Synthesis, Theoretical Study, and Anticonvulsant Evaluation of N-Arylenaminones.

N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted N-(4-R-phenyl)enaminones 3 a (R=NO2), 3 b (R=F), 3 c (R=H), and 3 d (R=OMe) with the goal of determining the influence of the substituents' electronic effects on tautomer stability and biological activity. These compounds were analyzed by means of Density Functional Theory calculations (DFT), to evaluate the relative stability of the possible tautomers. We found that the enaminone structure is the most stable with respect to the ketoimine and iminoenol forms. In addition, all four compounds display anticonvulsant activity, with 3 d being the one that mostly increased latency and mostly decreased the number of convulsions with respect to the control group. The suggested mechanism of action involves blockage of the voltage-dependent Na+ channels, considering that these molecules meet the structural characteristics needed to block the receptor, as is the case of the positive control molecules phenytoin (PHT) and valproic acid (VPA).

Structural Features of Diacyldodecaheterocycles with Pseudo-C2-Symmetry: Promising Stereoinductors for Divergent Synthesis of Chiral Alcohols.

Pseudo-C2-symmetric dodecaheterocyclic structures, which possess two acyl/aroyl groups disposed on either a cis- or trans-relative configuration, were prepared from the naturally occurring (-)-(1R)-myrtenal. Addition of Grignard reagents (RMgX) to the diastereoisomeric mixture of these compounds unexpectedly showed that nucleophilic additions to the two prochiral carbonyl centers gave the same stereochemical result in both cis/trans diastereoisomers, making unnecessary the separation of this mixture. Noticeably, both carbonyl groups showed different reactivity because one of them is attached to an acetalic carbon and the other to a thioacetalic carbon. Furthermore, addition of RMgX to the carbonyl attached to the former carbon takes place through the re face, while addition to the second one proceeds through the si face, thus affording the corresponding carbinols in a highly diastereoselective process. This structural feature allowed the sequential hydrolysis of both carbinols, yielding separately (R)- and (S)-1,2-diols after reduction with NaBH4. The mechanism of the asymmetric Grignard addition was explained by density functional theory calculations. This approach contributes to the development of the divergent synthesis of structurally and/or configurationally different chiral molecules.

SANT esplénico: tumoración infrecuente / Splenic SANT: Uncommon tumor

La Transformación Nodular Angiomatoide Esclerosante del bazo (SANT) es una patología poco común, que afecta a vasos sanguíneos de forma benigna con esclerosis extensa de la pulpa roja. Paciente masculino, 24 años, consulta en centro privado (Paraguay) por un cuadro de 7 meses de evolución de disnea paroxística y sudoración fría. Al examen físico y laboratorial sin datos de valor. La ecografía abdominal demuestra bazo con parénquima inhomogéneo con imagen pseudonodular 48x41 mm de diámetro, la RMN con contraste confirma hallazgo por nódulo irregular, con realce que predomina en la periferia de la fase arterial, con aspecto radiado y relleno centrípeto en fase venosa y tardía, la histopatología confirma diagnóstico clínico-imagenológico de SANT. Esta tumoración es frecuente entre los 45 a 48 años, manifestada con esplenomegalia, poca sintomatología, llama la atención la presentación del caso que se contrapone con la bibliografía. Considerando la falta de métodos auxiliares para descartar la malignidad, se aplica esplenectomía como conducta terapéutica.

Nodular Angiomatoid Sclerosing Transformation of the Spleen (SANT) is a rare pathology, which affects blood vessels benignly with extensive sclerosis of the red pulp. A 24-year-old man consulted in a private center (Paraguay) for a 7-month course of paroxysmal dyspnea and cold sweating. Physical examination and laboratory evaluation show no abnormalities. Abdominal ultrasound shows a spleen with heterogeneous parenchyma and a pseudonodular image that is 48mm x 41mm in diameter. Contrasted MRI confirms the finding of an irregular nodule, with enhancement that predominates in the periphery of the arterial phase, with radiated appearance and centripetal filling in venous and late phase. Histopathology confirms diagnosis of SANT. SANT is frequent between 45 and 48 years of age, manifested with splenomegaly and scarce symptomatology. The presentation of this case differs with literature. Considering the lack of auxiliary methods to rule out malignancy, a splenectomy is performed.

