The crystallization mechanisms of a series of fourteen 7-chloro-4-substituted-quinolines (substituents: (
1
) OCH
3
, (
2
) OCH
2
CH
3
, (
3
) OCH
2
CH&z.dbd;CH
2
, (
4
) O(CH
2
)
2
OH, (
5
) O(CH
2
...)
3
OH, (
6
) NH(CH
2
)
2
CH
3
, (
7
) NH(CH
2
)
3
CH
3
, (
8
) NH(CH
2
)
2
OH, (
9
) NHCH(CH
2
CH
3
)CH
2
OH, (
10
) NH(CH
2
)
2
Cl, (
11
) NHN&z.dbd;CH(C
6
H
5
), (
12
) NHN&z.dbd;CH(2-FC
6
H
4
), (
13
) NHN&z.dbd;CH(3-FC
6
H
4
), and (
14
) NHN&z.dbd;CH(4-FC
6
H
4
)) were proposed based on a retrocrystallization approach using the supramolecular cluster as demarcation. Crystallization mechanism stage parameters -
N
CG
% and NG/NC - were determined. The 4-substituents present in quinolines caused six different mechanisms, starting from the monomers in solution to dimers, 1D nuclei, and 2D nuclei (
6
,
11
,
12
); 2D nucleus formation (
5
); 1D nuclei to 2D nuclei (
7
,
9
); concomitant dimers and 1D nuclei to a 3D crystal (
8
); 1D nuclei directly to a 3D crystal lattice (
1-4
,
10
,
14
), and dimers to 2D nuclei and then to a 3D crystal (
13
). Analysis of
G
AI
showed atom atom intermolecular interactions in the proposed first nuclei for compounds
4
and
5
. The nucleation process inferred in the solid state was partially confirmed during the formation of the proto-crystal in solution due to the changes of the hydrogen chemical shift in variable-concentration
1
H-NMR experiments. Results revealed that the size of the alkyl chain and the presence of different functional groups in the 4-substituents influenced the crystallization process.
The crystallization mechanisms of a series of fourteen 7-chloro-4-substituted-quinolines were proposed based on a retrocrystallization approach using the supramolecular cluster as demarcation.
Carboxamide groups are interesting models of study in crystal engineering as they can be hydrogen-bond acceptors and donors. In this sense, organic molecules containing carboxamide groups could act ...as acceptors for water molecules, enabling hydrate formation. To study amide-based hydrate formation, a series of crystal structures of pyridine-2,6-dicarboxamides (carboxamide groups are −C(O)-NH-R, where R = (1) CH2CHPh2, (3) CH2CH2Ph, (4) CH2Ph, (5) Ph-4-F, (6) Ph-4-Cl, (7) Ph-4-Br, and (8) naphth-1-yl) were chosen. A similar compound containing benzene 1,3-dicarboxamide substituted (2) was also included. Compounds 1 and 3–8 presented a structure with folded molecular conformation, where the amide chains showed the two NH groups positioned between both chains. Compound 2 had a linear molecular structure, where the amide chains were distant from each other. Compounds 1 and 3 presented hydrate phases (1:1), with 1 showing three polymorphic phases. Compounds 2 and 4–8 had anhydrous crystalline phases. Crystallization mechanisms of compounds 1–8 were proposed using the supramolecular cluster as demarcation and corroborated with the concentration-dependent 1H NMR experiments. Our findings enabled us to propose the stages in which each polymorph was formed, and the proposed crystallization mechanisms presented as first-stage stacking molecules for 1I-1II and 4–8 (one-dimensional nuclei), two-dimensional growth for 2, and dimer formation for 1III and 3. QTAIM analysis was used for a more detailed evaluation of intermolecular interaction contributions. The steric hindrance caused by the aryl groups is the possible reason for the greatest difficulty in forming hydrates for compounds 4–8. The water molecules in 1I-1III and 3 occupy the cavity formed by the organic molecules since the early crystallization stage. In this sense, it was possible to contribute insights regarding the influences between molecular conformation and the formation of hydrate structures.
A series of
N
-arylbenzamides containing amide groups and phenyl-perfluorinated rings were used as the smallest molecules to investigate the direct influence of hydrogen bonds and aromatic ...donor-acceptor complementarity in the solid state.
