The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state (1)H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far.

Oxidation of the spirocyclic oxindole derivative, isamic acid 1, led to decarboxylation and ring expansion to quinazolino[4,5-b]quinazoline-6,8-dione 7 rather than, as previously believed, its isomer 6. The structure of 7 was confirmed by X-ray crystallography. Condensation of isatin (indole-2,3-dione) and 2-aminobenzamide led to the spirocyclic molecule, spiro[3H-indole-3,2′(1H)quinazoline]-2,4′(1H,3H)dione 8, which was also identified as an intermediate in the oxidation of isamic acid. Mild hydrolysis of 7 gave the 10-membered molecule 22. Isamic acid could easily be converted to N-nitrosoisamic acid, which when heated in ethanol underwent a ring expansion to a hydroximino derivative, 38, of compound 6. The structure of 38 was confirmed by X-ray crystallography.

The number of antibiotic-resistant bacteria is increasing worldwide, and the demand for novel antimicrobials is constantly growing. Antimicrobial peptides (AMPs) could be an important part of future treatment strategies of various bacterial infection diseases. However, AMPs have relatively low stability, because of proteolytic and chemical degradation. As a consequence, carrier systems protecting the AMPs are greatly needed, to achieve efficient treatments. In addition, the carrier system also must administrate the peptide in a controlled manner to match the therapeutic dose window. In this work, lyotropic liquid crystalline (LC) structures consisting of cubic glycerol monooleate/water and hexagonal glycerol monooleate/oleic acid/water have been examined as carriers for AMPs. These LC structures have the capability of solubilizing both hydrophilic and hydrophobic substances, as well as being biocompatible and biodegradable. Both bulk gels and discrete dispersed structures (i.e., cubosomes and hexosomes) have been studied. Three AMPs have been investigated with respect to phase stability of the LC structures and antimicrobial effect: AP114, DPK-060, and LL-37. Characterization of the LC structures was performed using small-angle X-ray scattering (SAXS), dynamic light scattering, ζ-potential, and cryogenic transmission electron microscopy (Cryo-TEM) and peptide loading efficacy by ultra performance liquid chromatography. The antimicrobial effect of the LCNPs was investigated in vitro using minimum inhibitory concentration (MIC) and time-kill assay. The most hydrophobic peptide (AP114) was shown to induce an increase in negative curvature of the cubic LC system. The most polar peptide (DPK-060) induced a decrease in negative curvature while LL-37 did not change the LC phase at all. The hexagonal LC phase was not affected by any of the AMPs. Moreover, cubosomes loaded with peptides AP114 and DPK-060 showed preserved antimicrobial activity, whereas particles loaded with peptide LL-37 displayed a loss in its broad-spectrum bactericidal properties. AMP-loaded hexosomes showed a reduction in antimicrobial activity.

Solubility is a frequently recurring issue within pharmaceutical industry, and new methods to proactively resolve this are of fundamental importance. Here, a novel methodology is reported for intrinsic solubility improvement, using in silico prediction of crystal structures, by perturbing key interactions in the crystalline solid state. The methodology was evaluated with a set of benzodiazepine molecules, using the two‐dimensional molecular structure as the only a priori input. The overall trend in intrinsic solubility was correctly predicted for the entire set of benzodiazepines molecules. The results also indicate that, in drug compound series where the melting point is relatively high (i.e., “brick dust” compounds), the reported methodology should be very suitable for identifying strategically important molecular substitutions to improve solubility. As such, this approach could be a useful predictive tool for rational compound design in the early stages of drug development.

A new redox couple, [Cu(bpye)2]+/2+, has been synthesized, and applied in dye-sensitized solar cells (DSSCs). Overall efficiencies of 9.0% at 1 sun and 9.9% at 0.5 sun were obtained, which are considerably higher than those obtained for cells containing the reference redox couple, [Co(bpy)3]2+/3+. These results represent a record for copper-based complex redox systems in liquid DSSCs. Fast dye regeneration, sluggish recombination loss processes, faster electron self-exchange reactions and suitable redox potentials are the main reasons for the observed increase in efficiency. In particular, the main disadvantage of cobalt complex-based redox couples, charge-transport problems, appears to be resolved by a change to copper complex redox couples. The results make copper complex-based redox couples very promising for further development of highly efficient DSSCs.

