Analog Synthesis - Variation of the Aryl Ring

Published by MatTodd on 27 November 2011 - 12:17pm

Open source is most powerful when people participate by creating. Open science is no different, and in the case of lab-based sciences, that means actually doing experiments. For the open source drug discovery for malaria project we need people to make molecules. In fact a lot of people need to make molecules. We have our first offer (November 2011).
Sanjay Batra at the Medicinal and Process Chemistry Division of the Central Drug Research Institute in Lucknow, India, has offered to ask a student to make some molecules as part of the current push to validate the GSK aryl pyrroles (thanks to Saman Habib for putting us in touch by email - Saman is going to be leading the Indian OSDD Malaria project that is starting in 2012). This opening post describes where we are, and what I think needs to be made next (though the post may change over time as the project changes).

Below are the compounds sent last week (Nov 24 2011) for biological evaluation. Included are the original TCAMS compounds, some “near neighbour” compounds, and a range of pro-drug possibilities (i.e., if the TCAMS compounds are actually prodrugs, given that that ester is unlikely to survive for long). Most were made by Paul Ylioja, and some by the undergraduate student Paul was mentoring, Laura White, who posted a nice report of what she did here. The compound codes will allow you to find the procedures in the ELNs.


According to wisdom received from the GSK Tres Cantos and MMV guys, we should be doing a broad and shallow SAR search, which is to say we ought to be picking several points of variation in the TCAMS structures and making a small number of changes in each position rather than exhaustively changing one position. The rationale there is that we need to see that the potency varies when we change things, otherwise there are a bunch of other hit series we can look at.
I think that means the best thing for Sanjay's lab to do is to finish off making variations in the aniline of the arylpyrrole synthesis – i.e. vary the fluorine:

We've done some of this – converting the F to H, Me and CF3. Not all of these have been taken all the way through to the end yet. Our undergrad student Zoe is working with Paul Ylioja to make a 3,5-CF3 variant. But I think it's important we change the position of the F, that we change the Ph ring to, for example, a pyridine, and we bulk out the ring with something like two methyls. I also think the biphenyl would be a good one to try (i.e., use 4-phenylaniline). Which compounds are made depends on which starting materials are available. I think we need 3-4 diverse anilines taken through to the end, so 8 final compounds. Whether intermediates should be saved for screening depends on whether the "prodrug" compounds sent for evaluation above look promising.

The pyrrole esters would then need to be hydrolysed, and coupled with the TCAMS R' groups according to procedures Paul has nicely worked out. Typical procedures are given as red URLs above, but generally the chemistry can be browsed at the ELN.
It would help a great deal if Sanjay was able to use the same lab book that we are using, i.e., to start an account on Labtrove and start a separate blog on this page called something like “CDRI Synthesis of Aniline Variants” where the experiments would be posted (we can create this if it's not easy/obvious). Crucially, this is an open science project, so all data must be deposited – check out the Six Laws. Our labs will be geographically separated, so we must have full access to each others' data. This also means that readers of the project can have faith in what we're doing because they can check the raw data.
I hope this project idea sounds good as a starter, Sanjay, and your students are happy!
Biological evaluation of compounds would happen either here in Australia, or better in India, if we are able to establish a willing venue for that. I suspect that will be no problem, but is not currently sorted out. The assays for the compounds made need to be similar to the ones being done elsewhere, and the same control compounds should be used. The controls should probably include one of the original TCAMS hits, and we could provide that compound if and when it's needed.

Note if you're reading this and want to take part by making some molecules, please say. You're both welcome and needed, provided you subscribe to the Six Laws. There's so much to do, we can't do it all on our own. Similarly, if you're a medicinal chemist who just can't help themselves, and think we're approaching this all wrong/right, please feel free to say why. Discussion can happen here. Project status will be most up to date on the wiki. You can tweet the project. Or you can catch up with some of us on Google+, which is a pretty useful addition to the project tools and gets us away from private email, which is generally useless for an open project.