N
-Phenylbenzamide and pentafluoro-
N
-(perfluorophenyl)benzamide were investigated in self-assembly as well as in cocrystal form. Moreover, the respective mixed phenyl-perfluorinated compounds were used in this study. Supramolecular cluster demarcation was used, and crystallization mechanisms were proposed based on the hierarchy of stabilization energies in one-, two-, or three-dimensional growth processes (1D, 2D, or 3D, respectively). At the molecular level, effects such as torsion, planes, and intramolecular interactions showed significant changes compared to the optimized structures, evidencing the supramolecular influence. When considering the supramolecular environment, crystallization mechanisms of the self-assembly of phenyl-phenyl amide offer a 2D → 3D process, whereas the other compounds were classified in a 1D (chains) → 2D (layers) → 3D stepwise process. The interchain links were driven by C-H π interactions in the self-assembly and π π interactions in the mixed compounds and cocrystal packing. QTAIM analysis evidences the importance and contribution of the strong NH O&z.dbd;C hydrogen bond of all crystals. MEP plots highlight the complementarity between amide sites and aromatic rings, helping to understand the cocrystal formation. Lastly, a comparison of the NH O&z.dbd;C bond strength of the cocrystal obtained (−11 kcal mol
−1
) with those of similar cocrystals linked by amide bonds deposited in the CSD showed the highest value of the presented cocrystal. These findings will be helpful in the modulation and design of new molecular solids.
Crystallization mechanisms were proposed to investigate hydrogen bond and aromatic donor-acceptor interactions in a series of phenyl-perfluorophenyl amides. The modulation of NH O&z.dbd;C bonds and aryl complementarity drove a new cocrystal growth.
The supramolecular architectures of amide-containing compounds are highly dependent on the side-chain substituents, although the potential impact of isoxazole substituents on polymorph formation has ...not been thoroughly explored. Hence, three distinct forms of N 1 , N 3 -bis(5-methylisoxazol-3-yl)malonamide (1) were obtained and characterized: two polymorphic forms and one solvate. An in-depth analysis of the interactions and energy content of the crystals based on supramolecular clusters allowed us to propose crystallization mechanisms (crystal retrosynthesis). Specifically, the energy similarities between the interaction of the first sites NH amide ⋯OC amide (form 1I) and the symmetric sites NH amide ⋯N isox (form 1II) were found to contribute to their formation. Nonetheless, the presence of DMSO resulted in the formation of form 1III, where the solvent molecule disrupted amide-amide interactions. The first nuclei are more stable than forms 1I and 1II. The compound of N 1 , N 2 -bis(5-methylisoxazol-3-yl)oxalamide (2) was used as a comparison, and through the absence of polymorphs, revealed that the central carbon in molecule 1 allows a flexible adaptation that leads to the three forms. These findings suggest that variations in solvents, flexibility, and the presence/absence of amide–amide interactions can modulate the competition between amide-containing isoxazole compounds.
The supramolecular organization of organic salts has been widely researched, revealing recurring patterns in crystalline lattices that describe their supramolecular properties. In recent years, our ...research group has underscored the importance of considering the crystalline structures as a whole, incorporating all the necessary energetic and topological information for a comprehensive understanding of the crystalline system. Given this context, we investigated a series of ammonium mono- and dicarboxylate salts (
1-12
) to determine whether subtle structural modifications in the anionic organic component lead to relevant energy and topology changes in the crystalline lattice. To achieve this, we selected structures whose carboxylate anion only possesses an alkyl chain and is devoid of other functional groups. The ammonium cation (NH
4
+
) was fixed to determine the effect of variations in the alkyl chains of the selected mono- and dicarboxylates, such as length and degree of unsaturation. Additionally, probable crystallization mechanisms were proposed to elucidate some of the topological and energetic aspects involved in the crystallization of these compounds. Destabilizing interactions were observed in 10 crystalline structures, and the MEP data showed that the most destabilizing interactions occur by the proximity of portions with the same type of charge. Some dimers have unexpectedly low intermolecular interaction energies despite having large contact areas. Based on these data we demonstrate the additivity of intermolecular interactions, that is, the low intermolecular interaction energy in these dimers is the result of the sum of destabilizing energies and stabilizing energies. The cluster energy efficiency data revealed that most crystal lattices display typical characteristics of uncharged organic compounds. The proposed crystallization mechanisms showed a gradual increase in nucleus complexity in the initial stages and the total number of nucleation stages, resulting in five main patterns: monomer → 1D → 3D (
1-2
), monomer → dimer → 2D → 3D (
3
), monomer → 1D → 2D → 3D (
4-5
), monomer → dimer → 3D (
6
), and monomer → 2D → 3D (
7-12
).
