Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines

The F₁F_O-ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.     

The extended boundary condition and thick axially symmetric antennas

The extended boundary condition of Waterman is applied to axially symmetric antennas. Infinite sets of non-singular integral equations for the surface current density are obtained. The numerical solution of these equations is investigated. Several sets of basis functions are used for expanding the surface current and their rates of numerical convergence are compared. The numerical methods introduced here are more useful than other known techniques for antennas with length to maximum diameter ratios from about 0.25 to 25, and with maximum diameters of about two wavelengths. Detailed numerical results are presented for half-wave cylindrical dipoles with rounded corners of varying curvature and for end-loaded cylindrical dipoles. Some confirmatory experimental results are reported. Comparison is made with results previously reported in the literature.     

A synthesis of 5-hydroxysedamine using hydroformylation

A synthesis of 5-hydroxysedamine, a Sedum alkaloid, has been completed using N,O-heterocycle chemistry to establish the aminoalcohol structure, hydroformylation to form the piperidine ring and diastereoselective dihydroxylation to introduce the 5-hydroxy group.     

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Solvent effects on the dissociation of weak acids of three charge types in water/N-methylacetamide media

In order to elecidate the role of charge type on the change of dissociation constant with increasing polarity of the solvent medium, the pK values and associated thermodynamic quantities for an uncharged acid (acetic acid), a cationic acid (protonated tris(hydroxymethyl)aminomethane), and two ampholytes (MOPS and Tricine) were determined in mixtures of water andN-methylacetamide (NMA). Electromotive-force measurements of cells without liquid junction containing hydrogen electrodes and silver-silver bromide electrodes were used to determine the pK at nine temperatures from 5 to 45°C. The solvent compositions varied from pure water to a mixture containing a mole fraction of NMA of 0.25 (57.5 mass % NMA). The solvent effects are compared with similar data for water/methanol solvents of decreasing polarity. They reflect both the reduction in interionic energy accompanying the elevation in dielectric constant and also the greater protophilic character of NMA as compared with methanol.     

Implantation of undifferentiated and predifferentiated human neural stem cells in the R6/2 transgenic mouse model of Huntington's disease

ABSTRACT: BACKGROUND: Cell therapy is a potential therapeutic approach for several neurodegenetative disease, including Huntington Disease (HD). To evaluate the putative efficacy of cell therapy in HD, most studies have used excitotoxic animal models with only a few studies having been conducted in genetic animal models. Genetically modified animals should provide a more accurate representation of human HD, as they emulate the genetic basis of its etiology. RESULTS: In this study, we aimed to assess the therapeutic potential of a human striatal neural stem cell line (STROC05) implanted in the R6/2 transgenic mouse model of HD. As DARPP-32 GABAergic output neurons are predominately lost in HD, STROC05 cells were also predifferentiated using purmorphamine, a hedgehog agonist, to yield a greater number of DARPP-32 cells. A bilateral injection of 4.5x105 cells of either undifferentiated or predifferentiated DARPP-32 cells, however, did not affect outcome compared to a vehicle control injection. Both survival and neuronal differentiation remained poor with a mean of only 161 and 81 cells surviving in the undifferentiated and differentiated conditions respectively. Only a few cells expressed the neuronal marker beta-III-tubulin. CONCLUSIONS: Although the rapid brain atrophy and short life-span of the R6/2 model constitute adverse conditions to detect potentially delayed treatment effects, significant technical hurdles, such as poor cell survival and differentiation, were also sub-optimal. Further consideration of these aspects is therefore needed in more enduring transgenic HD models to provide a definite assessment of this cell line's therapeutic relevance. However, a combination of treatments is likely needed to affect outcome in transgenic models of HD.     

Stannous chloride-mediated reductive cyclization-rearrangement of nitroarenyl ketones

Cyclization products are produced in excellent yields from using standard reaction conditions for nitroarene reduction to aminoarene with SnCl2. Thus, 4-methyl-2-(2-nitrobenzyl)-2H-1,4-benzothiazin-3(4H)-one (2b) upon treatment with SnCl2 in ethanol did not produce the expected aniline derivative. Instead, 6-methyl-11a, 12-dihydro-6H-quino[3,2-b][1,4]benzothiazine (3) was produced in excellent yield, presumably via novel Sn (IV)-mediated amidine formation from the initial aniline reduction product. Under identical reaction conditions, 2-(2-nitrophenyl)-thiochroman-4-one (6) produces ethyl 5,11-dihydrodibenzo[b,e][1,4]thiazepin-11-ylacetate (7). A novel semipinacol rearrangement is proposed to account for this extensive skeletal rearrangement. Aniline derivative (14) (from 6 treated with FeSO4.7H2O) forms 12-ethoxy-11,12-dihydro-6H-6,12-methanodibenzo[b,f][1,5]thiazocine (15) upon treatment with SnCl2 in ethanol. Thiophene analogues of 6 and 14 (18 and 19, respectively) react similarly, forming the analogous thiazepine (20) and cyclic N,O-acetals (21), respectively.     

Rigid Arrangements of Ionic Charge in Zeolite Frameworks Conferred by Specific Aluminum Distributions Preferentially Stabilize Alkanol Dehydration Transition States

Zeolite reactivity depends on the solvating environments of their micropores and the proximity of their Brønsted acid sites. Turnover rates (per H⁺) for methanol and ethanol dehydration increase with the fraction of H⁺ sites sharing six-membered rings of chabazite (CHA) zeolites. Density functional theory (DFT) shows that activation barriers vary widely with the number and arrangement of Al (1–5 per 36 T-site unit cell), but cannot be described solely by Al–Al distance or density. Certain Al distributions yield rigid arrangements of anionic charge that stabilize cationic intermediates and transition states via H-bonding to decrease barriers. This is a key feature of acid catalysis in zeolite solvents, which lack the isotropy of liquid solvents. The sensitivity of polar transition states to specific arrangements of charge in their solvating environments and the ability to position such charges in zeolite lattices with increasing precision herald rich catalytic diversity among zeolites of varying Al arrangement.