Exploring the trifluoromenadione core as a template to design antimalarial redox-active agents interacting with glutathione reductase

Menadione is the 2-methyl-1,4-naphthoquinone core used to design potent antimalarial redox-cyclers to affect the redox equilibrium of Plasmodium-infected red blood cells. Exploring the reactivity of fluoromethyl-1,4-naphthoquinones, in particular trifluoromenadione, under quasi-physiological conditions in NADPH-dependent glutathione reductase reactions, is discussed in terms of chemical synthesis, electrochemistry, enzyme kinetics, and antimalarial activities. Multitarget-directed drug discovery is an emerging approach to the design of new antimalarial drugs. Combining in one single 1,4-naphthoquinone molecule, the trifluoromenadione core with the alkyl chain at C-3 of the known antimalarial drug atovaquone, revealed a mechanism for CF(3) as a leaving group. The resulting trifluoromethyl derivative 5 showed a potent antimalarial activity per se against malarial parasites in culture.     

Vom Teerfarbstoff zum Insektizid

Wilhelm von Miller, professor of chemistry in Munich, invented the first synthetic organic insecticide called “Antinonnin” which the Bayer Company of Elberfeld, Germany, brought onto the market in 1892. Its active principle was the potassium salt of 4,6‐dinitro‐o‐cresol (DNOC). The compound, already synthesized in the late 1860's, was used in the beginning as a yellow textile dye. After the invention of azo dyes, the substance started being used as food‐colorant and later also as an insecticide, fungicide, herbicide and defoliant. Until the early 1970's it was especially popular for the winter treatment of orchards as a larvicide and ovicide. The paper connects the biographical history of Wilhelm von Miller with a discussion of the early history of plant protection in Germany.     

Uniform estimates for order statistics and Orlicz functions

We establish uniform estimates for order statistics: Given a sequence of independent identically distributed random variables ξ ₁, … , ξ _n and a vector of scalars x = (x ₁, … , x _n ), and 1 ≤ k ≤ n, we provide estimates for \mathbb E   k-min_{1 ￡ i ￡ n} |x_ix_i|{\mathbb E \, \, k-{\rm min}_{1\leq i\leq n} |x_{i}\xi _{i}|} and \mathbb E k-max_{1 ￡ i ￡ n}|x_ix_i|{\mathbb E\,k-{\rm max}_{1\leq i\leq n}|x_{i}\xi_{i}|} in terms of the values k and the Orlicz norm ||y_x||_M{\|y_x\|_M} of the vector y _x  = (1/x ₁, … , 1/x _n ). Here M(t) is the appropriate Orlicz function associated with the distribution function of the random variable |ξ ₁|, G(t) = \mathbb P ({ |x₁| ￡ t}){G(t) =\mathbb P \left(\left\{ |\xi_1| \leq t\right\}\right)}. For example, if ξ ₁ is the standard N(0, 1) Gaussian random variable, then G(t) = ?{\tfrac2p}ò₀^t e^-\fracs22ds {G(t)= \sqrt{\tfrac{2}{\pi}}\int_{0}^t e^{-\frac{s^{2}}{2}}ds }  and M(s)=?{\tfrac2p}ò₀^se^-\frac12t2dt{M(s)=\sqrt{\tfrac{2}{\pi}}\int_{0}^{s}e^{-\frac{1}{2t^{2}}}dt}. We would like to emphasize that our estimates do not depend on the length n of the sequence.     

Pyridazines 92. Synthesis of dialkyldipyridazinodiazepinones as potential HIV‐1 reverse transcriptase inhibitors

Two methods for the preparation of dialkylsubstituted dipyridazino[4,3‐b:3′,4′‐e][1,4]diazepinones and dipyridazino[3,4‐b:3′,4′‐e][1,4]diazepinones are reported. The new compounds were evaluated for their inhibitory effects against the replication of human immunodeficiency virus [HIV‐1(III_B) and HIV‐2(ROD)] in MT‐4 cells.     

