Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity. In particular, 32 exhibits an in vitro EC50 value of 0.5 µM against Trypanosoma brucei rhodesiense, and analogues 29, 30 and 33 show antitrypanosomal activities in the <1 µM range. We have demonstrated that substituted 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidines present promising antitrypanosomal hit molecules with potential for further preclinical development.

NMR spectral analysis of strongly second-order 6-, 8-, 9- and 10- spin-systems (1 H─19 F, 19 F─19 F, and 13 C─19 F) in perfluorotoluyl- and tetrafluoro-pyridyl-aromatics using the lineshape method ANATOLIA.

A simple to use nuclear magnetic resonance analysis method has been tested on complex 1 H, 19 F, and 13 C multiplets. This open-source line-shape analysis method analysis of total lineshape (ANATOLIA)1 provides some significant advantages over traditional assign-iterate methods of NMR spectral analysis by avoiding false minima and progressing optimisation to the global minimum. The target molecules are 1-perfluorotol-4-yl-2-perfluorotol-4-yl-oxymethyl-1H-benzimidazole (molecule-I) and 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-yl-thio-1H-benzimidazole (molecule-II) which were produced as part of a family of fluorinated drug scaffolds prepared for anticancer and antiparasitic screening. Spectra display significant second-order effects with 1 H Δδ = 3.68 and 4.67 Hz for the aromatic hydrogen "triplets", with 19 F 4 JAA' , 4 JBB' , 4 JXX' , and 4 JYY' coupling constants range from +4.8 to -14.0 Hz and for 13 C-isotopomers 19 F Δδ of up to 111.56 Hz. A spin-system of six coupling nuclei (Ha Hb Hc Hd FY FY' ) was analysed in 12 s, a spin-system of nine coupling fluorine nuclei (AA'BB'CCC-YY') was analysed within 2 min, and 10 coupling nuclei (XX'YY'ZZZ-BB'-Hd ) was optimised in 6 min using a laptop computer. ANATOLIA was also robust enough to be able to yield accurate spectral values from inaccurate input values. In both compounds, a fluorine-fluorine coupling constant was identified between the two fluoro-aromatic rings (FBB' and FYY' ) of +4.05 and +4.67 Hz and attributed to a through-space interaction. Ab initio structure optimisations and coupling constant calculations provided useful input data for spectral analysis. A modern 19 F nuclear magnetic resonance spectrum of perfluorotoluene (octafluorotoluene) and analysis from 1975 was used as a test data set to assess ANATOLIA.

3D printed fluidics with embedded analytic functionality for automated reaction optimisation.

Additive manufacturing or '3D printing' is being developed as a novel manufacturing process for the production of bespoke micro- and milliscale fluidic devices. When coupled with online monitoring and optimisation software, this offers an advanced, customised method for performing automated chemical synthesis. This paper reports the use of two additive manufacturing processes, stereolithography and selective laser melting, to create multifunctional fluidic devices with embedded reaction monitoring capability. The selectively laser melted parts are the first published examples of multifunctional 3D printed metal fluidic devices. These devices allow high temperature and pressure chemistry to be performed in solvent systems destructive to the majority of devices manufactured via stereolithography, polymer jetting and fused deposition modelling processes previously utilised for this application. These devices were integrated with commercially available flow chemistry, chromatographic and spectroscopic analysis equipment, allowing automated online and inline optimisation of the reaction medium. This set-up allowed the optimisation of two reactions, a ketone functional group interconversion and a fused polycyclic heterocycle formation, via spectroscopic and chromatographic analysis.

Nutritional content of fresh and canned peaches.

BACKGROUND: The objective of this study was to assess whether canned peaches could deliver nutrient levels comparable to fresh peaches. Fresh freestone peaches, fresh cling peaches and canned cling peaches were analyzed for vitamins A, C and E, folate, antioxidants, total phenolics and total carotenoids to assess how these nutrients were affected by the canning process and whether storage further changed these components. RESULTS: The vitamins and phytochemicals measured in this study were found to be present in canned cling peaches versus fresh freestone at statistically significantly higher levels (vitamin C, antioxidants and folate); higher but not statistically different levels (vitamin A); or lower, but not statistically different levels (vitamin E, total phenolics and total carotenoids). There were no statistically significant changes in nutrient content during storage for 3 months. CONCLUSIONS: The nutritional content of canned peaches has been shown in this study to be comparable to that of fresh peaches. There were no statistically significant decreases in those nutritional parameters measured in this study between fresh freestone peaches and canned cling peaches. Vitamins A and E along with total carotenoids decrease immediately upon processing, but appear to stabilize after the processing step, showing minimal additional changes upon storage for 3 months. This study shows that canned peaches can provide comparable nutrient levels to the consumer as fresh peaches, meaning that consumers can enjoy peaches year round without worrying about loss of nutrients in their diet.

