The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC50 value of 0.38 µM and a promising off-target ADME-Tox profile in vitro. In silico molecular target investigations showed rhodesain to be a putative candidate, supported by STD and WaterLOGSY NMR experiments, however, in vitro evaluation of compound 13 against rhodesain exhibited low experimental inhibition. Therefore, our reported library of drug-like pyrimidines present promising scaffolds for further antikinetoplastid drug development for both phenotypic and target-based drug discovery.

NMR spectral analysis of strongly second-order 6-, 8-, 9- and 10- spin-systems (1 H─19 F, 19 F─19 F, and 13 C─19 F) in perfluorotoluyl- and tetrafluoro-pyridyl-aromatics using the lineshape method ANATOLIA.

A simple to use nuclear magnetic resonance analysis method has been tested on complex 1 H, 19 F, and 13 C multiplets. This open-source line-shape analysis method analysis of total lineshape (ANATOLIA)1 provides some significant advantages over traditional assign-iterate methods of NMR spectral analysis by avoiding false minima and progressing optimisation to the global minimum. The target molecules are 1-perfluorotol-4-yl-2-perfluorotol-4-yl-oxymethyl-1H-benzimidazole (molecule-I) and 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-yl-thio-1H-benzimidazole (molecule-II) which were produced as part of a family of fluorinated drug scaffolds prepared for anticancer and antiparasitic screening. Spectra display significant second-order effects with 1 H Δδ = 3.68 and 4.67 Hz for the aromatic hydrogen "triplets", with 19 F 4 JAA' , 4 JBB' , 4 JXX' , and 4 JYY' coupling constants range from +4.8 to -14.0 Hz and for 13 C-isotopomers 19 F Δδ of up to 111.56 Hz. A spin-system of six coupling nuclei (Ha Hb Hc Hd FY FY' ) was analysed in 12 s, a spin-system of nine coupling fluorine nuclei (AA'BB'CCC-YY') was analysed within 2 min, and 10 coupling nuclei (XX'YY'ZZZ-BB'-Hd ) was optimised in 6 min using a laptop computer. ANATOLIA was also robust enough to be able to yield accurate spectral values from inaccurate input values. In both compounds, a fluorine-fluorine coupling constant was identified between the two fluoro-aromatic rings (FBB' and FYY' ) of +4.05 and +4.67 Hz and attributed to a through-space interaction. Ab initio structure optimisations and coupling constant calculations provided useful input data for spectral analysis. A modern 19 F nuclear magnetic resonance spectrum of perfluorotoluene (octafluorotoluene) and analysis from 1975 was used as a test data set to assess ANATOLIA.

3D printed fluidics with embedded analytic functionality for automated reaction optimisation.

Additive manufacturing or '3D printing' is being developed as a novel manufacturing process for the production of bespoke micro- and milliscale fluidic devices. When coupled with online monitoring and optimisation software, this offers an advanced, customised method for performing automated chemical synthesis. This paper reports the use of two additive manufacturing processes, stereolithography and selective laser melting, to create multifunctional fluidic devices with embedded reaction monitoring capability. The selectively laser melted parts are the first published examples of multifunctional 3D printed metal fluidic devices. These devices allow high temperature and pressure chemistry to be performed in solvent systems destructive to the majority of devices manufactured via stereolithography, polymer jetting and fused deposition modelling processes previously utilised for this application. These devices were integrated with commercially available flow chemistry, chromatographic and spectroscopic analysis equipment, allowing automated online and inline optimisation of the reaction medium. This set-up allowed the optimisation of two reactions, a ketone functional group interconversion and a fused polycyclic heterocycle formation, via spectroscopic and chromatographic analysis.

Design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes.

Current treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 < 1 µM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.

Nutritional content of fresh and canned peaches.

