Syntheses of novel 4-azapaullones as potential antitrypanosomal agents

Bestimmte Paullone hemmen die Trypanothionsynthetase, ein für Krankheitserreger aus den Familien der Trypanosomen und Leishmanien essentielles Enzym. Paullone sind auch Inhibitoren humaner Kinasen, was Ursache für unerwünschte toxische Wirkungen sein könnte. Seit dem Jahr 2004 ist bekannt, dass das Grundgerüst der 4-Azapaullone im Gegensatz zu den 4-carbanalogen Verbindungen keine inhibitorische Aktivität gegenüber den CDK1-, CDK5- und den GSK-3-Proteinkinasen aufweist. Das Ziel dieser Arbeit bestand daher in der Synthese neuer 4-Azapaullone als potentiell antitrypanosomale Wirkstoffe unter Verbesserung des Toxizitätsprofils. Des Weiteren zeigen Paullon-Chalkon-Hybride gute antileishmanielle und antitrypanosomale Effekte. Die Kombination der Strukturmerkmale der 4-Azapaullone und der Paullon-Chalkon-Hybride stellte einen Schwerpunkt dieser Arbeit dar. 4-Azapaullon-Chalkon-Hybride wurden synthetisiert und biologisch evaluiert. Ein 4-Azapaullon-Chalkon-Hybrid stellt dabei die potenteste Verbindung mit einem EC50-Wert von 180 nM dar und wirkt nicht zytotoxischen auf primäre Mausmakrophagen. Es wurden auch 4-Azapaullon-Zimtsäureamid-Hybride hergestellt, die ebenfalls auf ihre antitrypanosomalen Aktivitäten untersucht. Bei dieser Substanzklasse weist wieder eine in 11-Position substituierte Verbindung die beste Wachstumsinhibition an T. b. brucei-Parasiten auf. Mit einem EC50-Wert von 120 nM ist ein Vertreter dieser Klasse die aktivste Substanz, die im Rahmen dieser Arbeit entstand. Diese weist gleichfalls keine Zytotoxizität an Mausmakrophagen auf. Die Inhibition des potentiellen Targets, der Trypanothionsynthetase (TryS), konnte anhand von Enzymaktivitätsmessungen mit den synthetisierten Verbindungen nicht bestätigt werden. Die Substanzen weisen keine signifikante Verminderung der TryS-Aktivität auf. Bisher konnte kein adressiertes Target identifiziert werden, welches zur Wachstumsinhibition der T. b. brucei-Parasiten durch die entsprechenden Verbindungen führt.Certain paullones inhibit the trypanothione synthetase, which is an essential enzyme of protozoan parasites of the genus Trypanosoma and Leishmania. However, paullones also inhibit human protein kinases. This biologival activity may cause undesirable toxic side effects. In 2004 it was reported that 4-azapaullones do not inhibit CDK1, CDK5 and GSK-3 protein kinases in contrast to the 4-carbanaloga. The aim of the study reported here was the synthesis of novel 4-azapaullones as potential antitrypanosomal drugs with an improvement of the toxic profile. Furthermore paullone-chalcone-hybrides have been described as antileishmanial and antitrypanosomal agents. The combination of the structural features of the 4-azapaullones and the paullone-chalcone-hybrides represented a focus of this work. The 4-azapaullone-chalcone-hybrides were synthesized and evaluated biologically. A 4-azapaullone-chalcone-hybride is one of the most potent substances with an EC50 value of 180 nM showing no cytotoxic effects on primary mouse macrophages. By retaining the alpha,beta-unsaturated carbonyl function within the sidechain, 4-azapaullone-cinnamamide-hybrides were synthesized and evaluated biologically, as well. Among this class of substances a derivative which is likewise substituted in 11-position shows considerable growth inhibition of T. b. brucei parasites. With an EC50 value of 120 nM one substance of this class is the most potent substance synthesized in this work, exhibiting no cytotoxicity towards murine macrophages. The inhibition of the potential target, the trypanothione synthetase (TryS), could not be confirmed by enzyme activity measurements with the synthesized compounds. The substances exhibit no significant reduction of the TryS activity. Until now no target has been identified, which could explain the T. b. brucei growth inhibition of the compounds

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Brands in the pull of new mobility : to what extend can German car manufacturers adapt and reposition themselves to the trend of new mobility by means of holistic brand management?