Synthesis of fluorinated fused benzofurans and benzothiophenes: Smiles-type rearrangement and cyclisation of perfluoro(het)aryl ethers and sulfides.

Lithium-bromine exchange in 2-bromophenyl perfluoroaryl ethers or sulfides affords fused fluorinated benzofurans or benzothiophenes respectively by S(N)Ar substitution of the adjacent fluorine in the perfluoroaryl substituent. The structures of the new compounds were confirmed by NMR spectroscopy and single crystal X-ray diffraction analysis. In the case of 2-bromophenyl tetrafluoropyrid-4-yl ether, lithiation promoted a Smiles-type rearrangement which led to formation of 4-(2-hydroxyphenyl)tetrafluoropyridine, for which the structure was confirmed by X-ray crystallography.

The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC50 value of 0.38 µM and a promising off-target ADME-Tox profile in vitro. In silico molecular target investigations showed rhodesain to be a putative candidate, supported by STD and WaterLOGSY NMR experiments, however, in vitro evaluation of compound 13 against rhodesain exhibited low experimental inhibition. Therefore, our reported library of drug-like pyrimidines present promising scaffolds for further antikinetoplastid drug development for both phenotypic and target-based drug discovery.

Methyl 2-methyl-4-(oxiran-2-ylmeth-oxy)-2H-1,2-benzothia-zine-3-carboxyl-ate 1,1-dioxide.

In the title compound, C(14)H(15)NO(6)S, the thia-zine ring adopts a distorted half-chair conformation. The structure displays several cooperative weak inter-molecular C-H⋯O hydrogen-bonding inter-actions, giving rise to a two-dimensional sheet packing motif. The CH(2) group in the meth-oxy linker to the oxirane ring, and the CH group in that ring, exhibit twofold positional disorder. The three-membered oxirane ring is twisted approximately perpendicular with respect to thia-zine ring (dihedral angle = 60/86° for the major/minor disorder components). 1,2-Benzothia-zines of this kind have a wide range of biological activities and are mainly used as medicines in the treatment of inflammation and rheumatoid arthritis.

Synthesis, characterization and antibacterial activity of azomethine derivatives derived from 2-formylphenoxyacetic acid.

A series of eight new azomethine derivatives were synthesized by reacting 2-formylphenoxyacetic acid with aromatic amines. The chemical structures of these compounds were confirmed by means of 1H-NMR, 13C-NMR, MS and elemental analysis. The compounds were assayed by the disc diffusion method for antibacterial against Staphylococcus aureus and Escherichia coli. Among the compounds tested, 2a, 2b, 2e, 2g and 2h exhibited good antibacterial activity, almost equal to that of Ciprofloxacin used as standard.

Unexpected ring expansion of an enantiopure imidazoline carbene ligand.

[reaction: see text] We report an unexpected ring expansion reaction of an enantiopure fenchone-derived imidazolinium salt during attempts to form copper complexes of the corresponding imidazoline carbene ligand. A N,N'-difenchyl piperazinone was formed in low yield together with the difenchyl-substituted five-membered urea.

Design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes.

Current treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 < 1 µM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.

Interest and attention in facial recognition.

When applied to facial recognition, the levels of processing paradigm has yielded consistent results: faces processed in deep conditions are recognized better than faces processed under shallow conditions. However, there are multiple explanations for this occurrence. The own-race advantage in facial recognition, the tendency to recognize faces from one's own race better than faces from another race, is also consistently shown but not clearly explained. This study was designed to test the hypothesis that the levels of processing findings in facial recognition are a result of interest and attention, not differences in processing. This hypothesis was tested for both own and other faces with 105 Caucasian general psychology students. Levels of processing was manipulated as a between-subjects variable; students were asked to answer one of four types of study questions, e.g., "deep" or "shallow" processing questions, while viewing the study faces. Students' recognition of a subset of previously presented Caucasian and African-American faces from a test-set with an equal number of distractor faces was tested. They indicated their interest in and attention to the task. The typical levels of processing effect was observed with better recognition performance in the deep conditions than in the shallow conditions for both own- and other-race faces. The typical own-race advantage was also observed regardless of level of processing condition. For both own- and other-race faces, level of processing explained a significant portion of the recognition variance above and beyond what was explained by interest in and attention to the task.