The supramolecular organization of organic salts has been widely researched, revealing recurring patterns in crystalline lattices that describe their supramolecular properties.
Doxazosin mesylate (DM) is a class II drug in the Biopharmaceutics Classification System (BCS) that is used in several types of hypertension treatments. DM presents almost 20 different polymorphs ...described in literature/patents, whose existence are usually supported by powder X-ray diffraction (PXRD) data. However, only the crystal form termed as polymorph A (DM-A) and one hydrated DM form present determined crystal structures. Despite its BCS class II classification, there is no preconized DM form for solid oral dosages in pharmaceutical compendia or literature. Also, there are few works comparing the solubility or dissolution rate of DM polymorphs or other solid-state doxazosin forms. This work aimed to describe for the first time the crystal structure of the doxazosin free-base (DB), which was determined here by single-crystal X-ray diffraction. The DB crystal structure was compared to the two known DM crystal structures (DM-A and DM dihydrate) previously determined by PXRD approaches. Additionally, the equilibrium solubility of the DB form was investigated and compared to the two polymorphic DM forms (DM-A and DM-H) in five aqueous media: pure water, 0.01 mol L–1 HCl, and pH 4.5, 5.8, and 7.2 phosphate buffers. Thermal analyses of DB, DM-A, and DM-H were also performed. The DB form had significant solubility only in the HCl medium, but it was less soluble than either DM-A or DM-H. The three forms demonstrated to be practically insoluble in the slightly acid-neutral pH range (pH 5.8 and 7.2 phosphate buffers). DM-A was shown to be more stable (higher melting point) and, consequently, less soluble (from 1.6- to 2-fold) than DM-H. The very low solubility of doxazosin free-base in water demonstrates the need to use its salt multicomponent crystal forms modifications to improve the drug solubility. Additionally, this study suggests DM-A as the polymorph that should be preconized for marketable solid oral dosages containing DM.
Proximal contact loss between implant-supported prostheses and adjacent natural teeth is a complication that has been reported in clinical practice. However, the prevalence of the condition is ...unclear.
The purpose of this systematic review and meta-analysis was to assess the proportion of reported proximal contact loss between implant-supported prostheses and adjacent natural teeth.
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology criteria and was registered on the international prospective register of systematic reviews (PROSPERO) platform (CRD42021225138). The electronic search was conducted by using the PubMed/MEDLINE, Embase, and Cochrane Library databases to September 2020. The formulated population, intervention, comparison, outcome (PICO) question was “Is there a correlation of the proximal contact loss between implant-supported prostheses and the adjacent natural tooth?” A single-arm meta-analysis of proportion was performed to evaluate the cumulative prevalence of survival and complication rates.
This review included 10 studies, half of which presented proximal contact loss rates higher than 50%. In the general analysis, the open proximal contact showed a cumulative proportion of 41% (confidence interval: 30% to 53%; heterogeneity: I2=98%; t2=0.578; P<.01). From the subanalysis, the mesial contact (47%; confidence interval: 32% to 62%; heterogeneity: I2= 96%; t2=0.657; P<.01) and the mandibular arch (41%; confidence interval: 30% to 52%; heterogeneity: I2=92%; t2=0.302; P<.01) were found to have higher prevalence.
The prevalence of proximal contact loss was high, occurring more frequently with the mesial contact and in the mandibular arch. Significant differences were not found in relation to sex or between the posterior and anterior regions.
