Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids

Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.     

Microbial products. II. Granaticinic acid,a new antibiotic from a thermophilic streptomycete

Streptomyces sp. XT-11989 produces a mixture of two antibiotics with litmus-like indicator properties. One of them was shown to be identical with granaticin, the other was identified as [1S,3S,4S,7R,9R,10S,13R]-4,7,9,10-tetrahydro-5,12-dioxo-4, 6,10,11,13-pentahydroxy-1,9-dimethyl-(1H,3H)-7,10-ethanonaphtho[2,3-c: 6,7-c]dipyran-3-acetic acid and termed granaticinic acid. Microbial production and nuclear magnetic resonance data of these antibiotics are discussed and the antibacterial properties of the antibiotics are compared.

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Mikrobielle produkte. II. Granaticinsäure, ein neues Antibiotikum von einem thermophilen Streptomyceten

Zusammenfassung Der Streptomycetenstamm XT-11989 produziert eine Mischung von zwei Antibiotika mit Lakmus-ähnlichen Indikatoreigenschaften. Eines dieser Antibiotika erwies sich als Granaticin, das andere wurde als [1S,3S,4S,7R,9R,10S,13R]-4,7,9,10-tetrahydro-5,12-dioxo-4,6,10,11,13-pentahydroxy-1,9-dimethyl-(1H,3H)-7,10-ethanonaphto[2,3-c: 6,7-c]dipyran-3-essigsäure identifiziert und Granaticinsäure benannt. Mikrobiologische Produktion und Kernresonanzdaten dieser antibiotika werden besprochen und ihre antibakteriellen Eigenschaften verglichen.

     

Conformational dependence of the intrinsic acidity of the aspartic acid residue sidechain in N-acetyl- -aspartic acid-N′-methylamide

The sidechain conformational potential energy hypersurfaces (PEHS) for the γ_L, β_L, α_L, and α_D backbone conformations of N-acetyl- -aspartate-N′-methylamide were generated. Of the 81 possible conformers initially expected for the aspartate residue, only seven were found after geometric optimizations at the B3LYP/6-31G(d) level of theory. No stable conformers could be located in the δ_L, _L, γ_D, δ_D, and _D backbone conformations. The ‘adiabatic’ deprotonation energies for the endo and exo forms of N-acetyl- -aspartic acid-N′-methylamide were calculated by comparing their optimized relative energies against those found for the seven stable conformers of N-acetyl- -aspartate-N′-methylamide. Sidechain conformational PEHSs were also generated for the estimation of ‘vertical’ deprotonation energies for both endo and exo forms of N-acetyl- -aspartic acid-N′-methylamide. All backbone–sidechain (N–H⁻O–C) and backbone–backbone (N–HO=C) hydrogen bond interactions were analyzed. A total of two backbone–backbone and four backbone–sidechain interactions were found for N-acetyl- -aspartate-N′-methylamide. The deprotonated sidechain of N-acetyl- -aspartate-N′-methylamide may allow the aspartyl residue to form strong hydrogen bond interactions (since it is negatively charged) which may be significant in such processes as protein–ligand recognition and ligand binding. As a primary example, the molecular geometry of the aspartyl residue may be important in peptide folding, such as that in the RGD tripeptide.     

Laser-spectroscopic laboratory studies of atmospheric aqueous phase free radical chemistry

Nitrate radical (NO(3)) reactions with benzene (R-1), toluene (R-2), p-xylene (R-3), p-cresol (R-4) and mesitylene (R-5) have been studied by laser photolysis/long path laser absorption (LP-LPLA) in aqueous solution. Rate constants of k(1)=(4.0+/-0.6). 10(8), k(2)=(1.2+/-0.3). 10(9), k(3)=(1.6+/-0.1). 10(9), k(4)= (8.4+/-2.3). 10(8) and k(5)=(1.3+/-0.3). 10(9) lmol(-1)s(-1) were obtained at T=298 K. In addition, reaction rate coefficients for SO(-)(5)+Fe(2+)-->prod. (R-6) and SO(-)(5)+Mn(2+)-->prod. (R-7) of k(6)=(4.3+/-2.4). 10(7) lmol(-1)s(-1) and k(7)=(4.6+/-1.0). 10(6) lmol(-1)s(-1) (T=298 K, I-->0) have been obtained by the application of laser photolysis/UV-VIS broadband diode array spectroscopy. A new laser photolysis/UV-long path laser absorption experiment has been applied to study the reaction of the Cl(-)(2) radical anion with dissolved sulfur(IV). For the reactions Cl(-)(2)+HSO(-)(3)-->2Cl(-)+H(+)+SO(-)(3) (R-8) and Cl(-)(2)+SO(2-)(3)-->2Cl(-)+SO(-)(3) (R-9) rate coefficients of k(8)=(1.7+/-0.2). 10(8) lmol(-1)s(-1) (T=298 K, I-->0) and of k(9)=(6.2+/-0.3). 10(7) lmol(-1)s(-1) (T=279 K, I-->0) were obtained.     

