Context. Calcifediol has been proposed as a potential treatment for COVID-19 patients. Objective: To compare the administration or not of oral calcifediol on mortality risk of patients hospitalized ...because of COVID-19. Design: Retrospective, multicenter, open, non-randomized cohort study. Settings: Hospitalized care. Patients: Patients with laboratory-confirmed COVID-19 between 5 February and 5 May 2020 in five hospitals in the South of Spain. Intervention: Patients received calcifediol (25-hydroxyvitamin D3) treatment (0.266 mg/capsule, 2 capsules on entry and then one capsule on day 3, 7, 14, 21, and 28) or not. Main Outcome Measure: In-hospital mortality during the first 30 days after admission. Results: A total of 537 patients were hospitalized with COVID-19 (317 males (59%), median age, 70 years), and 79 (14.7%) received calcifediol treatment. Overall, in-hospital mortality during the first 30 days was 17.5%. The OR of death for patients receiving calcifediol (mortality rate of 5%) was 0.22 (95% CI, 0.08 to 0.61) compared to patients not receiving such treatment (mortality rate of 20%; p < 0.01). Patients who received calcifediol after admission were more likely than those not receiving treatment to have comorbidity and a lower rate of CURB-65 score for pneumonia severity ≥ 3 (one point for each of confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years), acute respiratory distress syndrome (moderate or severe), c-reactive protein, chronic kidney disease, and blood urea nitrogen. In a multivariable logistic regression model, adjusting for confounders, there were significant differences in mortality for patients receiving calcifediol compared with patients not receiving it (OR = 0.16 (95% CI 0.03 to 0.80). Conclusion: Among patients hospitalized with COVID-19, treatment with calcifediol, compared with those not receiving calcifediol, was significantly associated with lower in-hospital mortality during the first 30 days. The observational design and sample size may limit the interpretation of these findings.
We report quantitative measurements of the relative reactivities of a series of C−H bonds of gaseous or liquid CnH2n+2 alkanes (n=1–8, 29 different C−H bonds) towards in situ generated electrophiles ...(copper, silver, and rhodium carbenes), with methane as the reference. This strategy surpasses the drawback of previous model reactions of alkanes with strong electrophiles suffering from C−C cleavage processes, which precluded direct comparison of the relative reactivities of alkane C−H bonds.
The relative reactivities of the C−H bonds of alkanes, CnH2n+2, acting as nucleophiles are reported, and range from n=1 (methane as the reference) to n=8 towards several silver, copper, or rhodium carbene complexes acting as strong electrophiles. The data collected evidence the lack of a general trend for the reaction sites in intermolecular processes.
Even in the context of hydrocarbons' general resistance to selective functionalization, methane's volatility and strong bonds pose a particular challenge. We report here that silver complexes bearing ...perfluorinated indazolylborate ligands catalyze the reaction of methane (CH4) with ethyl diazoacetate (N2CHCO2Et) to yield ethyl propionate (CH3CH2CO2Et). The use of supercritical carbon dioxide (scCO2) as the solvent is key to the reaction's success. Although the catalyst is only sparingly soluble in CH4/CO2 mixtures, optimized conditions presently result in a 19% yield of ethyl propionate (based on starting quantity of the diazoester) at 40°C over 14 hours. PUBLICATION ABSTRACT
One of the pathological hallmarks of Alzheimer’s disease (AD) is the formation of amyloid-β plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this ...enzyme could slow down the progression of amyloid-β aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on Aβ40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the Aβ40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.
Two cobalt(III) complexes containing different β-ketoesters, namely CoIII(L1)(py2en)(ClO4)2·H2O (1) and CoIII(L2)(py2en)(ClO4)2 (2) (py2en = N,N′-bis(pyridin-2-ylmethyl)ethylenediamine; ...L1− = methylacetoacetate; L2− = ethyl 4-chloroacetoacetate) have been prepared and investigated as prototypes of bioreductive prodrugs. The presence of β-ketoester and py2en ligands in 1 and 2, as well as the perchlorate counterions, was supported by IR spectroscopy and CHN elemental analysis. The composition molecular structure of both complexes was confirmed by NMR spectroscopy and ESI mass spectrometry. Structural information was also obtained for 2via X-ray diffraction analysis. The redox properties indicate that 1 and 2 are suitable for reduction under biological conditions. Investigation of DNA-interacting suggest that 1 and 2 bind DNA via electrostatic forces. Both complexes may be employed as possible platforms for the delivery of biologically active compounds, since their reaction with ascorbic acid in PBS at pH 6.2 and 7.4 at 37°C results in the release of the β-ketoester ligands upon Co(III)/Co(II) reduction.
