New antimalarial drugs

Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.     

Determination and interpretation of environmental water samples contaminated by uranium mining activities

Interpretation of environmental behavior of uranium is based on several steps of data analysis and statistical inference. First step is sampling and analyzing of uranium in field samples by routine laboratory methods. Such methods have to fulfill multiple requirements like robustness, efficiency, low detection limit and precision. A comparison of different approaches in assigning uncertainty to experimentally obtained analytical data shows that classical error estimation is not significantly inferior to more sophisticated modern techniques like inverse regression or orthogonal regression. A second step is the correlation of analytical data with current state of insight into environmental behavior of uranium. Such a correlation furthers the choice of adequate geochemical models and quality of geochemical data base for subsequent detailed analysis, e.g. by geochemical modeling. An appraisal of the individual steps in this complex analysis is given on the basis of statistical procedures for calibration and an E_H-pH diagram of uranium for atmospheric conditions.     

Dynamics of liquid interfaces under various types of external perturbations

Dynamic interfacial parameters are the key properties of interfaces in many modern technologies and can be studied in various ways. For applications like foams and emulsions, the dynamics of adsorption and the dilational and shear rheology of liquid–fluid interfaces are investigated most frequently. This work gives an insight into recently developed new experimental approaches, such as fast capillary pressure tensiometry for growing and oscillating drops. These experiments are presented in comparison to more classical techniques like drop profile tensiometry and capillary wave damping. Progress in these experiments based on generated interfacial perturbations can be expected only by a close link to respective CFD simulations. We also present the state of the art of CFD simulations, which have reached a high level during the last decade and provide a substantial basis for dynamic interfacial experiments.     

Iron(II)-induced degradation of antimalarial beta-sulfonyl endoperoxides: evidence for the generation of potentially cytotoxic carbocations

Reactions of antimalarial beta-sulfonyl endoperoxides 9 and 10, which, like yingzhaosu A (2), derive from the 2,3-dioxabicyclo[3.3.1]nonane system 3, with iron(II) salts were studied. Product analysis of the iron(II)-induced degradations provided evidence for the intermediacy of carbon-centered cyclohexyl radicals 20 and 31 and their possible oxidation to the corresponding carbocations 21 and 32. It is conceivable that the antimalarial activity of beta-sulfonyl endoperoxides of type 5 may derive from alkylation of vital intraparasitic biomolecules by free radicals and/or carbocations, generated within the malaria parasite through a similar iron(II)-induced degradation process.     

Artemisinin

Artemisinin was first extracted in the 1970s from sweet wormwood (Artemisia annua), which was used for the treatment of malaria in traditional Chinese Medicine for more than 1600 years. Meanwhile the biosynthetic pathway of artemisinin, which derives from terpene‐metabolism is well established. In the past 30 years numerous total syntheses have been published, which impressively illustrate the achievements in modern organic chemistry. Nowadays, on industrial scale artemisinin is produced by extraction from wormwood and by fermentation and partial synthesis.     

Hydrating the Bispropionate Notch in Malaria Pigment: A New Structural Motif in the Iron(III)(deuteroporphyrin) Dimer

Treating deuterohemin, chloro(deuteroporphyrinato)iron(III), with a non-coordinating base in DMSO/methanol allows for the isolation of [(deuteroporphyrinato)iron(III)]₂, deuterohematin anhydride (DHA), an analogue of malaria pigment, the natural product of heme detoxification by malaria. The structure of DHA obtained from this solvent system has been solved by X-ray powder diffraction analysis and displays many similarities, yet important structural differences, to malaria pigment. Most notably, a water molecule of solvation occupies a notch created by the propionate side chains and stabilizes a markedly bent propionate ligand coordinated with a long Fe−O bond, and a carboxylate cluster associated with water molecules is generated. Together, these features account for its increased solubility and more open structure, with an increased porphyrin–porphyrin separation. The IR spectroscopic signature associated with this structure also accounts for the strong IR band at 1587 cm⁻¹ seen for many amorphous preparations of synthetic malaria pigment, and it is proposed that stabilizing these structures may be a new objective for antimalarial drugs. The important role of the vinyl substituents in this biochemistry is further demonstrated by the structure of deuterohemin obtained by single-crystal X-ray diffraction analysis.     