Miniature Wide-Band Noise-Canceling CMOS LNA.

In this paper, a wide-band noise-canceling (NC) current conveyor (CC)-based CMOS low-noise amplifier (LNA) is presented. The circuit employs a CC-based approach to obtain wide-band input matching without the need for bulky inductances, allowing broadband performance with a very small area used. The NC technique is applied by subtracting the input transistor's noise contribution to the output and achieves a noise figure (NF) reduction from 4.8 dB to 3.2 dB. The NC LNA is implemented in a UMC 65-nm CMOS process and occupies an area of only 160 × 80 µm2. It achieves a stable frequency response from 0 to 6.2 GHz, a maximum gain of 15.3 dB, an input return loss (S11) < −10 dB, and a remarkable IIP3 of 7.6 dBm, while consuming 18.6 mW from a ±1.2 V DC supply. Comparisons with similar works prove the effectiveness of this new implementation, showing that the circuit obtains a noteworthy performance trade-off.

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products.

A representative number of decalin and hydrindane derivatives 2a-l were prepared in 11-91% yield by means of a cascade reaction of cyclohexanone/cyclopentanone enolates and methyl acrylate through a Michael-Michael ring closure (MIMIRC) process. The relative stereochemistry of the four stereogenic centers formed in all products was determined by analyzing the vicinal coupling constants from the 1H NMR and X-ray crystallography. Such a stereochemical outcome was corroborated by conformational analysis supported by DFT calculations and simulating the 1H NMR spectra of representative products. All products showed the same relative stereochemistry at C-1 and C-8a, while at C-3 and bridgehead carbon C-4a, configurational changes were observed. The present results provide some insights about the scope and limitations of the triple cascade reaction between cycloalkanone enolates with methyl acrylate. This synthetic protocol is still a simple and very practical alternative to generate decalin and hydrindane derivatives with great structural diversity.

Pulmonary Thromboendarterectomy in Klinefelter Syndrome. Literature Review.

Klinefelter syndrome  is a form of male hypogonadism due to testicular sclerohyalinosis with atrophy and azoospermia, which is the most common cause of male infertility. The syndrome is usually accompanied by metabolic, morphological, and neurobehavioral manifestations; Venous thromboembolic diseases such as deep vein thrombosis and pulmonary embolism. The existence of chronic thromboembolic pulmonary hypertension in patients with Klinefelter syndrome   is scarce in the literature. We present the imaging and genetic analysis of a 37 -year-old male with a history of deep vein thrombosis who was admitted for exertional dyspnea.

Voltage-Dependent Sodium Channel Blocker Anticonvulsants: An Approach to the Structure-Activity Relationship.

BACKGROUND: Anticonvulsants are drugs used in the treatment of seizures; their pharmacology includes promoters of brain inhibition and inhibitors of brain activity. Of the latter, voltagedependent sodium channel blockers (VGSCB) are the most widely used in therapeutics. OBJECTIVE: The study aimed at proposing the structural requirements of VGSC blockers through a quantitative structure-activity relationship analysis of drugs with proven activity. METHODS: IC50 values of anticonvulsant drugs on VGSCs were considered under similar experimental conditions; some physicochemical properties of the molecules that were correlated with their biological activity were determined in silico. RESULTS: Relationships were observed between the dipole moment, pKa, EHOMO, and MR with the biological activity, which infers that between greater polarity and basicity of the drugs, their activity as blockers will increase. Subsequently, the structural subclassification of the drugs was carried out, based on the urea derivation, the groups of which were: Group 1 (direct and bioisostere derivatives) and Group 2 (homologue and vinylogue derivatives of urea). CONCLUSION: The biological activity depends on the polarity, basicity, and electronic density of the drugs. The derivation of urea is essential, which is present in its original substituted form or a bioisosteric form. Urea can be in the form of a homologue or a vinylogue at the ends of the molecule. Aromatic substitution to the urea portion is necessary.

Effect of Gold Electronic State on the Catalytic Performance of Nano Gold Catalysts in n-Octanol Oxidation.