BACKGROUND: The objective of this study was to assess whether canned peaches could deliver nutrient levels comparable to fresh peaches. Fresh freestone peaches, fresh cling peaches and canned cling peaches were analyzed for vitamins A, C and E, folate, antioxidants, total phenolics and total carotenoids to assess how these nutrients were affected by the canning process and whether storage further changed these components. RESULTS: The vitamins and phytochemicals measured in this study were found to be present in canned cling peaches versus fresh freestone at statistically significantly higher levels (vitamin C, antioxidants and folate); higher but not statistically different levels (vitamin A); or lower, but not statistically different levels (vitamin E, total phenolics and total carotenoids). There were no statistically significant changes in nutrient content during storage for 3 months. CONCLUSIONS: The nutritional content of canned peaches has been shown in this study to be comparable to that of fresh peaches. There were no statistically significant decreases in those nutritional parameters measured in this study between fresh freestone peaches and canned cling peaches. Vitamins A and E along with total carotenoids decrease immediately upon processing, but appear to stabilize after the processing step, showing minimal additional changes upon storage for 3 months. This study shows that canned peaches can provide comparable nutrient levels to the consumer as fresh peaches, meaning that consumers can enjoy peaches year round without worrying about loss of nutrients in their diet.

Synthesis of fluorinated fused benzofurans and benzothiophenes: Smiles-type rearrangement and cyclisation of perfluoro(het)aryl ethers and sulfides.

Lithium-bromine exchange in 2-bromophenyl perfluoroaryl ethers or sulfides affords fused fluorinated benzofurans or benzothiophenes respectively by S(N)Ar substitution of the adjacent fluorine in the perfluoroaryl substituent. The structures of the new compounds were confirmed by NMR spectroscopy and single crystal X-ray diffraction analysis. In the case of 2-bromophenyl tetrafluoropyrid-4-yl ether, lithiation promoted a Smiles-type rearrangement which led to formation of 4-(2-hydroxyphenyl)tetrafluoropyridine, for which the structure was confirmed by X-ray crystallography.

Methyl 2-methyl-4-(oxiran-2-ylmeth-oxy)-2H-1,2-benzothia-zine-3-carboxyl-ate 1,1-dioxide.

In the title compound, C(14)H(15)NO(6)S, the thia-zine ring adopts a distorted half-chair conformation. The structure displays several cooperative weak inter-molecular C-H⋯O hydrogen-bonding inter-actions, giving rise to a two-dimensional sheet packing motif. The CH(2) group in the meth-oxy linker to the oxirane ring, and the CH group in that ring, exhibit twofold positional disorder. The three-membered oxirane ring is twisted approximately perpendicular with respect to thia-zine ring (dihedral angle = 60/86° for the major/minor disorder components). 1,2-Benzothia-zines of this kind have a wide range of biological activities and are mainly used as medicines in the treatment of inflammation and rheumatoid arthritis.

Synthesis, characterization and antibacterial activity of azomethine derivatives derived from 2-formylphenoxyacetic acid.

A series of eight new azomethine derivatives were synthesized by reacting 2-formylphenoxyacetic acid with aromatic amines. The chemical structures of these compounds were confirmed by means of 1H-NMR, 13C-NMR, MS and elemental analysis. The compounds were assayed by the disc diffusion method for antibacterial against Staphylococcus aureus and Escherichia coli. Among the compounds tested, 2a, 2b, 2e, 2g and 2h exhibited good antibacterial activity, almost equal to that of Ciprofloxacin used as standard.

Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin.

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone , mackinazolinone , tryptanthrin , luotonin A and rutaecarpine were synthesised by radical cyclisation onto 3H-quinazolin-4-one.

Unexpected ring expansion of an enantiopure imidazoline carbene ligand.

[reaction: see text] We report an unexpected ring expansion reaction of an enantiopure fenchone-derived imidazolinium salt during attempts to form copper complexes of the corresponding imidazoline carbene ligand. A N,N'-difenchyl piperazinone was formed in low yield together with the difenchyl-substituted five-membered urea.