This study focused on the mechanistic interpretation of ex vivo oxidation of a candidate drug in blood plasma samples. An unexpected lipid peroxide-mediated epoxidation followed by a dramatic rearrangement led to production of a five-membered oxazole derivative from the original six-membered pyrazinone-carboxamide core of a human neutrophil elastase inhibitor, 6-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-N-ethyl-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxamide (AZD9819). The rearranged oxidation product 2-(1-(4-cyanophenyl)-1H-pyrazol-5-yl)-5-(N-ethylacetamido)-N-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide was characterized by accurate-mass tandem mass spectrometry fragmentations, by two-dimensional NMR and X-ray crystallography of an authentic standard, and by incorporation of an (18)O atom from molecular (18)O2 to the location predicted by our proposed mechanism. The lipid peroxide-mediated oxidation was demonstrated by using human low-density lipoprotein (LDL) in pH 7.4 phosphate buffer and by inhibiting the oxidation with ascorbic acid or l-glutathione, two antioxidants effective in both plasma and the LDL incubation. A nucleophilic mechanism for the epoxidation of AZD9819 by lipid hydroperoxides explains the prevention of its ex vivo oxidation by acidification of the plasma samples. The discovery of the lipid peroxide-dependent oxidation of an analyte and the means of prevention could provide valuable information for biotransformation and bioanalysis.

Glioblastoma remains an incurable brain cancer. Drugs developed in the past 20 years have not improved the prognosis for patients, necessitating the development of new treatments. We have previously reported the therapeutic potential of the quinoline methanol Vacquinol-1 (1) that targets glioblastoma cells and induces cell death by catastrophic vacuolization. Compound 1 is a mixture of four stereoisomers due to the two adjacent stereogenic centers in the molecule, complicating further development in the preclinical setting. This work describes the isolation and characterization of the individual isomers of 1 and shows that these display stereospecific pharmacokinetic and pharmacodynamic features. In addition, we present a stereoselective synthesis of the active isomers, providing a basis for further development of this compound series into a novel experimental therapeutic for glioblastoma.

2,2′-Biindolyl has been condensed with aromatic and aliphatic aldehydes and products featuring 10-membered rings have been obtained. Thus, benzaldehyde gave compound 24a as the primary product, which readily underwent transannular oxidative coupling to 25a. The structures of both compounds were confirmed by X-ray crystallography. The product from 2,2′-biindolyl and formaldehyde under strongly acidic conditions was slightly different leading to compound 11, whose structure also was confirmed by X-ray crystallography. In this case, two molecules of 2,2′-biindolyl reacted with six molecules of formaldehyde.

A method for the preparation of [3'-3H]-4-(2'-chloro-6'- hydroxyphenyl)-2-thioxo-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-5 (2H)-one (1), a TRPA1 inhibitor, was developed for the evaluation of imaging properties of a class of TRPA1 inhibitors. 1 was prepared via tritiation of a protected benzaldehyde followed by a tetrachlorosilane catalyzed multicomponent one-step fusion and was obtained at a specific activity of 0.9 TBq/mmol. A 3H-NMR spectrum on 13.5MBq at 75 μM was recorded.

The synthetic route and properties of three 2D hybrid organic/inorganic lead iodide perovskite materials are reported. The 2D perovskites were synthesized from the reaction between PbI₂and the di-cations of 1,4-diaminobutane, 1,6-diaminohexane, and 1,8-diaminooctane. The resulting products were [NH₃(CH₂)₄NH₃]PbI₄ (BdAPbI₄), [NH₃(CH₂)₆NH₃]PbI₄ (HdAPbI₄), and [NH₃(CH₂)₈NH₃]PbI₄ (OdAPbI₄). Structural characterization shows that two dimensional perovskite structures were formed with inorganic structural planes separated by organic layers. Absorption spectra show band gaps of 2.37 eV (BdAPbI₄), 2.44 eV (HdAPbI₄), and 2.55 eV (OdAPbI₄). The 2D perovskite materials were investigated as light absorbing materials in solid state solar cells. The best performing material under moist, ambient conditions was BdAPbI₄(1.08% efficiency), which was comparable to methylammonium Pb(II) iodide (MAPbI₃) solar cells (2.1% efficiency) manufactured and studied under analogous conditions. When compared to MAPbI₃, the 2D materials have larger band gaps and lower photoconductivity, while BdAPbI₄based solar cells shows a comparable absorbed photon-to-current efficiency as compared toMAPbI₃ based ones.