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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.

A series of n-alkyl/aryl esters were synthesized and their in vitro antiplasmodial activity was measured alongside that of previously synthesized aminoethylethers of artemisinin ozonides against various strains of Plasmodium falciparum. The cytotoxicity against human cell lines was also assessed. The esters were synthesized in a one-step reaction by derivatization on carbon C-10 of dihydroartemisinin. Both classes were active against both the 3D7 and K1 strains of P. falciparum, with all compounds being significantly more potent than artemether against both strains. The majority of compounds possessed potency either comparable or more than artesunate with a high degree of selectivity towards the parasitic cells. The 10a-n-propyl 11 and 10a-benzyl 18 esters were the most potent of all synthesized ozonides, possessing a moderate ( 3-fold) and significant (22- and 12-fold, respectively) potency increases against the 3D7 and K1 strains, respectively, in comparison with artesunate. http://www.journals.elsevier.com/bioorganic-chemistry/

Series of bisquinolines 4e15 and bispyrrolo[1,2a]quinoxalines 16e20 containing various polyamine linkers were synthesized. The aqueous solubility and distribution coefficient were experimentally determined. The compounds were screened for antimalarial activity alongside chloroquine against D10 and Dd2 strains of Plasmodium falciparum. The growth inhibitory effects of biscompounds 4e9 were assessed against various cancer cell lines. The aqueous solubility was found to increase with an increase in potential proton.ation sites. Bisquinolines 8 and 9 featuring triethylenetetramine and N,N0-bis(3- aminopropyl)ethylene-diamine linkers, respectively, were the most active of all synthesized compounds. They were found as potent as chloroquine against D10 but significantly more potent against the Dd2 strain, with good selectivity towards parasitic cells. Compound 4 containing a diethylenetriamine bridge displayed the most important anticancer activity of the series, and was a more effective antiproliferative inhibitor than etoposide against all three TK10, UACC62 and MCF7 cancer cell lines National Research Foundation (NRF) and the North-West University (NWU)

In this study, a series of 11 10-aminoethylether derivatives of artemisinin were synthesised and their antimalarial activity against both the chloroquine sensitive (D10) and resistant (Dd2) strains of Plasmodium falciparum was determined. The compounds were prepared by introducing aliphatic, alicyclic and aromatic amine groups with linkers of various chain lengths through an ethyl ether bridge at C-10 of artemisinin using conventional and microwave assisted syntheses, and their structures were confirmed by NMR and HRMS. All derivatives proved to be active against both strains of the parasite. The highest overall activity was displayed by the short chain aromatic derivative 8 (IC50 = 1.44 nM), containing only one nitrogen atom, while long chain polyamine derivatives were found to have the lowest activity against both strains. An interesting correlation between the IC50, pKa values and resistance index (RI) was found National Research Foundation (NRF), the North- West University (NWU)

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.