This study aims to identify the role of the various electronic states of gold in the catalytic behavior of Au/MxOy/TiO2 (where MxOy are Fe2O3 or MgO) for the liquid phase oxidation of n-octanol, under mild conditions. For this purpose, Au/MxOy/TiO2 catalysts were prepared by deposition-precipitation with urea, varying the gold content (0.5 or 4 wt.%) and pretreatment conditions (H2 or O2), and characterized by low temperature nitrogen adsorption-desorption, X-ray powder diffraction (XRD), energy dispersive spectroscopy (EDX), scanning transmission electron microscopy-high angle annular dark field (STEM HAADF), diffuse reflectance Fourier transform infrared (DRIFT) spectroscopy of CO adsorption, temperature-programmable desorption (TPD) of ammonia and carbon dioxide, and X-ray photoelectron spectroscopy (XPS). Three states of gold were identified on the surface of the catalysts, Au0, Au1+ and Au3+, and their ratio determined the catalysts performance. Based on a comparison of catalytic and spectroscopic results, it may be concluded that Au+ was the active site state, while Au0 had negative effect, due to a partial blocking of Au0 by solvent. Au3+ also inhibited the oxidation process, due to the strong adsorption of the solvent and/or water formed during the reaction. Density functional theory (DFT) simulations confirmed these suggestions. The dependence of selectivity on the ratio of Brønsted acid centers to Brønsted basic centers was revealed.

Enantiopure 4-oxazolin-2-ones and 4-methylene-2-oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles.

Enantiopure 3-((R)- and 3-((S)-1-phenylethyl)-4-oxazoline-2-ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N-(R)- or N-(S)-1-phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4- and 5-positions of the 4-oxazolin-2-one ring through thermal and MW-promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six-membered carbo- and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4-methylene-2-oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero-Diels-Alder cycloaddition.

Foot-and-mouth disease vaccines: recent updates and future perspectives.

Foot-and-mouth disease (FMD) is a major worldwide viral disease in animals, affecting the national and international trade of livestock and animal products and leading to high economic losses and social consequences. Effective control measures of FMD involve prevention through vaccination with inactivated vaccines. These inactivated vaccines, unfortunately, require short-term protection and cold-chain and high-containment facilities. Major advances and pursuit of hot topics in vaccinology and vectorology are ongoing, involving peptide vaccines, DNA vaccines, live vector vaccines, and novel attenuated vaccines. DIVA capability and marker vaccines are very important in differentiating infected animals from vaccinated animals. This review focuses on updating the research progress of these novel vaccines, summarizing their merits and including ideas for improvement.

Synthesis of exo-Imidazolidin-2-one Dienes, Their Isomerization, and Selectivity in Diels-Alder Cycloadditions.

An efficient and alternative synthesis of exo-imidazolidin-2-one dienes is described. A condensation reaction was carried out with bis-imino derivatives, diacetyl, and triphosgene, affording symmetrically N, N-disubstituted dienes. The use of alkyl methyl α-diketones led to the formation of nonsymmetrical dienes, which underwent isomerization to provide more stable inner-outer-ring dienes under Lewis acid conditions. Evaluation was made of the reactivity as well as regio- and stereoselectivity of these dienes in Diels-Alder reactions. They proved to be highly reactive and selective. DFT calculations of the transition states accounted for their behavior.

Molecular biological tools applied for identification of mastitis causing pathogens.

The molecular diagnostic tools became the gold standard of mastitis diagnosis in the last few years. They enable rapid, qualitative, quantitative and large scale diagnosis. In addition to their role in diagnosis, they can identify pathogens at the subspecies level which is necessary for the epidemiological studies. They are increasingly used in mastitis control programs through identification of suitable candidates for vaccine production and through the selection of mastitis resistant cattle breeds. The present molecular techniques are continuously improved and new techniques are developed in order to provide higher sensitivity and specificity and to minimize the costs. The present work aims to provide an overview of the modern molecular tools, discuss why they replaced the traditional tools and became the new gold standard in mastitis diagnosis through comparing both traditional and molecular tools, explore the prospective of the molecular diagnostic techniques in mastitis diagnosis and control and to explore new horizons of using molecular assays in near future.

Heterogeneity of Genetic Damage in Cervical Nuclei and Lymphocytes in Women with Different Levels of Dysplasia and Cancer-Associated Risk Factors.

