Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities

Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas' disease. Diaryl sulfides with a central anilino moiety, decorated with a flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465'/Glu466' of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the "mepacrine binding site" near Trp21 and Met113. Systematic alteration of the carboxylate-binding fragments and the diaryl sulfide core of the inhibitor scaffold provided evidence for the proposed binding mode. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense as well as the malaria parasite Plasmodium falciparum.     

Development of a selective and sensitive spectrophotometric method for the trace determination of thallium(III) using 3-methyl-2-benzothiazolinone hydrazone hydrochloride and N-(1-naphthyl)-ethylenediamine dihydrochloride

A simple, selective, sensitive, and rapid spectrophotometric method has been developed for the determination of thallium(III) using 3-methyl-2-benzothiazolinone hydrazone hydrochloride and N-(1-naphthyl)-ethylenediamine dihydrochloride. The obtained product had an absorption maximum of 590 nm. Beer's law was valid over the concentration range of 0.15-8 microg/mL. The molar absorptivity and Sandell's sensitivity of the colored system were 2.93 x 10(4) L/mol x cm and 0.00723 microg/mL, respectively. The effect of different acids on the sensitivity of the method, interference by foreign substances, the optimum reaction conditions, and other analytical parameters were evaluated. The proposed method has been successfully applied in the analysis of T1(III) in standard reference materials, synthetic mixtures, and water and urine samples. The performance of the proposed method was evaluated in terms of Student's t-test and variance ratio F-test, which indicated the significance of the proposed method over reported methods.     

Comparison of the quality of aqueous dispersions of single wall carbon nanotubes using surfactants and biomolecules

The use of single wall carbon nanotubes (SWCNTs) in current and future applications depends on the ability to process SWCNTs in a solvent to yield high-quality dispersions characterized by individual SWCNTs and possessing a minimum of SWCNT bundles. Many approaches for the dispersion of SWCNTs have been reported. However, there is no general assessment which compares the relative quality and dispersion efficiency of the respective methods. Herein we report a quantitative comparison of the relative ability of "wrapping polymers" including oligonucleotides, peptides, lignin, chitosan, and cellulose and surfactants such as cholates, ionic liquids, and organosulfates to disperse SWCNTs in water. Optical absorption and fluorescence spectroscopy provide quantitative characterization (amount of SWCNTs that can be suspended by a given surfactant and its ability to debundle SWCNTs) of these suspensions. Sodium deoxy cholate (SDOCO), oligonucleotides (GT)(15), (GT)(10), (AC)(15), (AC)(10), C(10-30), and carboxymethylcellulose (CBMC-250K) exhibited the highest quality suspensions of the various systems studied in this work. The information presented here provides a good framework for further study of SWCNT purification and applications.     

Bioorthogonal Probes for the Study of MDM2‐p53 Inhibitors in Cells and Development of High‐Content Screening Assays for Drug Discovery

To study the behavior of MDM2‐p53 inhibitors in a disease‐relevant cellular model, we have developed and validated a set of bioorthogonal probes that can be fluorescently labeled in cells and used in high‐content screening assays. By using automated image analysis with single‐cell resolution, we could visualize the intracellular target binding of compounds by co‐localization and quantify target upregulation upon MDM2‐p53 inhibition in an osteosarcoma model. Additionally, we developed a high‐throughput assay to quantify target occupancy of non‐tagged MDM2‐p53 inhibitors by competition and to identify novel chemical matter. This approach could be expanded to other targets for lead discovery applications.     

Synthesis of Aristotelia‐Type Alkaloids,Part XVI

Two independent total syntheses of the Aristotelia alkaloid (−)‐serratenone ((−)‐ 1 ) are disclosed, one starting with (−)‐α‐pinene, the other one with (S)‐α‐terpineol. These correlations led to a revision of the originally proposed absolute configuration of the natural product. In the course of systematic investigations of the behavior of the indole alkaloids (+)‐makomakine ((+)‐ 18 ) and (−)‐hobartine ((−)‐ 22 ) towards oxidizing reagents, it was found that treatment with I₂ leads to no less than five different products. Depending on the exact reaction conditions, each of them can be obtained as the major component in yields between 40 and 60%. One of these compounds was shown to be identical with the natural product (+)‐11,12‐didehydromakonin‐10‐one ((+)‐ 28 ).     