O2-dependent redox activation of a cobalto(III) complex with release of β-ketoester drug prototypes. Display omitted
•CoIII complexes have been designed for hypoxia-selective anticancer drug delivery.•Redox potential of CoIII-β-ketoesters complexes has been tuned by ancillary ligands.•Biological redox activation was successfully simulated using ascorbate reducing agent.•O2-dependent dissociation of the β-ketoesters has been achieved upon Co3+/Co2+ reduction.•DNA-interaction assays suggest that 1 and 2 bind DNA via electrostatic forces.
A first quantitative model for calculating the nucleophilicity of alkanes is described. A statistical treatment was applied to the analysis of the reactivity of 29 different alkane C−H bonds towards ...in situ generated metal carbene electrophiles. The correlation of the recently reported experimental reactivity with two different sets of descriptors comprising a total of 86 parameters was studied, resulting in the quantitative descriptor‐based alkane nucleophilicity (QDEAN) model. This model consists of an equation with only six structural/topological descriptors, and reproduces the relative reactivity of the alkane C−H bonds. This reactivity can be calculated from parameters emerging from the schematic drawing of the alkane and a simple set of sums.
The QDEAN model constitutes a first approach to the quantitative modeling of the reactivity of alkane C−H bonds towards electrophiles. A remarkable correlation between experimental and calculated values was achieved with just six topological descriptors for the C−H bonds under evaluation.
Tetrahedral copper(II) and zinc(II) coordination compounds from 5-nitroimidazole derivatives, viz
.
1-(2-chloroethyl)-2-methyl-5-nitroimidazole (cenz) and ornidazole ...1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (onz), were synthesized and spectroscopically characterized. Their molecular structures were determined by X-ray diffraction studies. The complexes Cu(onz)
2
X
2
, Zn(onz)
2
X
2
, Cu(cenz)
2
X
2
and Zn(cenz)
2
X
2
(X
−
= Cl, Br), are stable in solution and exhibit positive LogD
7.4
values that are in the range for molecules capable of crossing the cell membrane via passive difussion. Their biological activity against
Toxoplasma gondi
was investigated, and IC
50
and lethal dose (LD
50
) values were determined. The ornidazole copper(II) compounds showed very good antiparasitic activity in its tachyzoite morphology. The interaction of the coordination compounds with DNA was examined by circular dichroism, fluorescence (using intercalating ethidium bromide and minor groove binding Hoechst 33258) and UV–Vis spectroscopy. The copper(II) compounds interact with the minor groove of the biomolecule, whereas weaker electrostatic interactions take place with the zinc(II) compounds. The spectroscopic data achieved for the two series of complexes (namely with copper(II) and zinc(II) as metal center) agree with the respective DNA-damage features observed by gel electrophoresis.
Graphical abstract
Malaria or Paludism is a tropical disease caused by parasites of the Plasmodium genre and transmitted to humans through the bite of infected mosquitos of the Anopheles genre. This pathology is ...considered one of the first causes of death in tropical countries and, despite several existing therapies, they have a high toxicity. Computational methods based on Quantitative Structure- Activity Relationship studies have been widely used in drug design work flows.
The main goal of the current research is to develop computational models for the identification of antimalarial hit compounds.
For this, a data set suitable for the modeling of the antimalarial activity of chemical compounds was compiled from the literature and subjected to a thorough curation process. In addition, the performance of a diverse set of ensemble-based classification methodologies was evaluated and one of these ensembles was selected as the most suitable for the identification of antimalarial hits based on its virtual screening performance. Data curation was conducted to minimize noise. Among the explored ensemble-based methods, the one combining Genetic Algorithms for the selection of the base classifiers and Majority Vote for their aggregation showed the best performance.
Our results also show that ensemble modeling is an effective strategy for the QSAR modeling of highly heterogeneous datasets in the discovery of potential antimalarial compounds.
It was determined that the best performing ensembles were those that use Genetic Algorithms as a method of selection of base models and Majority Vote as the aggregation method.
A strict adherence to the Mediterranean Diet (MedDiet) has repeatedly been linked to a low risk of cardiovascular disease in several situations. Initially, the mechanisms considered as possible ...causes of this were based on the effects of this dietary pattern on the so-called traditional risk factors (especially lipids and blood pressure). However, the high relative reduction in the prevalence of cardiovascular morbidity and mortality were not proportional to the limited findings about regulation of those traditional risk factors. In addition to several studies confirming the above effects, current research on the MedDiet is being focused on defining its effects on non-traditional risk factors, such as endothelial function, inflammation, oxidative stress, or on controlling the conditions which predispose people to cardiovascular events, such as obesity, metabolic syndrome or type 2 diabetes mellitus. In the current article, after briefly reviewing the known effects of the MedDiet on the traditional risk factors, we will mainly focus on reviewing the current evidence about the effects that this dietary pattern exerts on alternative factors, including postprandial lipemia or coagulation, among others, as well as providing a short review on future directions.
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