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25th September 2013 @ 09:23

At the end of May, an open consultation was held to decide the next aminothienopyrimidines for synthesis as part of the OSM project. The team postulate that this round of synthesis might be the last for the aminothienopyrimidines (ATPs) and want to select the 'best' compounds to give a detailed SAR for this series.

A summary of the compounds tested to date can be found in scheme 1 of the open consultation and activities of all compounds can be found on the summary page.

The compounds below have already been synthesised and are ready for testing:

The synthesis of the 'final' compounds is going to be divided between different chemistry labs but firstly, the team need some assistance in prioritisation of or selection of new compounds. The next compounds that have been proposed are (numbering matches that used in the open consultation to avoid confusion):

Mike Robins recently produced a really nice voting tool for us to use when making project decisions. Please vote here for your favourite compounds by placing them in rank order and/or providing comments to explain your choice. If you would like to suggest alternative compounds please upload to the blog or alternatively send the structures to opensourcemalaria@gmail.com and one of the team will upload your suggestion(s)/comment(s) for you.

Many Thanks for your help!

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11th September 2013 @ 12:06

The team has received some experimental details used for the synthesis of a representative triazolopyrazine (11). I am planning to use this route as a basis for the synthesis of triazolopyrazine analogs but it would be great to hear any ideas about how to improve this synthesis. You can post comments below, send a tweet or a G+ post or as a last resort email opensourcemalaria@gmail.com.

Synthesis of triazolopyrazine core

The synthesis of the triazolopyrazine core commences with the reaction of commercial 2,6-dichloropyrazine 1 with hydrazine hydrate and subsequent condensation with an aromatic aldehyde to give imine 3. Treatment with the oxidant phenyliodonium diacetate causes 3 to undergo cyclisation to generate the triazolopyrazine core 4.

 

Side chain synthesis

Synthesis of the side chain commences with the nucleophilic addition of cyanide to an aromatic aldehyde 5 and concomitant silylation to give 6. Deprotection under acidic conditions and esterification gives 8 which can be treated with freon gas to provide the fluorinated ester 9.

QUESTION I'm not entirely sure if we are able to used freon in Australia...does anyone know if the gas is still allowed or an alternative way to alkylate the alcohol with a difluoromethyl group?

Hydrolysis of the ester reveals acid 10 which can be driectly coupled with the chlorotriazolopyrazine 4.

 

 

 

 

 

 

 

At some stage it might prove interesting to synthesise 11 (or other analogs) in an enantiomerically pure form. One possible synthesis could make use of some chemistry that I developed during my PhD along with Dr. Aurelien Bigot. Enantioselective copper-catalysed arylation of a silylketenimide (derived from a commercial N-acyloxazolidinone) with a diaryliodonium salt installs the required chiral centre. 

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10th September 2013 @ 13:46

Very excited to introduce OSM Series 4 - a new chemical starting point for the project. This was announced today by MMV.

For a list of all the compounds inherited from MMV (structures and potencies) see: Updated Data on Amounts Remaining in MMV Stock of Series 4

 

Representative TP Compound


What makes this series unusual is the amount of specific investigatory work that has gone into it already. Series 1-3 started from compounds that had been discovered through a screen by Big Pharma, but no follow-up work was done, nor the development of an understanding of what the active compounds might be doing.

Series 4 comes to the project from MMV, who have decided to place all the data they have in the public domain - once again Paul Willis has been the OSM project champion here. The compound was also discovered by Big Pharma, and was investigated by them. The project was stopped (not because of any perceived shortcoming of the compounds) and was passed to MMV who have employed a CRO to investigate further. These two projects generated a lot of data, with much of it suggesting that the series looks very promising. Members of the series are potent antimalarials with good pharmacokinetic properties. These need improving, which is what OSM is now going to do in the public domain. Please join the consortium in exploring this new series.

Another interesting difference with Series 4 is that there is some suggestion of what the compounds are doing - they have come up positive in Kiaran Kirk's ion regulation assay, which implies that these compounds may be hitting PfATP4, a new an interesting target in antimalarial drug discovery. Kiaran's going to be carrying out this screen as a member of the consortium.

So there's lots to do. The series was announced today. All the data the OSM project has to date are now in the public domain. If you're a medicinal chemist you'll want to read through the briefing document from MMV for all the current details. If you know any chemists, ask them if they know of any molecules anywhere that look like these TPs. If they don't look busy, ask them if they'd like to make and share a molecule. If you know any biologists, ask them about what an ion regulation assay is and why these compounds can kill the malaria parasite and not the human host (how cool is that?). If you'd ilke to be involved in some other way, you can check out the non-science list - a project like this generates lots of non-lab-science tasks like writing and data curation and wiki maintenance.

You can comment below if you sign in through one of the ID providers (like Google) - you don't need to make an account - or you can get in touch in lots of other ways - look at the "Join the Team" tab on the Landing Page.

(Note to existing members of the consortium: In my lab in Sydney we're currently making some remaining compounds for Series 3, as is Patrick Thomson in Edinburgh, since there is great promise there, but it's likely we'll transfer attention to Series 4 fully once we have planned the first 10 Series 4 compounds to make and have established they are novel. Naturally this leaves Series 1-3 open to anyone to explore using the OSM infrastructure.)

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