The comet assay can be used to assess genetic damage, but heterogeneity in the length of the tails is frequently observed. The aims of this study were to evaluate genetic damage and heterogeneity in the cervical nuclei and lymphocytes from patients with different levels of dysplasia and to determine the risk factors associated with the development of cervical cancer. The study included 97 females who presented with different levels of dysplasia. A comet assay was performed in peripheral blood lymphocytes and cervical epithelial cells. Significant genetic damage (P ≤ 0.05) was observed only in patients diagnosed with nuclei cervical from dysplasia III (NCDIII) and lymphocytes from dysplasia I (LDI). However, the standard deviations of the tail lengths in the cervical nuclei and lymphocytes from patients with dysplasia I were significantly different (P ≤ 0.0001) from the standard deviations of the tail lengths in the nuclei cervical and lymphocytes from patients with DII and DIII (NCDII, NCDIII and LDII, LDIII), indicating a high heterogeneity in tail length. Results suggest that genetic damage could be widely present but only manifested as increased tail length in certain cell populations. This heterogeneity could obscure the statistical significance of the genetic damage.

Use of the harmonic mean to the determination of dissociation constants of stereoisomeric mixtures of biologically active compounds.

Herein we introduce the derivation of a mathematical expression to evaluate the dissociation constant of a mixture of stereoisomers in equal amounts (KdMIX), when the corresponding dissociation constants (Kd) or medium response (MR50) of the pure stereoisomers are known; the final equation takes the form of the harmonic mean. In order to validate the equation, we carried out a bibliographic search of experimental data of enantiomeric molecules with biological activity, considering the Kd's or MR50's of the isolated enantiomers as well as that of the racemate. The comparisons between the experimental dissociation constants of the mixtures (KdEXP or MR50EXP) and the calculated values (KdMIX or MR50MIX) were consistent; the similarity between these values is supported through statistical analyses of group comparison and simple linear correlation. The equation we obtained, which corresponds to the harmonic mean, was used to predict the values of KdMIX (or MR50MIX) or Kd (or MR50) in systems when only two of the experimental values are known: either the dissociation constants of both enantiomers or the Kd (or MR50) of one of the enantiomers and dissociation constant of the racemate.

A concise total synthesis of the natural carbazole clauraila A.

A short and efficient total synthesis of naturally occurring carbazole clauraila A (1) is described. The approach is designed on the basis of the key regioselective Diels-Alder reaction of the properly substituted exo-2-oxazolidinone diene 3 with acrolein (4) to give the corresponding adduct 2. The latter is converted to functionalised diarylamine 8, which is cyclised to the desired carbazole 1 through a Pd-promoted or -catalysed double C-H bond activation process in a fairly good overall yield.

Intramolecular H-bonding interaction in angular 3-π-EWG substituted imidazo[1,2-a]pyridines contributes to conformational preference.

BACKGROUND: The proton at position 5 of imidazo[1,2-a]pyridines substituted with an angular electron withdrawing group (EWG) at position 3, shows an unusual downfield chemical shift, which is usually explained in terms of a peri effect. However usage of this term is sometimes confusing. In this investigation, it is proposed that the aforementioned shift is in fact a combination of several factors: Anisotropy, long-distance mesomerism and an attractive intramolecular interaction of the electrostatic hydrogen bond type. RESULTS: Theoretical calculations were performed aimed to obtain evidence of the existence of an intramolecular non-bonding interaction between H-5 and the oxygen atom of the EWG. Results derived from conformational and vibrational analysis at the DFT B3LYP/6-311++G(d,p) level of theory, the determination of Bond Critical Points derived from AIM theory, and the measurement of some geometrical parameters, support the hypothesis that the higher stability of the prevailing conformation in these molecules (that in which the oxygen of the EWG is oriented towards H-5) has its origin in an intramolecular interaction. CONCLUSION: Computational calculations predicted correctly the conformational preferences in angular 3-π-EWG-substituted imidazo[1,2-a]pyridines. The existence of an electrostatic hydrogen bond between H-5 and the oxygen atom of the π-EWG was supported by several parameters, including X-ray crystallography. The existence of such structural array evidently impacts the H-5 chemical shift.

Efficient preparation of α-ketoacetals.

The Weinreb amides 2a,b were prepared from the α,α-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded α-ketoacetals 3a-j in 70-99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol.

Diastereoselective preparation of (R)- and (S)-2-methoxy-2-phenylpent-3-ynoic acids and their use as reliable chiral derivatizing agents.

