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Desired Compounds Consultation Phase 2
Communitymalaria research community
SubjectRequest for Help
The evaluation of the arylpyrroles has gone well, in that we've identified promising new antimalarial compounds. Besides their high potency, they exhibit high levels of activity in a late-stage gametocyte assay which is very exciting. (As an open source project, anyone may take these results and work on them - made easy by all our data being available.) It's for these reasons of potency that we're going to explore one more iteration of the series, despite three of the compounds showing no oral activity in mice. It's thought the problem could be low solubility. This round will only be including compounds with low (<5) logP, and we'd like to play around with the structure a little more.
If this round does not throw out any improved compounds we'll probably park the series. Hence it's important that we choose a good set of compounds to evaluate. We decided to list the top 10 "most wanted" compounds that we could access commercially, as well as a similar list of compounds we could not buy and wanted to make. We'd then attempt to source those commercial compounds, and ask the synthesis community to volunteer to make the other necessary compounds.
We're now assembling the lists. We'd compiled a first-pass list of attractive compounds. We've now modified that list to give two new lists of commercial vs. synthetic compounds - below. We now need to consult the community again on these new lists. Before embarking on synthesis or purchase we will have the compounds checked by the original authors of the GSK TCAMS set to see whether any of the compounds have been evaluated and found to be inactive - we'll send the SMILES of all these compounds to GSK and see what they say. We know that's a big ask.
First the compounds we'd like to get our hands on which are commercially-available:
If any of these are known by GSK, we'll fill up the spaces with compounds from these backups, or any others people might like to see tested:
The compounds we'd like to evaluate which are not commercially-available are:
(note that primary, secondary and tertiary terminal amides are all of interest here and ought to be made concurrently.
And again, these are the backups in case these compounds have already been evaluated:
In the synthesis set:
1) We've included a couple of pyrazoles. Fused pyrazoles quite different to the GSK hit compounds are commercially-available, and we've not included those because of the substantial differences - those options are shown here, and we could include some if needed.
2) We've taken the curveballs out as being a little speculative, but if anyone knows how to make these, or wants to have a go, please say.
3) We've de-prioritised the thiazolidinones as being too insoluble, even with some obvious tweaks. This means we have three slots available for the synthesis "top 10 most-wanted." Our final phase of consultation will be to fill those slots.
The final consultation will hopefully be a public hangout on the web for a final discussion, technology permitting. Date to be advised. This will finish the "Most Wanted" lists and begin the next phase of compound evaluation. So this is where we stand - would anyone do this differently?
On a side note, that will probably need a post of its own, the logPs in the above are approximate. We've been using available tools to calculate these, e.g. Chemdraw, but there's a lot of variability depending on the tool used. We have no access here to one that performs well, from ACDLabs. While it's likely the above figures are inaccurate (vs. truth) it's unlikely they are so far out as to invalidate a target).