Genetic variation in adaptive traits and seed transfer zones for Pseudoroegneria spicata (bluebunch wheatgrass) in the northwestern United States.

A genecological approach was used to explore genetic variation in adaptive traits in Pseudoroegneria spicata, a key restoration grass, in the intermountain western United States. Common garden experiments were established at three contrasting sites with seedlings from two maternal parents from each of 114 populations along with five commercial releases commonly used in restoration. Traits associated with size, flowering phenology, and leaf width varied considerably among populations and were moderately correlated with the climates of the seed sources. Pseudoroegneria spicata populations from warm, arid source environments were smaller with earlier phenology and had relatively narrow leaves than those from mild climates with cool summers, warm winters, low seasonal temperature differentials, high precipitation, and low aridity. Later phenology was generally associated with populations from colder climates. Releases were larger and more fecund than most of the native ecotypes, but were similar to native populations near their source of origin. Differences among native populations associated with source climates that are logical for survival, growth, and reproduction indicate that genetic variation across the landscape is adaptive and should be considered during restoration. Results were used to delineate seed transfer zones and population movement guidelines to ensure adapted plant materials for restoration activities.

Mapping the global emergence of Batrachochytrium dendrobatidis, the amphibian chytrid fungus.

The rapid worldwide emergence of the amphibian pathogen Batrachochytrium dendrobatidis (Bd) is having a profound negative impact on biodiversity. However, global research efforts are fragmented and an overarching synthesis of global infection data is lacking. Here, we provide results from a community tool for the compilation of worldwide Bd presence and report on the analyses of data collated over a four-year period. Using this online database, we analysed: 1) spatial and taxonomic patterns of infection, including amphibian families that appear over- and under-infected; 2) relationships between Bd occurrence and declining amphibian species, including associations among Bd occurrence, species richness, and enigmatic population declines; and 3) patterns of environmental correlates with Bd, including climate metrics for all species combined and three families (Hylidae, Bufonidae, Ranidae) separately, at both a global scale and regional (U.S.A.) scale. These associations provide new insights for downscaled hypothesis testing. The pathogen has been detected in 52 of 82 countries in which sampling was reported, and it has been detected in 516 of 1240 (42%) amphibian species. We show that detected Bd infections are related to amphibian biodiversity and locations experiencing rapid enigmatic declines, supporting the hypothesis that greater complexity of amphibian communities increases the likelihood of emergence of infection and transmission of Bd. Using a global model including all sampled species, the odds of Bd detection decreased with increasing temperature range at a site. Further consideration of temperature range, rather than maximum or minimum temperatures, may provide new insights into Bd-host ecology. Whereas caution is necessary when interpreting such a broad global dataset, the use of our pathogen database is helping to inform studies of the epidemiology of Bd, as well as enabling regional, national, and international prioritization of conservation efforts. We provide recommendations for adaptive management to enhance the database utility and relevance.

Synthesis and antibacterial activity of bis[2-amino-4-phenyl-5-thiazolyl] disulfides.

Different dimeric disulfides, having the basic skeleton of bis[2-amino-4-phenyl-5-thiazolyl] disulfides were synthesized in a straightforward manner from acetophenones. 2-Amino-4-phenyl-1,3-thiazoles were prepared by the reaction of thiourea with substituted acetophenones in the presence of iodine which were then converted to the title compounds. All the compounds were subjected to preliminary evaluation for their biological activity against Gram positive and Gram negative bacteria. Some of the assayed compounds showed marked activity against Bacillus cereus and Pseudomonas aeruginosa.

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin.

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone , mackinazolinone , tryptanthrin , luotonin A and rutaecarpine were synthesised by radical cyclisation onto 3H-quinazolin-4-one.

Uncovering the structure of a memorist's superior "basic" memory capacity.

After extensive laboratory testing of the famous memorist Rajan, Thompson, Cowan, and Frieman (1993) proposed that he was innately endowed with a superior memory capacity for digits and letters and thus violated the hypothesis that exceptional memory fully reflects acquired "skilled memory." We successfully replicated the empirical phenomena that led them to their conclusions. From additional analyses and new experiments, we found support for an alternative hypothesis, namely that Rajan's superior memory for digits was mediated by learned encoding techniques that he acquired during nearly a thousand hours of practice memorizing the mathematical constant pi. Our paper describes a general experimental approach for studying the structure of exceptional memory and how Rajan's unique structure is consistent with the general theoretical framework of long-term working memory (Ericsson and Kintsch, 1995).