Phase Transitions and Critical Behaviour of Binary Liquid Mixtures

Summary.  Compared to the simple one-component case, the phase behaviour of binary liquid mixtures shows an incredibly rich variety of phenomena. In this contribution we restrict ourselves to so-called binary symmetric mixtures, i.e. where like-particle interactions are equal (Φ₁₁(r) = Φ₂₂(r)), whereas the interactions between unlike fluid particles differ from those of likes ones (Φ₁₁(r) ≠ Φ₁₂(r)). Using both the simple mean spherical approximation and the more sophisticated self-consistent Ornstein-Zernike approximation, we have calculated the structural and thermodynamic properties of such a system and determine phase diagrams, paying particular attention to the critical behaviour (critical and tricritical points, critical end points). We then study the thermodynamic properties of the same binary mixture when it is in thermal equilibrium with a disordered porous matrix which we have realized by a frozen configuration of equally sized particles. We observe – in qualitative agreement with experiment – that already a minute matrix density is able to lead to drastic changes in the phase behaviour of the fluid. We systematically investigate the influence of the external system parameters (due to the matrix properties and the fluid–matrix interactions) and of the internal system parameters (due to the fluid properties) on the phase diagram. Received June 27, 2001. Accepted July 2, 2001     

A synchrotron diffraction study of two polymorphic forms of 2,5‐bis[2‐(4‐methoxyphenyl)ethenyl]pyrazine

Two polymorphs, α and γ, of the title compound, C₂₂H₂₀N₂O₂, have been characterized by means of single‐crystal synchrotron X‐ray diffraction. In the α form, the mol­ecules pack in a herring‐bone fashion, linked via weak C—H?N intermolecular interactions (H?N 2.58 Å). In the γ form, the mol­ecules are arranged in nearly planar sheets, which form a network held together by intermolecular hydrogen bonds of the type C—H?O (H?O 2.49 Å) and C—H?N (H?N 2.50 Å). The stacking distance between the sheets is 3.40 Å.     

Napoleons Kontinentalsperre und ihre Folgen: Hochkonjunktur der Ersatzstoffe

200 years ago, in 1806, began Napoleon's continental blockade of Great Britain. Especially in Germany and France this triggered an intensive search for substitutes for a variety of British colonial goods and manufactured wares which had become rare and expensive. For the first time, chemists and pharmacists developed substitutes for coffee, china‐bark, indigo, cochenille, cane‐sugar and other products. Napoleon's economic pressure particularly affected the development of chemistry and chemical industry in France and Germany. The paper shows the clear and close relationship of chemical research and the political situation of the Napoleonic Era.     

In Vitro Degradation of Poly(lactic-co2-glycolic) Acid Random Copolymers

We have investigated the in vitro degradation of poly(lactic-co-glycolic) acid copolymer with a lactic to glycolic ratio of 65/35. The degradation studies were performed on solvent-cast films of controlled thickness and shape. The samples were then incubated at 37 °C in phosphate buffered saline solution. The degradation was followed using potentiometry, light microscopy, gravimetry, gel permeation chromatography and differential scanning calorimetry. Water was found to diffuse inside the film as soon as the sample was placed in the degradation media. Wrinkles formed on the upper layer while degradation took place via chain scission in the bulk of the film. After 10 days, this led to the creation of a vesicle where liquid low molecular weight oligomers were trapped inside a thin film of high molecular weight polymer. This thin film acted as a membrane allowing only low molecular weight compounds to diffuse out of the film.     

New Poly(arylene ethynylene)s Consisting of Electron‐Deficient Aryleneimide Units

Summary: A new class of poly(arylene ethynylene)s (PAEs) containing an electron‐deficient N‐alkylphthalimide unit was prepared by means of a Sonogashira reaction. Complete solubility of the PAEs was observed by utilizing a 2,6‐diisopropylphenyl side chain. The chemical structure of the novel soluble polymer 3c was confirmed by NMR spectra, whereas the insoluble polymers were characterized by elemental analysis and IR spectra. Fluorescence measurements of 3c indicate a rigid structure and high symmetry in the excited state.