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The treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson’s disease represent significant challenges in healthcare. Enzymes that metabolise neurotransmitter amines are important drug targets for these disorders and inhibitors of these enzymes have played key roles as therapeutic agents. For example, inhibitors of monoamine oxidase (MAO) A have been used for decades as antidepressant agents and act by inhibiting the central metabolism of serotonin and noradrenaline, while MAO-B inhibitors conserve central dopamine supply and have been used to treat Parkinson’s disease. Literature reports that benzoxathiolone derivatives act as potent MAO inhibitors with specificity for the MAO-B isoform. To expand on these findings, the present study synthesised series of benzoxathiolone derivatives and investigated their human MAO inhibition properties. The results showed that the benzoxathiolone derivatives were potent MAO inhibitors, with the most potent compounds exhibiting IC50 values of 0.083 and 0.086 µM (4d and 5e) and 0.0069 and 0.0066 µM (3a and 3b) for MAO-A and MAO-B, respectively. Compounds 4d and 5e are significantly more potent MAO-A inhibitors compared to those reported previously. It may be concluded that benzoxathiolone derived compounds may act as future leads for the development of new treatments for depression and Parkinson’s disease. Graphical Abstract

It has been shown that methylene blue has antimicrobial properties although few studies have determined its minimum inhibitory concentration (MIC), which is the gold standard used to measure antimicrobial activity. The exact antimicrobial mode of action of methylene blue is still unclear and to our knowledge no pharmacophore model has yet been created to investigate methylene blue's mode of action. The aim of this study was to determine the MIC of methylene blue and a number of its analogous against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Salmonella enterica and Candida albicans, and to use these data to develop and validate a common feature pharmacophore model. Three statistical metrics, i.e. the enrichment factor (EF), hit rate (HR) and the area under the curve of a receiver operator characteristic (ROC-AUC), were used to determine the pharmacophore model's ability to differentiate between active/decoy compounds. The validated pharmacophore model was used to map similar antibacterial compounds in an attempt to elucidate methylene blue's antimicrobial mode of action. Most test compounds only had activity against S. aureus, S. epidermidis and K. pneumoniae. Dimethyl methylene blue, new methylene blue and acriflavine proved to be the most active compounds against S. aureus [1 µg/ml (dimethyl methylene blue); 4 µg/ml (new methylene blue); 8 µg/ml (acriflavine)], S. epidermidis [1 µg/ml (dimethyl methylene blue); 4 µg/ml (new methylene blue); 2 µg/ml (acriflavine)] and K. pneumoniae [8 µg/ml (dimethyl methylene blue); 0.5 µg/ml (new methylene blue); 2 µg/ml (acriflavine)]. A common feature pharmacophore model was created (rank score: 26.664, max. fit value: 4), which was able to accurately identify active methylene blue analogous out of the test set (EF2%: 51, HR2%: 100%, ROC-AUC: 1.00 ± 0.00). Six phenothiazine derivatives with known antibacterial activity had high fit values when mapped with the validated pharmacophore model, i.e. >3.4. Dimethyl methylene blue, new methylene blue and acriflavine had potent antibacterial activity against S. aureus, S. epidermidis and K. pneumoniae. The MIC data will allow other researchers to compare the activity across different laboratories. The common feature pharmacophore model was able to identify methylene blue analogous with known in vitro antibacterial activity out of a database containing active/decoy compounds and highlighted the importance of two hydrophobic features, an aromatic feature and a hydrogen bond acceptor. The validated pharmacophore model also correctly mapped six phenothiazine derivatives with known antibacterial activity suggesting that they may share a common antibacterial mechanism of action.

Low dietary calcium intake and absorption may increase the risk of hypocalcaemia disease states. Reducing the particle size of calcium-containing powders and increasing the specific surface area (SSA), may have high oral calcium bioavailability. The absorption of a single dose of different sized calcium carbonate nanoparticles was traced in Sprague-Dawley rats with radioactive calcium-45 (half-life = 162.6 days, β− endpoint = 258 keV; 100%). Four calcium carbonate formulations (calcium-45) were administered to Sprague-Dawley rodents (6 per treatment; n = 24). The groups were [45Ca]CaCO3 SSA 3 m2/g, [45Ca]CaCO3 36 m2/g, [45Ca]CaCO3 64 m2/g and a separate [45Ca]CaCO3 36 m2/g formulation produced by flame assisted pyrolysis. Blood and urine were sampled periodically, and organs collected and analysed after euthanasia. No changes in SSA or crystallinity were observed when powders before or after irradiation were compared. The [45Ca]CaCO3 64 m2/g formulation presented with higher levels in blood 2 h after administration and a higher liver and femur concentration. These findings suggest [45Ca]CaCO3 64 m2/g could lead to increased oral bioavailability.

The Psalms in the first Bible translation and its versification by Totius The versification of the Psalms in Afrikaans by Totius is regarded as a part of Afrikaans literature. Its publication and the first edition of the Bible in Afrikaans in the thirties both coincided with a renewal in Afrikaans literature. In this article the relation between the versification of the Psalms and the Biblical Psalms is investigated.

The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine their partition coefficients, and to assess whether they deliver the parent drug in the plasma. If increased plasma concentrations of eflornithine could be achieved in this way, an oral dosage form would be possible. The derivatives, nine in total, were successfully synthesized by multi-step derivatisation of eflornithine on either its alpha-carboxylic or/and alpha-amino or/and delta-amino groups by either esterification or/and amidation or/and carbamylation, and their structures confirmed by NMR and MS spectroscopy. The majority of derivatives were more lipophilic than eflornithine with log D values in phosphate buffer solution (pH 7.4) ranging from -1.34 to 1.59 (vs. -0.98 for eflornithine). The in vivo absorption after oral administration to Sprague-Dawley rats showed that no derivative delivered eflornithine in the plasma, indicating that the derivatives were either not absorbed from the gastrointestinal tract or not metabolized to the parent drug. Two of the monosubstituted activities were toxic for T. brucei blood stream forms.