An improved, Weinreb amide-based, synthesis of anti-trypanosomal lysine-containing vinyl sulfones is described incorporating, as a feature, diversity at the ε-lysine amino group. Members of this family demonstrated moderate to good efficacy as anti-trypanosomal agents and a fluorescent dansyl (19) derivative was used to investigate subcellular localisation of the compound class.

An approach is described to access 1,2,3‐triazole‐derived peptidyl vinyl sulfones as Trypanosoma brucei brucei inhibitors by using click chemistry, starting from a common azide intermediate. Among the triazole analogues, biotinylated inhibitors 11 and 12 offer possibilities as probes for the elucidation of target proteases for this compound class. The development of two syntheses of a 1,2,3‐triazole‐based vinyl sulfone 5 are also presented. This compound was accessed through a click reaction of a lysine‐derived azide (itself accessed by diazo transfer), and a phenylalanine‐derived alkyne synthesised by both Ohira–Bestmann and Corey–Fuchs‐based alkynylation protocols. Several members of this family of compounds showed promising anti‐trypanosomal activity. Unexpectedly, one of the most active compounds was allyl sulfone 24, which stems from the isomerisation of vinyl sulfone 5, and is presumably a reversible inhibitor. A docking study of the analogues in the active site of the parasitic cysteine protease rhodesain was carried out in order to gain an insight into their likely interactions with these enzymes.

No abstract

Near-infrared (NIR) and frequency modulated spectroscopy (FMS) were employed, for non-invasive moisture determination of a lyophilized biologic drug product (DP). Development of NIR and FMS provides a rapid non-invasive means of residual moisture measurement, and would be beneficial compared with traditional time consuming, product destructive methods such as Karl Fischer (KF). A model therapeutic enzyme in a sucrose-based formulation was employed for proof of concept studies, and NIR and FMS methods were compared side by side for residual moisture analysis. Moisture models were created using lyophilized vials and comparisons were made between the methods using different moisture preparation approaches:1) direct water droplet addition to the vial headspace, 2) use of elevated temperature (80°C), and 3) using various levels of moisture in stoppers generated during the washing and drying procedures, then lyophilizing using the stoppers and placing the sealed vials on stability. The results for direct water addition gave an average percent error for residual moisture of 5.7% for NIR and 9.4% for FMS when compared to KF. The elevated temperature method resulted in an average percent error for residual moisture of 54% for NIR and 43% for FMS compared to KF. The stopper moisture stability study, for FMS, provided an average percent error for residual moisture of 31% compared to KF. The error was greater for the elevated temperature and stopper methods, due to the low moisture values, which resulted in greater error. At this lower range of moisture (<1%) both NIR and FMS were less accurate, but from 1 to 5% their accuracy increased, based on the models used in this study. NIR and FMS methods can be used to complement KF at these lower moisture levels and models could be further improved with additional data points. NIR and FMS methods have advantages and disadvantages for residual moisture analysis when compared to each other, but both provided an accurate measurement of drug product moisture (depending on the method used for moisture increase), they can be used as process analytical technology (PAT), and both can be used for fast non-invasive moisture determination.