Diese Bachelorarbeit befasst sich mit der Forschungsfrage, inwieweit sich die deutschen Automobilhersteller mittels einer ganzheitlichen Markenführung an den Megatrend Mobilität anpassen und neu positionieren können. Nach der Aufbereitung des aktuellen Forschungsstandes stellt die empirische Forschung den bereits ansatzweise erreichten Imagewandel von BMW durch eine quantitative Online-Befragung heraus. Dabei wird die Schwierigkeit einer selbstähnlichen Weiterentwicklung des Markenkerns im Zuge einer Neupositionierung deutlich. Weiterführend wird die Strategie von Experten aus dem Bereich der strategischen Markenführung eingeordnet und bewertet. Im Zuge dessen ergibt sich die Bedeutung des Markenkerns als einer der zentralen Faktoren in der Bestimmung des Ausmaßes der Neupositionierung. Die Auswertung des Interviews basiert auf einer qualitativen Inhaltsanalyse nach Mayring und ermöglicht es, im Abschluss zentrale Handlungsempfehlungen für die Markenführung in der deutschen Automobilbranche zu geben

Insight into the Structure and Properties of Novel Imidazole-Based Salts of Salicylic Acid

The preparation of new active pharmaceutical ingredient (API) multicomponent crystal forms, especially co-crystals and salts, is being considered as a reliable strategy to improve API solubility and bioavailability. In this study, three novel imidazole-based salts of the poorly water-soluble salicylic acid (SA) are reported exhibiting a remarkable improvement in solubility and dissolution rate properties. All structures were solved by powder X-ray diffraction. Multiple complementary techniques were used to solve co-crystal/salt ambiguities: density functional theory calculations, Raman and 1H/13C solid-state NMR spectroscopies. In all molecular salts, the crystal packing interactions are based on a common charged assisted +N-H(SA) ⋯ O−(co-former) hydrogen bond interaction. The presence of an extra methyl group in different positions of the co-former, induced different supramolecular arrangements, yielding salts with different physicochemical properties. All salts present much higher solubility and dissolution rate than pure SA. The most promising results were obtained for the salts with imidazole and 1-methylimidazole co-formers.Peer Reviewe

A database to compare possible MOFs for volumetric hydrogen storage, taking into account the cost of their building blocks

Physical adsorption at cryogenic temperature can increase the density of the stored hydrogen at a lower pressure than conventional compressed gas systems. This mechanism is also reversible and involves faster kinetics than chemical storage. Materials with certain structural and porous properties are necessary for volumetrically efficient hydrogen storage, including large specific surface areas, pore volumes, and appropriated bulk densities. Metal-organic frameworks (MOF) materials are remarkable candidates as adsorbents due to their porous properties and high crystallinity. Large databases like the MOF subset from the CSD or the CoRE-MOF can be used to find the best materials for this application, providing crystallographic information, composition, and porous properties. Herein, we created a database which includes crystallographic and porous properties, metallic and organic composition, and the minimum available cost for their linkers and corresponding suppliers for those for which it was publicly available. The database is also helpful for selecting structures with potential for industrial production and starting material for computational tools like machine learning or artificial intelligence approaches that relate the composition of MOFs with their performance in different applications. A user interface allows for creating customized selections of suitable MOF structures, looking for their porous and crystalline properties, gravimetric and volumetric total uptakes, and metallic and organic composition, as well as properties for the organic linkers like name, molecular mass, price, or presence of specific functional groups. This information was used to select potential structures from up to two metals and two linkers for the volumetric cryostorage of hydrogen

Optimizing the Green Synthesis of ZIF‑8 by Reactive Extrusion Using <i>In Situ</i> Raman Spectroscopy

We report the scale-up of a batch solid synthesis of zeolitic imidazolate framework-8 (ZIF-8) for reactive extrusion. The crystalline product forms in the extruder directly under the mixture of solid 2-methylimidazole and basic zinc carbonate in the presence of a catalytic amount of liquid. The process parameters such as temperature, liquid type, feeding rate, and linker excess were optimized using the setup specifically designed for in situ Raman spectroscopy. Highly crystalline ZIF-8 with a Brunauer–Emmett–Teller (BET) surface area of 1816 m2 g–1 was quantitatively prepared at mild temperature using a catalytic amount of ethanol and a small excess of the linker. Finally, we developed a simple and comprehensive approach to evaluating the environmental friendliness and scalability of metal–organic framework (MOF) syntheses in view of their large-scale production

