Jaco C. Breytenbach

Chiral resolution by β-cyclodextrin polymer-impregnated ceramic membranes

Abstract In this study, a porous tubular ceramic membrane was impregnated with a β-cyclodextrin (CD) polymer to obtain a chiral-selective membrane. The membrane was evaluated in terms of the effectiveness of impregnation as well as the ability to separate the enantiomers of the racemic pharmaceutical chlorthalidone (CT). Impregnation into the pores of the ceramic support was shown by the increase in weight and confirmed by porosimetry. In spite of polymer loss from the membrane during the permeation of CT, an average separation factor (α) of 1.24 was attained. The proposed mechanism of selectivity permits continual retrieval of both enantiomers in a process similar to the permeation swing adsorption.

Synthesis and antimicrobial activity of some isoindolin-1-ones derivatives

A range of N-substituted isoindolin-1-ones was prepared and their potential as novel antimicrobial agents was investigated. MIC values for active compounds were determined and reported.

Artemisinin–quinoline hybrid-dimers: Synthesis and in vitro antiplasmodial activity

Novel artemisinin-quinoline hybrid-dimers were synthesized from dihydroartemisinin and different aminoquinolines at elevated temperatures (90-110°C). All compounds were obtained as the β-isomers and were tested against both chloroquine sensitive and resistant strains of Plasmodium falciparum. Hybrid-dimer 8 showed the highest antiplasmodial activity, inheriting the optimum chain length of three carbon atoms.

Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids.

Dihydroartemisinin (DHA) was coupled to different aminoquinoline moieties forming hybrids 9-14, which were then treated with oxalic acid to form oxalate salts (9a-14a). Compounds 9a, 10a, 12, 12a, and 14a showed comparable potency in vitro to that of chloroquine (CQ) against the chloroquine sensitive (CQS) strain, and were found to be more potent against the chloroquine resistant CQR strain. Hybrids 12 and its oxalate salt 12a were the most active against CQR strain, being 9- and 7-fold more active than CQ, respectively (17.12 nM; 20.76 nM vs 157.9 nM). An optimum chain length was identified having 2 or 3 Cs with or without an extra methylene substituent.

Antimalarial and anticancer activities of artemisinin-quinoline hybrid-dimers and pharmacokinetic properties in mice

Malaria, one of the three most important life-threatening infectious diseases, is recommended to be treated with ACT (artemisinin combination therapy) against which Plasmodium falciparum already displayed resistance. Two artemisinin-4-amino-quinoline hybrid-dimers (1 and 2), previously synthesized, possessed low nanomolar in vitro antiplasmodial activity, while poorly toxic against mammalian cells. They are here investigated to ascertain whether this antimalarial activity would be carried on in vivo against Plasmodium vinckei. During the four day treatment, parasitemia of less than 1% were observed on day 5 after doses from 2.5 mg/kg ip and 50 mg/kg po for hybrid-dimer 1, and from 7.5 mg/kg ip and 25 mg/kg po for hybrid-dimer 2. Snapshot pharmacokinetic analysis demonstrated that the antiplasmodial activity of these C-10-acetal artemisinin dimers may be due to active metabolites, which were confirmed by in silico findings. Hybrid-dimer 1 also displayed potent in vitro activity against tumor cells and was found to be more active than etoposide against TK10, UACC62 and MCF7 cell lines (TGI values 3.45 vs. 43.33 μM, 2.21 vs. 45.52 μM and 2.99 vs. >100 μM, respectively). The 1,3-diaminopropane linker, present in hybrid-dimer 1, was therefore identified as the optimum linker.

Synthesis of methoxypoly(ethylene glycol) carbonate prodrugs of zidovudine and penetration through human skin in vitro

Objectives The aim of this study was to synthesise a series of novel methoxypoly (ethylene glycol) carbonate prodrugs of the antiretroviral drug zidovudine (azidothymidine, AZT) in an attempt to enhance the physicochemical properties for transdermal delivery, which may reduce the severe side‐effects and toxicity associated with high oral doses of AZT.

Synthesis, antimalarial activity and cytotoxicity of 10-aminoethylether derivatives of artemisinin

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 (IC(50)=1.44nM), 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 IC(50), pK(a) values and resistance index (RI) was found.

Correlation between the physicochemical properties of organic solvents and their biocompatibility toward epoxide hydrolase activity in whole-cells of a yeast, Rhodotorula sp.

Epoxides are often highly hydrophobic substrates and the presence of an organic co-solvent within an aqueous bioreactor is in such cases indicated. The effect of 40 water-miscible and -immiscible organic solvents on epoxide hydrolase activity in whole-cells of the yeast Rhodotorula sp. UOFS Y-0448 was investigated. No formal correlation between solvent biocompatibility and physicochemical properties was deductible, although the introduction of hydroxyl groups increased biocompatibility. 1-Pentanol, 2-methylcyclohexanol and 1-octanol were the most biocompatible resulting in relatively low activity losses when used at up to 20% (v/v).

Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin

Objectives  The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains.

1-Bromo-2-(10β-dihydro­artemisin­oxy)ethane

The title compound, C17H27BrO5, DEB, is a derivative of artemisinin which is used in malara therapy. The OR-group at C12 is cis to the CH3-group at C11 and axially oriented on ring D which has a chair conformation. The crystal packing is stabilized by several weak intermolecular C—H⋯O interactions, which combine to form a C—H—O bonded network parallel to (001).