Novel Type II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents

Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood‐ and pre‐erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver‐stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood‐stage parasite growth with IC₅₀ values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver‐stage parasites than the gold‐standard drug, primaquine.     

Butyltin(IV) Benzoates: Inhibition of Thioredoxin Reductase,Tumor Cell Growth Inhibition,and Interactions with Proteins

Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di‐ and tri‐n‐butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT‐29 and MCF‐7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di‐n‐butyltin(IV) complex as an example.     

In-Operation Monitoring of the Soot Load of Diesel Particulate Filters: Initial Tests

Diesel particulate filters (DPF) are indispensable parts of modern automotive exhaust gas aftertreatment systems due to the stringent emissions legislation. For a fuel-efficient control strategy, it would be beneficial to determine directly and in-operation their actual trapped soot mass. Two novel approaches—based on the electrical conductivity of trapped soot particles—emerged recently. By measuring the electrical resistance between different single walls inside the filter, the soot load is determined with local resolution. The microwave-based technique is a contactless approach that gives an integral value depending on the soot mass in the DPF. We present investigations on loading and regeneration of DPFs in a dynamometer test bench applying both methods. The results are compared with each other and correlated with the differential pressure and the soot mass. Especially the microwave-based technique has a potential for serial application.     

Influence of Aluminium Alkyl Compounds on the High‐Pressure Polymerization of Ethylene with Ternary Metallocene‐Based Catalysts. Investigation of Chain Transfer to the Aluminium

The influence of aluminium alkyl compounds on metallocene‐catalyzed high pressure polymerizations of ethylene has been investigated at 150 MPa and 180°C in a continuously operated autoclave. The catalysts were based on the metallocenes bis(cyclopentadienyl)zirconium dichloride (Cp₂ZrCl₂) and diphenylmethylene (cyclopentadienylfluorenyl)zirconium dichloride (Ph₂C‐(CpFlu)ZrCl₂), which were preactivated outside the reactor with triisobutylaluminium (TiBA) and N,N‐dimethylanilinium tetrakis(pentafluorophenyl)borate (DMAP, [PhNHMe₂][B(C₆F₅)₄]). The concentrations of triisobutylaluminium (TiBA) and triethylaluminium (TEA) in the reactor were varied over a wide range, using a separate dosing for these two aluminium alkyl compounds. Productivity and polymer properties strongly depended on the type and the concentration of the aluminium alkyl compound used. Highest productivities and molecular weights were obtained with low concentrations of TiBA in the reactor. Up to a concentration of 30 molppm Al in the reactor, unimodal polymers were formed with M̄_w/M̄_n between 2 and 3. With higher aluminium concentrations the products formed contained small amounts of waxes, due to oligomerization catalyzed by the aluminium alkyl compounds. The molecular weight distributions (MWDs) of these products could be described as a superimposition of two Schulz‐Zimm distributions. All MWDs were analyzed with regard to the amount of waxes produced by ethylene oligomerization and with regard to the influence of chain transfer reactions to the aluminium. The rate constants of chain transfer to aluminium, in relation to the rate constants of insertion of ethylene, were estimated.     

Synthesis of Ultrahigh-Temperature Si–B–C–N Ceramic from Polymeric Waste Gas

A "green" route to ultrahigh-temperature Si–B–C–N ceramic from vacuum-degassing waste gas of polyborosilazane {B[C₂H₄Si(CH₃)NH]₃} _n (T2-1) has been developed. After gas-to-gel transformation, an amorphous ceramic Si_5.3B_1.0C₁₉N_3.7 was derived from the gel by dehydrocoupling and polymer-to-ceramic transformation. The ceramic started to form a nanostructure at 1700°C and resisted thermal degradation up to 2200°C in argon. This suggests that vacuum-degassing waste gases of polymer precursors may be perfect raw materials for various advanced ceramics.     

Identification of the Trail Pheromone of the Pavement Ant Tetramorium immigrans (Hymenoptera: Formicidae)

Journal of Chemical Ecology - Four species of Tetramorium pavement ants are known to guide foraging activities of nestmates via trail pheromones secreted from the poison gland of worker ants, but...     

Synthesis of 9,12-Dioxo-10(Z)-dodecenoic acid, a new fatty acid metabolite derived from 9-hydroperoxy-10,12-octadecadienoic acid in lentil seed (Lens culinaris medik.)

The previously unknown linoleic acid peroxidation product 9,12-dioxo-10(Z)-decenoic acid (Z5) was detected in lentil seed fluor (Lens culinaris Medik.) by electron impact mass spectrometry (El-MS) after derivatization with pentafluorobenzyl-hydroxylamine-hydrochloride, methylation of acidic groups with diazomethane, and protection of hydroxylic groups with N-methyl-N-trimethylsilyl-trifluoroacetamide. The structure of the natural product was confirmed by synthesis of Z5, 9,12-dioxo-10(E)-decenoic acid, and derivatives. EI-MS, nuclear magnetic resonance and gas chromatographic data of these compounds and synthetic intermediates are discussed.