Plasmodial Kinase Inhibitors Targeting Malaria: Recent Developments

Recent progress in reducing malaria cases and ensuing deaths is threatened by factors like mutations that induce resistance to artemisinin derivatives. Multiple drugs are currently in clinical trials for malaria treatment, including some with novel mechanisms of action. One of these, MMV390048, is a plasmodial kinase inhibitor. This review lists the recently developed molecules which target plasmodial kinases. A systematic review of the literature was performed using CAPLUS and MEDLINE databases from 2005 to 2020. It covers a total of 60 articles and describes about one hundred compounds targeting 22 plasmodial kinases. This work highlights the strong potential of compounds targeting plasmodial kinases for future drug therapies. However, the majority of the Plasmodium kinome remains to be explored.     

N‐Heterocyclic Carbene Organocatalysis: Activation Modes and Typical Reactive Intermediates

N‐Heterocyclic carbene (NHC) organocatalysis has been developed as an important approach in modern organic synthesis. Versatile activation modes within NHC organocatalysis have been established with countless transformations being realized in both efficient and selective fashion. We would like to provide an overview on the key progresses achieved within this field in the past two decades. Since numerous excellent reviews have been documented within this area, we will mainly focus on the scientific development of this research field based on the basic reaction modes and typical reaction intermediates.      

DSPMP: Discriminating secretory proteins of malaria parasite by hybridizing different descriptors of Chou's pseudo amino acid patterns

Identification of the proteins secreted by the malaria parasite is important for developing effective drugs and vaccines against infection. Therefore, we developed an improved predictor called “DSPMP” (Discriminating Secretory Proteins of Malaria Parasite) to identify the secretory proteins of the malaria parasite by integrating several vector features using support vector machine‐based methods. DSPMP achieved an overall predictive accuracy of 98.61%, which is superior to that of the existing predictors in this field. We show that our method is capable of identifying the secretory proteins of the malaria parasite and found that the amino acid composition for buried and exposed sequences, denoted by AAC(b/e), was the most important feature for constructing the predictor. This article not only introduces a novel method for detecting the important features of sample proteins related to the malaria parasite but also provides a useful tool for tackling general protein‐related problems. The DSPMP webserver is freely available at http://202.207.14.87:8032/fuwu/DSPMP/index.asp . © 2015 Wiley Periodicals, Inc.     

Multielement ultratrace analysis in tungsten using secondary ion mass spectrometry

Summary The ever increasing demands on properties of materials creates a trend also towards ultrapure products. Characterization of these materials is only possible with modern, highly sophisticated analytical techniques such as activation analysis and mass spectrometry, particularly SSMS, SIMS and GDMS [1].Analytical strategies were developed for the determination of about 40 elements in a tungsten matrix with high-performance SIMS. Difficulties like the elimination of interferences had to be overcome. Extrapolated detection limits were established in the range of pg/g (alkali metals, halides) to ng/g (e. g., Ta, Th).Depth profiling and ion imaging gave additional information about the lateral and the depth distribution of the elements.

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Multielementepurenanalyse in Wolfram mittels SIMS

     

The origin of the formation of cavities in galvanized coatings

The role of water‐soluble corrosion products on galvanized wires was examined. The samples used were industrial hot‐dip galvanized wires, which were exposed to the open air under all weather conditions for a relatively short time (6 and 12 months), in an urban environment close to the sea. The samples were studied by different methods, i.e. scanning electron microscopy (SEM), transmission electron microscopy (TEM), X‐ray diffraction (XRD) and optical microscopy (OM). Several phases were detected because of the galvanization procedure and the steel substrate. Furthermore, phases which were formed as a result of the reaction of zinc with the atmosphere were also detected. These were oxides like ZnO, carbonates like ZnCO₃ and hydrated Zn and Fe sulfates. Their presence influences the corrosion resistance of the wires, which finally, strongly depends on the solubility of the wires in water. The SO₄^2? compounds especially are very soluble and consequently are easily removed from the coating surface, leading to its degradation by the formation of cavities. In any case, their presence, even after a short period of exposure, implies that the coating is highly affected by the atmosphere of the modern city. Copyright © 2006 John Wiley & Sons, Ltd.     