3-(1&lt;em&gt;H&lt;/em&gt;-Indol-3-yl)-4-(morpholin-4-yl)cyclobut-3-ene-1,2-dione

3-(1&lt;em&gt;H&lt;/em&gt;-Indol-3-yl)-4-(morpholin-4-yl)cyclobut-3-ene-1,2-dione was obtained in good yields (72–82%) by nucleophilic substitution of 3-chloro-4-(1&lt;em&gt;H&lt;/em&gt;-indol-3-yl)cyclobut-3-ene-1,2-dione with morpholine

Extraterrestrial Particles Examined by Shifted Excitation Raman Difference Spectroscopy

Shifted Excitation Raman Difference Spectroscopy (SERDS) was applied to extraterrestrial particles. These particles were returned from an S-type near-Earth asteroid 25143 (“Itokawa”) by the JAXA space probe mission “Hayabusa” in 2010. Sample return missions are of particular interest for space research, because of the available state-of-the-art ground-based techniques and instrumentation. After complex treatments for first investigations such as in, the particles were examined with Raman spectroscopy. These Raman spectra are as a rule masked by a broad intense background, dominantly due to enhanced fluorescence, and do not allow clear interpretation. SERDS was applied using 488 nm laser excitation wavelength in order to separate the Raman signal from the background and therefore, to enable clear identification of mineralogical composition of the particles. Knowledge of the mineralogical composition is, among others, a necessary condition for the derivation of the particles’ exposure ages that are important for understanding the evolutionary history of the asteroid’s regolith

9- and 11-substituted 4-azapaullones are potent and selective inhibitors of African trypanosoma.

International audienceTrypanosomes from the "brucei" complex are pathogenic parasites endemic in sub-Saharan Africa and causative agents of severe diseases in humans and livestock. In order to identify new antitrypanosomal chemotypes against African trypanosomes, 4-azapaullones carrying α,β-unsaturated carbonyl chains in 9- or 11-position were synthesized employing a procedure with a Heck reaction as key step. Among the so prepared compounds, 5a and 5e proved to be potent antiparasitic agents with antitrypanosomal activity in the submicromolar range

Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.

International audienceBACKGROUND:The search for novel chemical entities targeting essential and parasite-specific pathways is considered a priority for neglected diseases such as trypanosomiasis and leishmaniasis. The thiol-dependent redox metabolism of trypanosomatids relies on bis-glutathionylspermidine [trypanothione, T(SH)2], a low molecular mass cosubstrate absent in the host. In pathogenic trypanosomatids, a single enzyme, trypanothione synthetase (TryS), catalyzes trypanothione biosynthesis, which is indispensable for parasite survival. Thus, TryS qualifies as an attractive drug target candidate.METHODOLOGY/PRINCIPAL FINDING:A library composed of 144 compounds from 7 different families and several singletons was screened against TryS from three major pathogen species (Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum). The screening conditions were adjusted to the TryS´ kinetic parameters and intracellular concentration of substrates corresponding to each trypanosomatid species, and/or to avoid assay interference. The screening assay yielded suitable Z' and signal to noise values (≥0.85 and ~3.5, respectively), and high intra-assay reproducibility. Several novel chemical scaffolds were identified as low μM and selective tri-tryp TryS inhibitors. Compounds displaying multi-TryS inhibition (N,N'-bis(3,4-substituted-benzyl) diamine derivatives) and an N5-substituted paullone (MOL2008) halted the proliferation of infective Trypanosoma brucei (EC50 in the nM range) and Leishmania infantum promastigotes (EC50 = 12 μM), respectively. A bis-benzyl diamine derivative and MOL2008 depleted intracellular trypanothione in treated parasites, which confirmed the on-target activity of these compounds.CONCLUSIONS/SIGNIFICANCE:Novel molecular scaffolds with on-target mode of action were identified as hit candidates for TryS inhibition. Due to the remarkable species-specificity exhibited by tri-tryp TryS towards the compounds, future optimization and screening campaigns should aim at designing and detecting, respectively, more potent and broad-range TryS inhibitors