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.     

Polygons in billiard orbits

We study the geometry of billiard orbits on rectangular billiards. A truncated billiard orbit induces a partition of the rectangle into polygons. We prove that thirteen is a sharp upper bound for the number of different areas of these polygons.     

Synthesis and Structure of Bismuth(III)-Containing Noncentrosymmetric Phosphates, Cs(3)KBi(2)M(4)(PO(4))(6)Cl (M = Mn, Fe). Monoclinic (Cc) and Tetragonal (P4(3)) Polymorphs Templated by Chlorine-Centered Cl(Bi(2)Cs) Acentric Units

Single crystals of three new noncentrosymmetric (NCS) phosphates, α (1) and β (2) forms of Cs(3)KBi(2)Mn(4)(PO(4))(6)Cl and α-Cs(3)KBi(2)Fe(4)(PO(4))(6)Cl (3), were grown in a reactive CsCl/KCl molten-salt media. Their structures were determined by single-crystal X-ray diffraction methods showing that the α form crystallizes in the space group Cc (No. 9), which is in one of the 10 NCS polar crystal classes, m (2/m) while the β form crystallizes in P4(3) (No. 78) of another polar class, 4 (4/m). The unit cell parameters of the α form can be approximately correlated with that of the β form via the 3 × 3 orientation matrix [0.5, 0.5, 0; -0.5, 0.5, 0; 0, 0, 2 sin β]. The structures of these otherwise complicated phosphates exhibit two types of channels with circular and elliptical windows where the Cl-centered Cl(Bi(2)Cs) acentric unit is located. The neighboring acentric units are arranged in a parallel fashion in the α form, resulting in the monoclinic (Cc) lattice, but "antiparallel" in the β form, thus giving the tetragonal (P4(3)) unit cell. 1-3 feature the compatible M-O-P unit that contains four crystallographically independent MO(x) (x = 4, 5) polyhedra, which are connected to the Cl(Bi(2)Cs) acentric unit through one short and one long M(II)···Cl bond. The compositions of 1 and 2 consist of three Mn(2+) (d(5)) and one Mn(3+) (d(4)) per formula unit and that of 3 has three Fe(2+) (d(6)) and one Fe(3+) (d(5)). Bond valence sums reveal that, in the α phase, the trivalent site adopts distorted tetrahedral M(1)(3+)O(4) coordination and, in the β phase, distorted trigonal-bipyramidal M(4)(3+)O(5). Thus far, the iron phase has only been isolated in the α form presumably because of little extra stabilization energy gain if the Fe(2+) d(6) ion were to occupy the M(1)O(4) site. The possible origins pertaining to the structural differences in the α and β forms are discussed.     

Covariant derivatives on null submanifolds

The degenerate nature of the metric on null hypersurfaces makes it difficult to define a covariant derivative on null submanifolds. Recent approaches using decomposition to define a covariant derivative on null hypersurfaces are investigated, with examples demonstrating the limitations of the methods. Motivated by Geroch’s work on asymptotically flat spacetimes, conformal transformations are used to construct a covariant derivative on null hypersurfaces, and a condition on the Ricci tensor is given to determine when this construction can be used. Several examples are given, including the construction of a covariant derivative operator for the class of spherically symmetric hypersurfaces.     

Hilbert space idempotents and involutions

Norms of idempotents, involutions, and the Hermitian and skew-Hermitian parts of involutions are shown to be elementary trigonometric functions of an angle between two subspaces of Hilbert space. When the spaces involved are nontrivial, the norm of a linear idempotent is the cosecant of the angle between its range and kernel; the norm of a linear involution is the cotangent of half the angle between the involution's eigenspaces.

     

Preparative Mass Spectrometry Using a Rotating-Wall Mass Analyzer

The design of functional interfaces is central to both fundamental and applied research in materials science and energy technology. We introduce a new, broadly applicable technique for the precisely controlled high-throughput preparation of well-defined interfaces containing polyatomic species ranging from small ions to nanocrystals and large protein complexes. The mass-dispersive deposition of ions onto surfaces is achieved using a rotating-wall mass analyzer, a compact device which enables the separation of ions using low voltages and has a theoretically unlimited mass range. We demonstrate an efficient deposition of singly charged Au₁₄₄(SC₄H₉)₆₀ ions (33.7 kDa), which opens up exciting opportunities for the structural characterization of nanocrystals and their assemblies using transmission electron microscopy. Our approach also enables the high-throughput deposition of mass-selected ions from multicomponent mixtures, which is of interest to the controlled preparation of surface gradients and rapid screening of molecules in mixtures for a specific property.     

Pore-Scale Study of Rarefied Gas Flows Using Low-Variance Deviational Simulation Monte Carlo Method

Transport in Porous Media - Gaseous flow through ultra-tight porous media, e.g. shale and some high-performance insulation materials, is often rarefied, invalidating an analysis by the continuum...     

Resolution Effects and Enslaved Finite-Difference Schemes for a Double Gyre, Shallow-Water Model

We study numerical solutions of the reduced-gravity shallow-water equation on a beta plane, subjected to a sinusoidally varying wind forcing leading to the formation of a double gyre circulation. As expected the dynamics of the numerical solutions are highly dependent on the grid resolution and the given numerical algorithm. In particular, the statistics of the solutions are critically dependent on the scheme's ability to resolve the Rossby deformation radius. We present a method, applicable to any finite-difference scheme, which effectively increases the spatial resolution of the given algorithm without changing its temporal stability or memory requirements. This enslaving method makes use of properties of the governing equations in the absence of time derivatives to reduce the overall truncation error. By examining statistical measures of stochastic solutions at resolutions near the Rossby radius, we show that the enslaved schemes are capable of reproducing statistics of standard schemes computed at twice the resolution. Received 29 August 1996 and accepted 6 March 1997     

Road traffic sound level distributions

A microprocessor-controlled instrument has been used to form a traffic noise level histogram with a resolution better than 0·1 dB per channel. The instrument calculates the mean, standard deviation, skewness and kurtosis of the distribution, along with L_N and L_eq values. The results of over 200 measurements, of 400 s duration, are shown to be in disagreement with predictions based on the commonly assumed Gaussian distribution. Skewness values ranging from +1 to ?1 have been observed, while kurtosis can exceed 4. Measurements taken near freely flowing, pulsed and banked traffic have been used to describe the “typical” distribution shape, it being observed that banked traffic noise has markedly different characteristics from other types of traffic. Simultaneous measurements taken on each side of the road have been related to the position of the traffic on the road and these data have led to a simple model for estimating the distribution shape and statistical parameters.