Benzoyl-S,O-acetals 1a and 1b were used as chiral auxiliaries to achieve the diastereoselective preparation of both enantiomers of 2-methoxy-2-phenylpent-3-ynoic acids (MPPAs). The latter were condensed with several chiral secondary alcohols and some primary amines to evaluate their potential as chiral derivatizing agents (CDAs). The (1)H NMR spectra of the corresponding esters and amides showed strong consistency with the absolute configuration of the carbinol and amine moieties, whose observed ΔδL(1) and ΔδL(2) values were in the ranges of 0.1-0.4 and 0.02-0.12 ppm, respectively.

Resistencia a penicilina G y oxacilina, de cepas de Staphylococcus aureus aisladas de mastitis bovina subclínica / Penicillin G and oxacillin resistance in Staphylococcus aureus strains isolated from bovine subclinical mastitis

Sixty-eigth out of 530 different S. aureus field strains isolated from subclinical cases of bovine mastitis from Germany (n = 26), Indonesia (n = 16), Mexico (n = 16) and Brazil (n = 10), respectively, were selected to be studied in the present work. The strains were tested phenotypically as well as genotypically for the presence of penicillin G- and oxacillin-resistance. For the primary phenotypical species identification of the 530 S. aureus strains, plasmacoagulase-test and Api 32 Staph system was applied. This was confirmed by molecular detection of the S. aureus specific genes encoding 23 S rRNA, thermostable nuclease (nuc), clumping factor (clfA), coagulase (coa) and protein A region Xr (spa). The selection of the 68 strains was carried out by the random selection of one strain per herd; additionally, only strains with different macrorestriction profiles were included here. Genotypic resistance to semisynthetic penicillins (methicillin/oxacillin) and penicillin G was studied through the identification of mecA- and blaZ-genes, respectively. The mecA gene was detected in only one S. aureus isolate from Brazil, which was not phenotypically resistant against methcillin, as shown by the use of standard disc diffusion method, BBL-Chromoagar and MIC-determination by Vitek II. In contrast penicillin-resistance of strains based on the presence of the blaZ-gene could be observed in 50 (73.5%) of the investigated strains. However, only 40 (58.8%) of these 50 blaZ-positive strains were phenotypically penicillin-resistant. According to the presented data, resistance to semisynthetic penicillins in S. aureus field strains seems to be not a major problem in dairy herds of the investigated countries despite the long-term use of these antibiotics in the field.

De 530 diferentes cepas de S. aureus aisladas de casos de mastitis subclínica bovina, se seleccionaron 68 cepas de S. aureus procedentes de Alemania (n = 26), Indonesia (n = 16), México (n = 16) y Brasil (n = 10), para estudiarlas en la presente investigación. Las cepas fueron analizadas fenotípica y genotípicamente para observar su resistencia a penicilina G y oxacilina. Para una identificación inicial se utilizó el sistema Api 32 Staph y la prueba de coagulasa. El resultado se confirmó por la detección molecular de los genes específicos de S. aureus 23S rRNA, nucleasa termoestable (nuc), factor aglutinante (clfA), coagulasa (coa) y la proteína A (spa) región Xr. La selección primaria de las cepas sospechosas se hizo al azar, seleccionando una cepa por hato; además sólo se incluyeron en el estudio cepas con diferentes perfiles de macrorrestricción. La resistencia genotípica a meticilina y penicilina se estudió mediante la identificación de los genes mecA y blaZ, respectivamente. El gen mecA fue detectado sólo en un aislamiento de S. aureus de Brasil y no fue resistente fenotípicamente a la meticilina, lo cual se demostró mediante los métodos de difusión estándar en discos, el uso del Chromoagar-BBL y la determinación de la concentración mínima inhibitoria (MIC, por sus siglas en inglés) por Vitek II. La detección genotípica de la resistencia de las cepas a la penicilina se basó en la detección del gen blaZ; y se observó en 50 cepas investigadas (73.5%). Sin embargo, sólo 40 cepas (58.8%) fueron fenotípicamente resistentes a la penicilina. Los resultados obtenidos muestran que la resistencia de las cepas aisladas de campo S. aureus a las penicilinas semisintéticas, actualmente no es un problema importante en las vacas lecheras, a pesar del uso extensivo de esas sustancias antibióticas en el campo en los países investigados.