Desempenho cardíaco e resposta hemodinâmica sob açäo do isoproterenol e D-isosorbitol em portadores de miocardiopatia dilatada / Cardiac performance and hemodynamic response under the effect of isoproterenol and D-isosorbitol in patients with dilated cardiomyopathy

Os autores estudaram o desempenho cardíaco de 36 pacientes com miocardiopatia dilatada (MD) através de cateterismo e cineventriculografia esquerda, estabelecendo relaçäo com grupo normal. Foi verificado que o VSF é mais sensível e melhor que a FE como indicador da presença e grau da disfunçäo sitólica. Foram utilizados isoproterenol (IP) (18 pacientes) e D-isosorbitol (IS) (18 pacientes) na avaliaçäo da resposta hemodinâmica da MD. Verificaram-se respostas equivalentes com as duas substâncias tais como: 1 - diminuiçäo do VSF e da Pd2; 2 - aumento do VSE e da FE. Os índices de contratilidade do VE, no entanto, apresentaram respostas diferentes com as duas substâncias: 1 - com o IP houve aumento do pico da dp/dt e da dp/dt PI 45 mmHg; 2 - com o IS näo houve variaçäo. Os autores concluem que: 1 - O Isoproterenol ou drogas similares podem ser utilizados na sala de cateterismo cardíaco para avaliar a reserva contrátil do miocárdio; 2 - o D-isosorbital pode ser utilizado no tratamento ambulatorial da MD por melhorar a funçäo ventricular através de uma tendência à normalizaçäo de relaçäo pressäo-volume intracardíaca

Miocardiopatia hipertrófica apical / Apical hypertrophic cardiomyopathy

Os autores fizeram a revisäo de 4591 pacientes submetidos ao cateterismo cardíaco com cineangiocoronariografia e encontraram 246 (5,3%) portadores de miocardiopatias em geral. Destes, 45 (0,98% do geral e 18,3% do grupo) apresentavam Cardiomiopatia Hipertrófica (CH), sendo que os últimos 34 pacientes foram estudados por apresentarem a cineventriculografia simultânea no VD-VE em OAE a 60 graus (CS VD-VE). Os autores encontraram 3 grupos de CH: 1 - CH clássica: 19 pacientes (55,9%). 2 - CH apical )MHA): 9 pacientes (26,5%) 3 - CH mista (grupo 1 + grupo 2): 6 pacientes (17,6%). Os autores estudaram particularmente a Miocardiopatia Hipertrófica Apical (grupo 2), que apresentou aspectos clínicos, radiológicos, eletrocardiográficos, ecocardiográficos, hemodinâmicos e cineangiocardiográficos especiais. Os autores concluíram que: 1 - A MHA é um tipo de CH näo obstrutiva que necessita ser devidamente procurada para se fazer o diagnóstico. 2 - O diagnóstico pode ser feito através do ecocardiograma e da CS VD-VE. 3 - Os nossos dados do E.C.G. na MHA näo apresentaram aspectos que pudessem ser imputados como características da doença

Desempenho da funçäo ventricular na pericardite crónica constritiva / Performance of ventricular function in chronic constrictive pericarditis

Os autores avaliaram a funçäo ventricular em 13 pacientes com PCC através dos registros pressóricos intracardíacos e da cineangiocardiografia dos ventrículos direito e esquerdo, e fizeram comparaçäo com umgrupo considerado normal. O estudo do ventrículo direito mostrou: 1 - Diminuiçäo do VDF, VSE, FE e CpE; 2 - Aumento da Pd2. No estudo do ventrículo esquerdo, encontraram: 1 - Diminuiçäo do VSE, FE e CpE; 2 - Aumento da Pd2 e do VDF. Todos os parâmetros acima apresentaram significaçäo estatistica (P < 0,001): näo foi observada variaçäo do VSF do ventrículo direito e do VDF do ventrículo esquerdo (P >0,05). Os autores concluem que, além das alteraçöes referentes à restriçäo diastólica ventricular, foram encontrados achados compatíveis com disfunçäo sistólica biventricular na maioria dos pacientes estudados