Determination and interpretation of environmental water samples contaminated by uranium mining activities

Interpretation of environmental behavior of uranium is based on several steps of data analysis and statistical inference. First step is sampling and analyzing of uranium in field samples by routine laboratory methods. Such methods have to fulfill multiple requirements like robustness, efficiency, low detection limit and precision. A comparison of different approaches in assigning uncertainty to experimentally obtained analytical data shows that classical error estimation is not significantly inferior to more sophisticated modern techniques like inverse regression or orthogonal regression. A second step is the correlation of analytical data with current state of insight into environmental behavior of uranium. Such a correlation furthers the choice of adequate geochemical models and quality of geochemical data base for subsequent detailed analysis, e.g. by geochemical modeling. An appraisal of the individual steps in this complex analysis is given on the basis of statistical procedures for calibration and an E_H-pH diagram of uranium for atmospheric conditions. Received: 30 July 1998 / Revised: 18 November 1998 / Accepted: 26 November 1998     

Artemisinin-derived dimers and their antimalarial activities

Malaria is a tropical disease that leads around half a million people to succumb annually. Antimalarial agents such as artemisinin and its derivatives are crucial to malaria treatment; however, the rapid development of drug resistance to clinically used antimalarials is still the major obstacle to effective chemotherapy. To tackle the growing resistance issue, new antimalarial agents are urgently needed. Using artemisinin-derived dimers as pharmacological scaffolds has demonstrated promising antimalarial activity; therefore, rational design of the dimers may provide valuable therapeutic intervention to treat malaria or even drug-resistant malaria. This review emphasized two aspects: (a) different linker-tethered artemisinin-derived dimers with potential antimalarial activity and (b) the structure-activity relationships discussed to provide an insight for rational design of dimers with improved efficiency.     

Comparison of the behavior of metal-organic frameworks and zeolites for hydrocarbon separations

The objective of this work was to study the adsorption and separation of the most important families of hydrocarbon compounds on metal-organic frameworks (MOFs), in comparison with zeolites. For this purpose, we have selected four probe molecules, each of them representing one of these families, i.e., o- and p-xylene as aromatics, 1-octene as an alkene, and n-octane as an alkane. The separation of these four molecules was studied by binary breakthrough experiments. To represent the large diversity of MOF structures, the experiments were carried out with (i) two MOFs with coordinatively unsaturated metal sites (CUS), i.e., Cu-btc (HKUST-1) and CPO-27-Ni, (ii) a MOF with an anionic framework and extraframework cations, i.e. RHO-ZMOF, and (iii) two rather apolar zeolitic imidazolate framework (ZIF) materials with different pore sizes, i.e. ZIF-8 and ZIF-76. Zeolite NaY and zeolite β were used as polar and apolar reference adsorbents, respectively. The results can be briefly summarized as follows: ZIFs (not carrying any polar functional groups) behave like apolar adsorbents and exhibit very interesting and unexpected molecular sieving properties. CUS-MOFs behave like polar adsorbents but show the specificity of preferring alkenes over aromatics. This feature is rationalized thanks to DFT+D calculations. MOFs with extraframework cations behave like polar (cationic) zeolites.     