SARs of the antiprotozoal action of 6,7-diaryl-bicyclo[2.2.2]octan-2-ols

Abstract  

Several 4-amino-6,7-diarylbicyclo[2.2.2]octan-2-ols bearing varying substituents on the aromatic rings were synthesized following a manual method for applying the Hansch approach. All new compounds were tested for their activity against the causative organisms of East African sleeping sickness and malaria tropica. Structure activity relationships are discussed.     

Bicyclic amido compounds with antiprotozoal activity

Abstract  

Aroyl derivatives of 2-aminobicyclo-octanes and 2-azabicyclo-nonanes have been synthesized and tested for their activities against the causative organisms of East African trypanosomiasis and malaria tropica. The acylation induced in general loss of antiprotozoal activity, but a single compound showed good antiplasmodial activity against a multiresistant strain of Plasmodium falciparum.     

Ancistrocladinium A and B, the first N,C-coupled naphthyldihydroisoquinoline alkaloids, from a Congolese ancistrocladus species

The isolation and structural elucidation of three novel-type naphthylisoquinoline alkaloids, ancistrocladinium A and B (the latter along with its atropisomer), from a Congolese Ancistrocladus species collected in the habitat Yeteto is reported. Their structures, including all stereochemical features, were elucidated by spectroscopic, chemical, and chiroptical methods. Ancistrocladinium A and B are the first N,C-coupled naphthyldihydroisoquinoline alkaloids found in nature, i.e., with an iminium-aryl axis. Although ancistrocladinium A, which is N,8'-coupled, is configurationally stable at this axis, ancistrocladinum B and its rotational isomer are based on a hitherto unprecedented N,6'-coupling type, with a slow rotation about the hetero biaryl axis at room temperature; they thus occur as a 46:54 mixture of two configurationally semistable atropo-diastereomers. For the isomerization of (P)-ancistrocladinium B to its (M)-diastereomer and for the opposite direction, the Gibbs free energies of activation were determined to be DeltaG double dagger1 = 105.8 kJ mol-1 and DeltaG double dagger2 = 105.7 kJ mol-1, respectively. In addition, the compounds were shown to have promising antileishmanial activities.     

Chern–Simons,Wess–Zumino and other cocycles from Kashiwara–Vergne and associators

Descent equations play an important role in the theory of characteristic classes and find applications in theoretical physics, e.g., in the Chern–Simons field theory and in the theory of anomalies. The second Chern class (the first Pontrjagin class) is defined as \(p= \langle F, F\rangle \) where F is the curvature 2-form and \(\langle \cdot , \cdot \rangle \) is an invariant scalar product on the corresponding Lie algebra \(\mathfrak g\). The descent for p gives rise to an element \(\omega =\omega _3+\omega _2+\omega _1+\omega _0\) of mixed degree. The 3-form part \(\omega _3\) is the Chern–Simons form. The 2-form part \(\omega _2\) is known as the Wess–Zumino action in physics. The 1-form component \(\omega _1\) is related to the canonical central extension of the loop group LG. In this paper, we give a new interpretation of the low degree components \(\omega _1\) and \(\omega _0\). Our main tool is the universal differential calculus on free Lie algebras due to Kontsevich. We establish a correspondence between solutions of the first Kashiwara–Vergne equation in Lie theory and universal solutions of the descent equation for the second Chern class p. In more detail, we define a 1-cocycle C which maps automorphisms of the free Lie algebra to one forms. A solution of the Kashiwara–Vergne equation F is mapped to \(\omega _1=C(F)\). Furthermore, the component \(\omega _0\) is related to the associator \(\Phi \) corresponding to F. It is surprising that while F and \(\Phi \) satisfy the highly nonlinear twist and pentagon equations, the elements \(\omega _1\) and \(\omega _0\) solve the linear descent equation.     

Hydrangenone, a new isoprenoid with an unprecedented skeleton from Salvia hydrangea

Hydrangenone, a new heptacyclic isoprenoid with a 6/7/6/5/5 membered carbon ring skeleton, was isolated from the aerial parts of Salvia hydrangea. The structure was established by extensive NMR spectroscopic methods. The relative and absolute configuration of 1 was assigned by NOESY and X-ray crystallographic analysis and by comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Compound 1 showed in vitro antiplasmodial activity, with an IC(50) value of 1.4 μM against P. falciparum. A plausible biosynthetic pathway of 1 was also proposed.