2-[N-(2,4-Difluoro­phen­yl)carbamo­yl]-3,4,5,6-tetra­fluoro­benzoic acid

The title compound, C14H5F6NO3, was synthesized by condensation of tetra­fluoro­phthalic anhydride and 2,4-difluoro­aniline. It was then recrystallized from hexane to give a nonmerohedral twin with two crystallographically unique mol­ecules in the asymmetric unit. The refined twin fraction is 0.460 (3). Torsional differences between the aryl rings and the central amide group account for the presence of two unique mol­ecules. The compound packs as double tapes formed by O—H⋯O and N—H⋯O hydrogen-bonding inter­actions between each unique mol­ecule and its symmetry equivalents

Solvent-induced micelle formation in a hydrophobic interaction model

We investigate the aggregation of amphiphilic molecules by adapting the two-state Muller-Lee-Graziano model for water, in which a solvent-induced hydrophobic interaction is included implicitly. We study the formation of various types of micelle as a function of the distribution of hydrophobic regions at the molecular surface. Successive substitution of non-polar surfaces by polar ones demonstrates the influence of hydrophobicity on the upper and lower critical solution temperatures. Aggregates of lipid molecules, described by a refinement of the model in which a hydrophobic tail of variable length interacts with different numbers of water molecules, are stabilized as the length of the tail increases. We demonstrate that the essential features of micelle formation are primarily solvent-induced, and are explained within a model which focuses only on the alteration of water structure in the vicinity of the hydrophobic surface regions of amphiphiles in solution.Comment: 11 pages, 10 figures; some rearrangement of introduction and discussion sections, streamlining of formalism and general compression; to appear in Phys. Rev.

3D printing of medicines: Engineering novel oral devices with unique design and drug release characteristics

YesThree dimensional printing (3DP) was used to engineer novel oral drug delivery devices, with specialised design configurations loaded with multiple actives, with applications in personalised medicine. A filament extruder was used to obtain drug-loaded - paracetamol (acetaminophen) or caffeine - filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3D printing. A multi-nozzle 3D printer enabled fabrication of capsule-shaped solid devices, containing paracetamol and caffeine, with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different from the drug in the adjacent layers; and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least squares component matching to produce false colour representations of distribution of the drugs showed clearly the areas that contain paracetamol and caffeine, and that there is a definitive separation between the drug layers. Drug release tests in biorelevant media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both drugs was simultaneous and independent of drug solubility. With the DuoCaplet design it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device, and the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.The full-text of this article will be released for public view at the end of the publisher embargo on 10 Oct 2016

Component Interactions and Electron Transfer in Toluene/o-Xylene Monooxygenase

The multicomponent protein toluene/o-xylene monooxygenase (ToMO) activates molecular oxygen to oxidize aromatic hydrocarbons. Prior to dioxygen activation, two electrons are injected into each of two diiron(III) units of the hydroxylase, a process that involves three redox active proteins: the ToMO hydroxylase (ToMOH), Rieske protein (ToMOC), and an NADH oxidoreductase (ToMOF). In addition to these three proteins, a small regulatory protein is essential for catalysis (ToMOD). Through steady state and pre-steady state kinetics studies, we show that ToMOD attenuates electron transfer from ToMOC to ToMOH in a concentration-dependent manner. At substoichiometric concentrations, ToMOD increases the rate of turnover, which we interpret to be a consequence of opening a pathway for oxygen transport to the catalytic diiron center in ToMOH. Excess ToMOD inhibits steady state catalysis in a manner that depends on ToMOC concentration. Through rapid kinetic assays, we demonstrate that ToMOD attenuates formation of the ToMOC–ToMOH complex. These data, coupled with protein docking studies, support a competitive model in which ToMOD and ToMOC compete for the same binding site on the hydroxylase. These results are discussed in the context of other studies of additional proteins in the superfamily of bacterial multicomponent monooxygenases.National Institute of General Medical Sciences (U.S.) (5-R01-GM032134)United States. National Institutes of Health (T32GM008334

Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress

Solubility of 2-Hydroxybenzoic Acid in Water, 1-Propanol, 2-Propanol, and 2-Propanone at (298.2 to 338.2) K and Their Aqueous Binary Mixtures at 298.2 K

Article discussing the solubility of 2-hydroxybenzoic acid in water, 1-propanol, 2-propanol, and 2-propanone at (298.2 to 338.2) K and their aqueous binary mixtures at 298.2 K