The Synaptic Leap

I've been working for six weeks now with the Todd Research Group at Sydney University as part of an undergraduate summer research program. The aim of my project is to synthesise analogues of this group of hits from the  antimalarial dataset released by GSK. They are referred to here as 'near neighbours' because they share the arylpyrrole moiety present in the two hits (TCMDC 123812 and 123794) Paul has been working on, but have a thiazolodinone side chain. The major components of my project are:

January 2012, Here’s a quick update on where we are regards the Bronsted Acid catalysed Pictet-Spengler reaction.
 

It’s been too long since I’ve updated the progress of this project on here but here’s a brief summary of where we are and what’s planned for the near future.  From late November we’ve had a summer student, Kat Badiola, working on the project.  She started with preparing pure, racemic samples of the 3 PZQ analogues shown below (compounds 6-8) via the Pictet-Spengler cyc

We have received encouraging biological results for the analogues we sent for testing before Christmas. Mat has discussed this here on TSL and on G+. Our best hit came from the "near-neighbour" compound and the original GSK hits came out slightly less active than in their original high throughput screen. However, Paul Willis at MMV rates TCMDC-123794 as a better lead than PMY 14-1 (TSL post).

Background
Relevant experiment.  Basically, the Pictet-Spengler to form 3 PZQ analogues and PZQ itself.
The mass spec is of a by-product of the acid mediated PS cyclisation of MNR10-1 to form KAB8-1, aka the dimethoxy N-benzoyl PZQ analogue.

 
I've now reached the end of my second week in the lab working on the Pictet-Spengler route to praziquantel.
 
It's been quite a steep learning curve so far, particularly in terms of analysis and familiarizing myself with the lab.  I've had experience (if you can call it that) with NMR and MS before, but that was only in the sense that I prepared my sample in the tube/bottle and a week later, I got a spectrum on my bench.  Now I'm preparing NMR and LCMS samples on a daily basis.  I'm finding it much easier to use the LCMS (however, interpreting data is another matter), and I've been introduced to the procedure for recording NMR spectra.
 

 I have just packaged up TCMDC-123794 (PMY 11-2) and -123812 (PMY 10-2) along with the parent acid (PMY 8-2), ester (PMY 6-1), aldehyde (PMY 2-4), near neighbour analogue (PMY 14-1) and also the acylurea by-product (PMY 12-1-A). These have been sent to GSK Tres Cantos where the original study was carried out for further testing.

I'm now happy with the data for TCMDC-123812 and TCMDC-123794. A bit of usual practical annoynce with TCMDC-123794 caused some trivial issues, namely a bit of repurification and acetone in the final spectra. These have now been taken care of and the compounds are ready for testing!
I've summarised the various intermediates and other compounds that are in the works on OpenWetWare. Please get in touch if you're interested in testing them.

Last week I was talking with Lei Liu from Tsinghua University, who was visiting Sydney to give a talk on his synthetic methodology research. I showed him the compounds that are the starting point of the open source drug discovery project for malaria, the arylpyrrole set. He said he'd seen these compounds before, in a different context, and after a little searching around we found the relevant paper here.

I'm now fairly confident that I've made TCMDC-123794 and TCMDC-123812. By fairly confident I mean that I've got a reasonable looking but crude 1H NMR and low res. mass spec of both of the compounds. They are not clean by NMR after a column and the yield of the reaction was pretty bad (~20%). Still this isn't too bad for a first go, using a quick and dirty acid chloride. Most of the mass seems to go toward turning the acid into the anhydride. This is supported by NMR but mass spec hasn't given a positive result so far.