratory capacity/total lung capacity ratio (IC/TLC) at rest (p < 0.01), but not at peak of exercise and showed significantly higher values in peak workload (p < 0.05) and in peak oxygen uptake (VO2), when expressed as absolute value (p < 0.05), but not when corrected by FFM. OB compared to NW experienced lower leg fatigue (p < 0.05), but similar dyspnea on exertion. In all patients, the regression equation by stepwise multiple regression analysis for peak workload and VO2, as dependent variables included both FFM and IC/TLC at rest, as independent variables (r(2) = 0.43 and 0.37, respectively). CONCLUSIONS: OB with COPD, as compared to NW patients matched for age, gender and airflow obstruction, had greater FFM and less resting lung hyperinflation and showed greater maximal exercise capacity. Pulmonary and non-pulmonary factors may explain the preservation of exercise tolerance in patients with COPD associated with obesity.

Reactive Deep Eutectic Solvent for an Eco-Friendly Synthesis of Cellulose Carbamate.

The limited solubility of natural cellulose in water and common organic solvents hinders its diverse applications, despite being one of the most abundant and easily accessible biopolymers on Earth. Chemical derivatization, such as cellulose carbamate (CC), offers a pathway to enhance both solubility and industrial processability. In this study, CC was synthesized by exploiting a novel type IV deep eutectic solvent (DES) composed of erbium trichloride and urea. This DES was shown to be not only an environmentally friendly reaction medium/catalyst but also actively participated in the synthetic process as a reagent. The resultant cellulose carbamate samples were characterized through FT-IR and elemental analysis. A nitrogen content value of 1.59% was afforded determining a degree of substitution corresponding to a value of 0.19. One of the key scientific advancements lies in the preparation of cellulose carbamate using a straightforward and cost-effective method. This approach utilizes non-toxic compounds, aligning with the principles of green chemistry and contributing to sustainable development in cellulose derivative production.

Synthesis of enantiopure sugar-decorated six-armed triptycene derivatives.

A new class of molecules with a triptycene rigid core surrounded by six monosaccharide residues was synthesized. Hexakis(bromomethyl) substituted triptycene was converted into a six-armed triptycene azide (2,3,6,7,14,15-hexakis(azidomethyl)-9,10-dihydro-9,10-[1',2']benzenoanthracene). The key step of the synthesis was the cycloaddition of the azide to 2-propyn-1-yl ß-D-gluco- or galactopyranosides. All products were isolated in good yields and were fully characterized.

Prefrontal alterations in Parkinson's disease with levodopa-induced dyskinesia during fMRI motor task.

Levodopa-induced dyskinesia represents disabling complication of long-term therapy with dopaminergic drugs in treating Parkinson's disease (PD). Recently, our group demonstrated that PD patients with levodopa-induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa-induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa-induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia.

Neuroanatomic correlates of psychogenic nonepileptic seizures: a cortical thickness and VBM study.

PURPOSE: Psychogenic nonepileptic seizures (PNES) are among the most common clinical manifestations of conversion disorder and consist of paroxysmal behavior that resembles epileptic seizures. Preliminary data from functional neuroimaging studies gave plausible evidence that limbic circuits and sensorimotor cortex might be engaged in conversion disorder. Nonetheless, no advanced magnetic resonance imaging (MRI) studies have focused on patients with PNES. METHODS: We enrolled 20 consecutive patients in whom the diagnosis of PNES was based on ictal video-electroencephalography (EEG) of the habitual episodes and 40 healthy subjects matched for age and sex All patients underwent a formal neuropsychological investigation and a neuropsychiatric assessment. All of the patients also underwent two distinct morphologic whole-brain MR measurements, voxel-based morphometry (VBM), and cortical thickness analysis, in a multimethod approach. KEY FINDINGS: None of the patients had serious medical or neurologic illness, substance abuse, or psychotic disorder, or were taking antipsychotic drugs. VBM and cortical thickness analyses in the patients with PNES revealed abnormal cortical atrophy of the motor and premotor regions in the right hemisphere and the cerebellum bilaterally. We also observed a significant association between increasing depression scores and atrophy involving the premotor regions. SIGNIFICANCE: The results of this study illustrate that motor and premotor regions in the right hemisphere and the cerebellum bilaterally play an important role in the pathogenesis of PNES and that these structures are correlated with depressive symptoms. Our findings suggest a multistep model in the pathogenesis of PNES, in which the phenomenology is driven by psychological factors interacting with specific biologic abnormalities.

Serum thyroid-stimulating hormone as a predictor of cognitive impairment in an elderly cohort.

BACKGROUND: It is unclear whether in late life serum thyroid-stimulating hormone (TSH) predicts risk of developing cognitive impairment. OBJECTIVE: This study investigated the prospective relationship of serum TSH with the risk of developing mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD) in an elderly cohort with a 4-year follow-up. METHODS: Data are for 660 subjects aged 65 years and older from an Italian population-based cohort who were cognitively normal at an extensive assessment in 1999/2000 and underwent follow-up assessment in 2003/2004. Serum TSH was measured at baseline. Multinomial logistic models adjusted for sociodemographic and cardiovascular risk factors were used to investigate the association of serum TSH (both as a tertile and continuous log-transformed variable) with risk of incident MCI, AD and VaD diagnosed according to international criteria. RESULTS: Over 3.8 ± 0.7 years of follow-up, there were 149 incident MCI cases (77 with impairment of memory and 72 with impairment of nonmemory domains) and 86 incident dementia cases (53 with AD, 28 with VaD). No association between baseline TSH and risk of developing any MCI subtype or AD was found. The highest TSH tertile had a threefold higher increased risk of VaD (OR: 3.25, 95% CI: 1.01-10.77, p = 0.048) compared to the lowest tertile. Risk of VaD increased about 60% for each 1 SD increase in log-transformed TSH (OR: 1.61, 95% CI: 1.06-2.44, p = 0.025). CONCLUSIONS: In this elderly cohort, baseline TSH was not related to the risk of developing MCI or AD, but high TSH was associated with an increased risk of VaD. These results suggest further need for research using larger samples to examine the role of TSH as a predictor of VaD and the role of thyroid autoimmunity in vascular cognitive impairment.