Most land surface models (LSMs), i.e. the land components of Earth system models
(ESMs), include representation of nitrogen (N) limitation on ecosystem
productivity. However, only a few of these ...models have incorporated phosphorus
(P) cycling. In tropical ecosystems, this is likely to be important as N
tends to be abundant, whereas the availability of rock-derived elements, such as
P, can be very low. Thus, without a representation of P cycling, tropical
forest response in areas such as Amazonia to rising atmospheric CO2
conditions remain highly uncertain. In this study, we introduced P dynamics
and its interactions with the N and carbon (C) cycles into the Joint UK Land
Environment Simulator (JULES). The new model (JULES-CNP) includes the
representation of P stocks in vegetation and soil pools, as well as key
processes controlling fluxes between these pools. We develop and evaluate
JULES-CNP using in situ data collected at a low-fertility site in the
central Amazon, with a soil P content representative of 60 % of soils
across the Amazon basin, to parameterize, calibrate, and evaluate JULES-CNP.
Novel soil and plant P pool observations are used for parameterization and
calibration, and the model is evaluated against C fluxes and stocks and
those soil P pools not used for parameterization or calibration. We then
evaluate the model at additional P-limited test sites across the Amazon and in
Panama and Hawaii, showing a significant improvement over the C- and CN-only
versions of the model. The model is then applied under elevated
CO2 (600 ppm) at our study site in the central Amazon to quantify the impact
of P limitation on CO2 fertilization. We compare our results against the
current state-of-the-art CNP models using the same methodology that was used
in the AmazonFACE model intercomparison study. The model is able to
reproduce the observed plant and soil P pools and fluxes used for evaluation
under ambient CO2. We estimate P to limit net primary productivity
(NPP) by 24 % under current CO2 and by 46 % under elevated
CO2. Under elevated CO2, biomass in simulations accounting for CNP
increase by 10 % relative to contemporary CO2 conditions, although it
is 5 % lower compared to CN- and C-only simulations. Our results
highlight the potential for high P limitation and therefore lower CO2 fertilization capacity in the Amazon rainforest with low-fertility soils.
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•A new series of fluorescent dyes of 1,2,3-triazole tail hybrid system is studied.•Compounds exhibit photophysical properties in solution and in the solid-state.•Fluorescence quantum ...yields and Stokes Shifts depend on the solvent polarity.•Time-resolved fluorescence shows variation according to the solvent polarity.•New possible fluorescent probes for small amounts of acid or protic species.
A four-step reaction method to synthesize a new series of 1-benzyl-4-((2-(1,5-diaryl-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)methyl)-1H-1,2,3-triazoles (5) and their photophysical and electrochemical evaluation is reported herein. The synthetic method comprises: (i) Michael condensation between 2-hydroxy-acetophenone and aryl aldehydes to obtain chalcones, (ii) a 3 + 2 cyclocondensation reaction involving chalcones and phenylhydrazine to reach the 2-pyrazolines (1), (iii) an O-alkylation reaction of 1 with propargyl bromide (2) to give O-propargylated 2-pyrazolines 3, and (iv) standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) involving benzyl azide (4) and 2-pyrazolines 3 to furnish the desired triazole series (5) as a new hybrid polycyclic system at total yields of up to 51%. Steady-state fluorescence emission exhibited a band in the blue region when excited at the least energetic transition of each compound, with varying values of fluorescence quantum yields (Φf) and Stokes Shift (SS), according to solvent polarity. In the solid state, the compounds showed similar behavior to the study of the absorption and emissive properties in solution. TD-DFT calculations revealed that all compounds had delocalized electron density along the pyrazoline unit and were not influenced by the attached substituent or change in solvent polarity. In addition, electrochemical and DPPH antioxidant analyses were performed.
Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, ...low statistical power precluded definitive answers.
We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT mITT analysis). This trial was registered at ClinicalTrials.gov, NCT04466540.
From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 6·4% and 57/683 8·3%, RR 0·77 95% CI 0·52–1·12, respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 9·0% and 55/471 11·7% events, RR 0·77 95% CI 0·53–1·12), respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 5·6%, and 88/1186 7·4%; RR 0·77 95% CI 0·57–1·04).
In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting.
COALITION COVID-19 Brazil and EMS.
