“Clicking“ fragment leads to novel dual-binding cholinesterase inhibitors

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using “clickable” fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC50 = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase

Some mechanistic aspects regarding the Suzuki–Miyaura reaction between selected ortho-substituted phenylboronic acids and 3,4,5-tribromo-2,6-dimethylpyridine

Background: Atropisomers are very interesting stereoisomers having axial chirality resulting from restricted rotation around single bonds and are found in various classes of compounds. ortho-Substituted arylpyridines are an important group of them. A regio- and atropselective Suzuki–Miyaura cross-coupling reaction on 3,4,5-tribromo-2,6-dimethylpyridine was studied.Results: Reactions with various amounts of ortho-substituted phenylboronic acids with 3,4,5-tribromo-2,6-dimethylpyridine gave a series of mono- di- and triarylpyridine derivatives which allowed to draw conclusions about the order of substitution. Also, the observed selectivity in the case of ortho-methoxyphenylboronic acid suggested an additional metal O-chelation effect in the transition state, apparently not present in the ortho-chloro analogues. The rotational barrier in selected atropisomers was determined on the basis of HT NMR and thermal epimerisation experiments. The structure of most presented atropisomeric derivatives of 2,6-dimethylpyridine was confirmed by single-crystal X-ray analysis. Racemic chiral, differently substituted atropisomers were also examined by 1H NMR spectroscopy in the presence of a chiral solvating agent.Conclusion: This regio- and atropselectivity may be generally applicable to other arylpyridine systems. A regio- and atropselective Suzuki–Miyaura cross-coupling process has been observed, giving an efficient access to a class of atropisomeric compounds. An opposite selectivity using a differently ortho-substituted phenylbornic acid was observed

New Polar Phases of 1,4-Diazabicyclo[2.2.2]octane Perchlorate, An NH⁺···N Hydrogen-Bonded Ferroelectric

Exceptionally rich diagram of ten phases, I–X, has been revealed for ferroelectric 1,4-diazabicyclo[2.2.2]­octane perchlorate, [C₆H₁₃N₂]⁺ClO₄^–, dabcoHClO₄. Pressure- and temperature-induced transformations of this NH⁺···N hydrogen bonded structure have been characterized by single-crystal X-ray diffraction, calorimetric, and dielectric measurements. At high pressure the single crystals were in situ grown in a diamond-anvil cell at isochoric conditions. There are nine phases of dabcoHClO₄ between 400 and 11 K at ambient pressure, whereas phase X is formed at 1.5 GPa and 296 K. Tetragonal phase I space group <i>P</i>4/<i>mmm</i> transforms to orthorhombic phases II (<i>Pm</i>2₁<i>n</i>), III (<i>Pc</i>2₁<i>n</i>), IV (<i>Pc</i>2<i>a</i>), and V (orthorhombic-modulated) on decreasing temperature. Phase II is stable up to 0.22 GPa, at 0.6 GPa phase III is formed, and above 1.50 GPa a new phase X (<i>Pc</i>2₁<i>a</i>) has been obtained. At normal conditions dabcoHClO₄ is isostructural with the ferroelectric crystal of dabcoHBF₄; however, their phase diagrams are very different. Above 1.8 GPa dabcoHClO₄ cocrystallizes with solvate molecules

Na[Li(NH2BH3)(2)] - the first mixed-cation amidoborane with unusual crystal structure

We describe the successful synthesis of the first mixed-cation (pseudoternary) amidoborane, Na[Li(NH2BH3)(2)], with theoretical hydrogen capacity of 11.1 wt%. Na[Li(NH2BH3)(2)] crystallizes triclinic (P (1) over bar ) with a = 5.0197(4) angstrom, b = 7.1203(7) angstrom, c = 8.9198(9) angstrom, alpha = 103.003(6)degrees, beta = 102.200(5)degrees, gamma = 103.575(5)degrees, and V = 289.98(5) angstrom(3) (Z = 2), as additionally confirmed by Density Functional Theory calculations. Its crystal structure is topologically different from those of its orthorhombic LiNH2BH3 and NaNH2BH3 constituents, with distinctly different coordination spheres of Li (3 N atoms and 1 hydride anion) and Na (6 hydride anions). Na[Li(NH2BH3)(2)], which may be viewed as a product of a Lewis acid (LiNH2BH3)/Lewis base (NaNH2BH3) reaction, is an important candidate for a novel lightweight hydrogen storage material. The title material decomposes at low temperature (with onset at 75 degrees C, 6.0% mass loss up to 110 degrees C, and an additional 3.0% up to 200 degrees C) while evolving hydrogen contaminated with ammonia

Magnetic phase diagram of the magnetocaloric compound MnFeSi

We have studied the magnetic phases of single-crystalline Mn3Fe2Si3 by neutron diffraction and magnetization measurements. Within the series Mn5−xFexSi3, an inverse magneto-caloric effect (MCE) has been observed for x=0, while for x=4 a moderately high direct MCE occurs [1]. Similarly to the parent compound Mn5Si3, Mn3Fe2Si3 exhibits two antiferromagnetic phase transitions to an AF1 and AF2 phase, respectively. The transition from AF1 → AF2 gives rise to an inverse MCE, i.e. the magnetic entropy is increased by the application of a magnetic field, albeit with complex field and temperature dependences. We discuss these changes in light of the preferential replacement of Mn by Fe on one of the two distinct lattice sites of the crystal structure (space group P63/mcm at RT). This leads to an increase in the transition temperatures and critical fields when compared to Mn5Si3. In addition, we find hints for ferromagnetic short-range correlations, which persist at temperatures twice as high as the Neel temperature. [1] Songlin et al, J. Alloys Compd, 334, 249−252 (2002