Ensemble modeling of very small ZnO nanoparticles

The detailed structural characterization of nanoparticles is a very important issue since it enables a precise understanding of their electronic, optical and magnetic properties. Here we introduce a new method for modeling the structure of very small particles by means of powder X-ray diffraction. Using thioglycerol-capped ZnO nanoparticles with a diameter of less than 3 nm as an example we demonstrate that our ensemble modeling method is superior to standard XRD methods like, e.g., Rietveld refinement. Besides fundamental properties (size, anisotropic shape and atomic structure) more sophisticated properties like imperfections in the lattice, a size distribution as well as strain and relaxation effects in the particles and-in particular-at their surface (surface relaxation effects) can be obtained. Ensemble properties, i.e., distributions of the particle size and other properties, can also be investigated which makes this method superior to imaging techniques like (high resolution) transmission electron microscopy or atomic force microscopy, in particular for very small nanoparticles. For the particles under study an excellent agreement of calculated and experimental X-ray diffraction patterns could be obtained with an ensemble of anisotropic polyhedral particles of three dominant sizes, wurtzite structure and a significant relaxation of Zn atoms close to the surface.     

Holographic pixel super-resolution in portable lensless on-chip microscopy using a fiber-optic array

We report a portable lensless on-chip microscope that can achieve <1 μm resolution over a wide field-of-view of ～ 24 mm(2) without the use of any mechanical scanning. This compact on-chip microscope weighs ～ 95 g and is based on partially coherent digital in-line holography. Multiple fiber-optic waveguides are butt-coupled to light emitting diodes, which are controlled by a low-cost micro-controller to sequentially illuminate the sample. The resulting lensfree holograms are then captured by a digital sensor-array and are rapidly processed using a pixel super-resolution algorithm to generate much higher resolution holographic images (both phase and amplitude) of the objects. This wide-field and high-resolution on-chip microscope, being compact and light-weight, would be important for global health problems such as diagnosis of infectious diseases in remote locations. Toward this end, we validate the performance of this field-portable microscope by imaging human malaria parasites (Plasmodium falciparum) in thin blood smears. Our results constitute the first-time that a lensfree on-chip microscope has successfully imaged malaria parasites.     

Gallium(III) protoporphyrin IX]2: a soluble diamagnetic model for malaria pigment

Gallium(III) protoporphyrin IX forms a dimeric propionate-bridged dimer, 2, that is a soluble diamagnetic analogue of hematin anhydride. The single-crystal structure of 2 corresponds to a nondisordered inversion-symmetric dimer similar to malaria pigment but, unlike it, has a six-coordinate metal and an intraporphyrin rather than an interporphyrin hydrogen bond. NMR NOE correlations demonstrate the presence of the propionate linkage in solutions with pyridine. Taken together, this is the first single-crystal X-ray diffraction study of a propionate-linked dimer as found in malaria pigment and the first evidence for its presence in solution.     

A Water-Soluble Polymer-Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria

Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria.     

Analysis of dihydroartemisinin in plasma by liquid chromatography—Mass spectrometry

Summary Artemisinin (ART), or qinghaosu, a sesquiterpene lactone containing an endoperoxide bridge, is an efficient drug against chloroquine-resistant strains ofPlasmodium falciparum in the treatment of cerebral malaria. ART and its derivatives are rapidly metabolized into dihydroartemisinin (DHA), which is responsible for the antimalarial activity. After a simple liquid-liquid extraction (LLE), determination of DHA in plasma was conducted by liquid chromatography-mass spectrometry (LC-MS) with an electrospray ionization (ESI) interface. Addition of dodecylamine to the mobile phase and analysis in selected-ion monitoring (SIM) mode resulted in enhanced sensitivity and selectivity. Use of a primary amine, e.g. propylamine, pentylamine, hexylamine or dodecylamine, in the mobile phase can inhibit the formation of multimer clusters and ion adducts by forming one dominating species (analyte-primary amine adduct). Dodecylamine (DDA) was selected after several assays as a competitive agent for adduct formation. The procedure was validated and precision and accuracy were found to be good for the matrix studied. The method was applied to samples provided by patients receiving artesunate (ARS) for antimalarial treatment.