Antiviral activity of gliotoxin, gentian violet and brilliant green against Nipah and Hendra virus in vitro

Background: Using a recently described monolayer assay amenable to high throughput screening format for the identification of potential Nipah virus and Hendra virus antivirals, we have partially screened a low molecular weight compound library (8,000 compounds) directly against live virus infection and identified twenty eight promising lead molecules. Initial single blind screens were conducted with 10 M compound in triplicate with a minimum efficacy of 90% required for lead selection. Lead compounds were then further characterised to determine the median efficacy (IC), cytotoxicity (CC) and the in vitro therapeutic index in live virus and pseudotype assay formats. Results: While a number of leads were identified, the current work describes three commercially available compounds: brilliant green, gentian violet and gliotoxin, identified as having potent antiviral activity against Nipah and Hendra virus. Similar efficacy was observed against pseudotyped Nipah and Hendra virus, vesicular stomatitis virus and human parainfluenza virus type 3 while only gliotoxin inhibited an influenza A virus suggesting a non-specific, broad spectrum activity for this compound. Conclusion: All three of these compounds have been used previously for various aspects of anti-bacterial and anti-fungal therapy and the current results suggest that while unsuitable for internal administration, they may be amenable to topical antiviral applications, or as disinfectants and provide excellent positive controls for future studies

The scope for synthesis of macro-RAFT agents by sequential insertion of single monomer units

The scope for synthesis of new macro-RAFT agents (Z-C(=S)S-(M)-R) by sequential insertion of monomers (M) 'one at a time' into an initial RAFT agent (Z-C(=S)S-R) has been explored. The process is illustrated with the preparation of a styrene-N-isopropylacrylamide (NIPAM) co-dimer macro-RAFT agent [(CH₃)₃C(CN)-CH₂CH(Ph)-CH₂CH(CONHiPr)-SC(=S)-S-alkyl] by successive single unit monomer insertions into a cyanoisopropyl trithiocarbonate. Critical factors for success are a high transfer constant for the RAFT agent and a high rate of addition of the radical (R·) to monomer relative to further propagation. With these conditions satisfied, the rate of reaction is largely determined by the rate of R· adding to monomer. Initiator-derived by-products (Z-C(=S)S-(M)-I) become an issue when R· is different from the initiator-derived radical (I·)

Parallel modification of tropane alkaloids

Various tropane alkaloids have been prepared by structural modification of the readily available natural product, scopolamine 1. Reaction of isocyanates with 6,7-dehydrotropine 5 provided a number of urethanes 6a-e. Reductive amination of tropinone 7 and subsequent reaction with isocyanates provided ureas 9a-f. Mitsunobu inversion of the C-3 alcohol of tropine 10 afforded the epimeric ester 11

Quasi-block copolymer libraries on demand 'via' sequential RAFT polymerization in an automated parallel synthesizer

A convenient synthetic method for the systematic preparation of quasi-diblock copolymer libraries utilizing a sequential RAFT polymerization strategy is described. This method utilizes a parallel synthesizer and allows the unattended and fully automated synthesis of this type of library in a short period of time. The materials obtained in this investigation have shown properties very similar to those expected in "pure" diblock copolymers as determined by differential scanning calorimetry. The described method can be a useful and less expensive alternative for the rapid preparation and screening of block copolymer libraries

Automated Parallel Freeze–Evacuate–Thaw Degassing Method for Oxygen-Sensitive Reactions: RAFT Polymerization

An automated and parallel freeze–evacuate–thaw degassing method in a commercially available synthesizer is disclosed and tested for its applicability to reversible addition–fragmentation chain transfer (RAFT) polymerization. The effectiveness of this method to eliminate oxygen in polymerization reactions is demonstrated by directly comparing it against experiments performed using conventional laboratory techniques. Apart from the demonstrated accuracy, the proposed method has also shown significant precision when performing RAFT polymerizations. The reported experimental technique can be easily adapted to other chemical systems where the removal of oxygen is mandatory. This new high-throughput method has the potential to significantly increase the productivity and/or research outcomes in laboratories where oxygen-sensitive reactions are carried out