Structure and magnetism of VnBz(n+1) sandwich clusters

Results on structural, energetic, electronic, and magnetic properties of linear sandwich VnBzn+1 clusters obtained using high-accuracy density functional computations are presented and analyzed. Energetically close-lying configurations and states of different spin-multiplicities are identified. The computed characteristics are in good agreement with the available experimental data. The computations predict that the most stable forms of the clusters in the size range n >/= 4 are chiral. This feature, combined with the magnetism of these systems, makes them of potential importance as building blocks of nanosystems with coupled optical and magnetic functionalities.     

Structural, Electronic, and Optical Properties of Noble Metal Clusters from First Principles

We examine low-energy isomeric forms, static polarizabilities, and optical absorption spectra of Ag _n , n = 2–8, and Au _n , n = 2–3, clusters using first principles computations within the static and time-dependent versions of the density functional theory. The noticeable decrease in the static polarizabilities of Ag₇ and Ag₈ compared to the values characteristic of Ag _n , n = 2–6, is correlated with the transition from two-dimensional to three-dimensional structures at n = 7. The optical spectra computed within the time-dependent local density approximation for the most stable structures are in good agreement with the available experimental data and the results of earlier theoretical studies. Optical spectra of higher-energy isomers typically present features that are not observed in the experimental spectra. The d electrons affect the spectra of noble metal clusters by quenching the oscillator strengths through screening of the s electrons and by getting directly involved in the excitations. Due to the larger s–d hybridization in Au compared to Ag, these effects are more pronounced in Au _n clusters.     

Differential thermal analysis of polyester/cotton blends treated with Thpc—urea—poly(vinyl bromide)

Differential thermal analyses (DTA) were made on a series of polyester/cotton blend fabrics before and after treatment with Thpc—urea—poly(vinyl bromide). This flame retardant did not affect the polyester melting endotherm, which was proportional to the polyester content and appeared at approximately 250°C. In nitrogen atmosphere, DTA of the treated blends showed exothermic peaks at 285°C for the cotton decomposition. and at 415°C for the polyester decomposition. In air, DTA of the treated blends showed exothermic peaks at 333°C for cellulose decomposition, at 431°C for polyester decomposition and at 490°C for char decomposition. The Thpc-urea component of the flame retardant is effective on the cotton cellulose portion of the blend; the poly(vinyl bromide) appears to decompose and act in the vapor state on the polyester.     

Enhancing 2-iodoxybenzoic acid reactivity by exploiting a hypervalent twist

A rearrangement of hypervalent bonds, or twisting, proves to be the rate-determining step in the 2-iodoxybenzoic acid (IBX) oxidation of alcohols. From this insight, derived from density functional theory calculations, we explain why IBX oxidizes large alcohols faster than small ones and propose a modification to the reagent predicted to make it more active.     

Laser-spectroscopic laboratory studies of atmospheric aqueous phase free radical chemistry

Nitrate radical (NO₃) reactions with benzene (R-1), toluene (R-2), p-xylene (R-3), p-cresol (R-4) and mesitylene (R-5) have been studied by laser photolysis/long path laser absorption (LP-LPLA) in aqueous solution. Rate constants of k₁=(4.0±0.6) 10⁸, k₂=(1.2±0.3)10⁹, k₃=(1.6±0.1)10⁹, k₄= (8.4±2.3)10⁸ and k₅=(1.3±0.3)10⁹ lmol^-1s^-1 were obtained at T=298 K. In addition, reaction rate coefficients for SO^-₅+Fe²⁺prod. (R-6) and SO^-₅+Mn²⁺prod. (R-7) of k₆=(4.3±2.4) 10⁷ lmol^-1s^-1 and k₇=(4.6±1.0)10⁶ lmol^-1s^-1 (T=298 K, I0) have been obtained by the application of laser photolysis/UV-VIS broadband diode array spectroscopy. A new laser photolysis/UV-long path laser absorption experiment has been applied to study the reaction of the Cl^-₂ radical anion with dissolved sulfur(IV). For the reactions Cl^-₂+HSO^-₃2Cl^-+H⁺+SO^-₃ (R-8) and Cl^-₂+SO^2-₃2Cl^-+SO^-₃ (R-9) rate coefficients of k₈=(1.7±0.2)10⁸ lmol^-1s^-1 (T=298 K, I0) and of k₉=(6.2±0.3)10⁷ lmol^-1s^-1 (T=279 K, I0) were obtained.     

Recognition and catalysis in allylic alkylations

[structure: see text] A cavitand outfitted with a chelated palladium atom catalyzes allylic alkylation reactions. Molecular recognition by the cavitand distinguishes between closely related structures and results in subtle substrate specificities.