Low-energy Sr2MSbO5.5 (M = Ca and Sr) structures show significant distortions near oxygen vacancies

Inspired by significant local distortions found near vacancies in a neutron pair distribution function analysis study (G. King et al., Inorg. Chem. 2012, 51, 13060) of Sr₂ MSbO_5.5 (M = Ca and Sr), this computational study finds minimum-energy structures with these and related distortions using density functional theory (DFT) with the Perdew-Burke-Ernzerhof (PBE) functional as implemented in the Vienna Ab Initio Simulations Package (VASP) (G. Kresse and J. Furthmüller, Phys. Rev. B, 1996, 54, 11169; G. Kresse and J. Hafner, Phys. Rev. B, 1993, 47, 558; G. Kresse and J. Furthmüller, Comput. Mater. Sci., 1996, 6, 15). All structures were optimized using the conjugate gradient method. The global minima found for both systems featured trigonal bipyramid SbO₅ structures and edge sharing with M-centered polyhedra. However, while calcium ions occupied full and partial octahedra, the larger strontium ions were more commonly found in full and partial pentagonal bipyramids. Molecular dynamics with velocity rescaling at 1200 K revealed movements of the oxygen vacancy via polyhedral rotations. This work highlights the need to consider both square pyramid to trigonal bipyramid rearrangements around small ions and rotational polyhedral movements in simulating oxygen vacancy conduction in oxygen-deficient double perovskites.     

Discovery,Synthesis and Evaluation of a Ketol-Acid Reductoisomerase Inhibitor

Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis. Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis (Mt) KARI and identified two compounds that have K_i values below 200 nm . In Mt cell susceptibility assays one of these compounds exhibited an IC₅₀ value of 0.8 μm . Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2H-benzo[b][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56 % identity with Mt KARI, NADPH and Mg²⁺ yielded a structure to 1.72 Å resolution. However, only a hydrolyzed product of the inhibitor (i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, 3-(methylsulfonyl)-2-oxopropanic acid was identified as a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug lead, especially given it has low toxicity against human cells. The study highlights that careful analysis of broad screening assays is required to correctly interpret cell-based activity data.     

Bioanalytical challenges and strategies for accurately measuring acyl glucuronide metabolites in biological fluids

Bioanalysis of unstable compounds such as acyl glucuronide metabolites represents a great analytical challenge owing to poor analyte stability in biological matrices. The primary goal for bioanalytical assay development is to minimize the breakdown of acyl glucuronide metabolite into its parent aglycone during sample collection, transportation, storage and analysis. Samples need to be stabilized ex vivo immediately after sample collection to minimize potential breakdown and thus to ensure accurate concentration measurement of both acyl glucuronide metabolite and its parent aglycone. In this review paper, formation of acyl glucuronide metabolites, the importance of establishing acyl glucuronide exposure measurement and safety coverage, optimization of sample pretreatment to stabilize the acyl glucuronide metabolites, current analytical strategy of assaying them as well as considerations for regulatory filings are discussed. It is important to identify acyl glucuronide metabolites that are capable of undergoing hydrolysis and pH-dependent intra-molecular migration as well as covalently binding to plasma and tissue proteins which can cause toxicity in vivo in the early stages of drug development. Carefully planning analytical experiments, identifying structures of acyl glucuronides and monitoring their concentrations in early drug development can help assess the risks associated with their exposures and potentially predict their concentrations in human circulation.     

Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade

A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,β-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.     

A threshold for charge transfer in aromatic interactions? A quantitative study of pi-stacking interactions

[structure: see text] Attractive interactions between substituted arenes in the parallel displaced configuration have been quantitatively studied using triptycene-derived molecular conformational reporters. Charge-transfer bands are observed for models where the interactions are between strong donor and acceptors. Substituent effects on the strength of the aromatic interaction follow opposite trends for strongly electron-deficient arenes and mildly perturbed arenes. The free energy of interactions for models with strong electron donors and acceptors does not follow a linear correlation in the Hammett plot. Electrostatic models alone do not account for the nonlinearity of the free energy-substituents plot.     

Observation of the hc(1P1) state of charmonium

The h(c)((1)P(1)) state of charmonium has been observed in the reaction psi(2S) --> pi(0)h(c) --> (gammagamma)(gammaeta(c)) using 3.08 x10(6) psi(2S) decays recorded in the CLEO detector. Data have been analyzed both for the inclusive reaction, where the decay products of the eta(c) are not identified, and for exclusive reactions, in which eta(c) decays are reconstructed in seven hadronic decay channels. We find M(h(c)) = 3524.4 +/- 0.6 +/- 0.4 MeV which corresponds to a hyperfine splitting DeltaM(hf)(1P) triple-bond pi(0)h(c)) x B(h(c) --> gammaeta(c)) = (4.0 +/- 0.8 +/- 0.7) x 10(-4).     

Thermodynamics and kinetics of complexation of iron(III) ion by picolinic and dipicolinic acids

The complexation reactions of iron(III) with 2-pyridine carboxylic acia (picolinic acid) and 2,6-pyridine dicarboxylic acid (dipicolinic acid) in aqueous solutions have been studied by spectrophotometric and stopped flow techniques. Equilibrium constants were determined for the 1 : 1 complexes at temperatures between 25 and 80°C. The values obtained are: Picolinic Acid (HL): Fe³⁺+ H₂L⁺? FeHL³⁺+H+(K₁ = 2.8,ΔH = 2 kcal mole^?1 at 25°C, μ = 2.67 M) Dipicolinic Acid (H₂D): Fe³⁺+H₂D? FeD⁺+2H⁺(K₁K_1A= 227 M, ΔH = 3.4 kcal mole^?1 at 25°C,μ = 1.0 M). The rate constants for the formation of these complexes are also given. The results are used to evaluate the effects of these two acids upon the rate of dissolution of iron(III) from its oxides.