Model compounds for evaluating the reactivity of amphetamine-type stimulants.

The use of controlled precursors for reaction optimisation is not always practical. One approach to limiting the use of controlled substances is to instead use 'model compounds'. Herein, two model compounds resembling norephedrine and ephedrine were selected based on their (i) structural similarity (i.e., presence of key functional groups) and (ii) availability from multiple suppliers without restriction. Model compounds 2-amino-1-phenylethanol and 2-(methylamino)-1-phenylethanol (halostachine), were compared to norephedrine and pseudoephedrine by firstly subjecting them to transformations known in the synthesis of amphetamines, and secondly, comparing the compounds using colourimetric spot tests, FTIR and NMR.

Correction to: Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD).

Jürgen B. Bulitta's name was misspelled in the original version of the article. It is correct as reflected here. The original article has been revised.

Lessons learned in the development of sustained release penicillin drug delivery systems for the prophylactic treatment of rheumatic heart disease (RHD).

The current prophylactic treatment to prevent rheumatic heart disease requires four-weekly intramuscular injection of a suspension of the poorly soluble benzathine salt form of penicillin G (BPG) often for more than 10 years. In seeking to reduce the frequency of administration to improve adherence, biodegradable polymer matrices have been investigated. Poly(lactide-co-glycolide) (PLGA)-based in situ forming precursor systems containing N-methyl-2-pyrrolidone as solvent and PLGA-based monolithic implants for surgical implantation containing BPG were developed. Long-term release studies indicated low and plateaued release of penicillin G, but continual favourable release profiles for the benzathine counterion, indicating degradation of the polymer and generation of acidic microenvironment being detrimental to penicillin stability. In order to avoid the issue of the acidic product, poly(caprolactone)(PCL) implants were also investigated, with favourable penicillin G release behaviour being achieved, and slow release over 180 days. However, when taking into account the mass of polymer, and the total dose of drug calculated from literature pharmacokinetic parameters for penicillin G, we concluded that an implant size of over 7 g would still be required. This may preclude clinical deployment of a polymer matrix type delivery system for this indication in children and adolescents. Therefore, we have learned that biodegradable PLGA-type systems are not suitable for development of sustained release BPG treatments and that although the PCL system provides favourable release behaviour, the total size of the implant may still present a hurdle for future development.

Structure-activity relationship studies of orally active antimalarial 3,5-substituted 2-aminopyridines.

In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.

Synthesis of azide-alkyne fragments for "click" chemical applications. Part 2. Formation of oligomers from orthogonally protected chiral trialkylsilylhomopropargyl azides and homopropargyl alcohols.

A small library of chiral, beta(3)-substituted homopropargyl alcohols and chiral beta(3)-substituted trimethylsilylhomopropargyl azides were generated starting from natural l-amino acids. The free alkynes and azides were then coupled, using a Huisgen 1,3-dipolar cycloaddition, to provide chiral oligomeric 1,4-disubstituted-1,2,3-triazoles as potential peptidomimetic compounds. The work is an extension to the previous synthesis of racemic, orthogonally protected 1,4-disubstituted-1,2,3-triazoles from the corresponding alpha-substituted propargyl alcohols and alpha-substituted trialkylsilylpropargyl azides.