Desired Compounds Consultation Phase 2

Published by MatTodd on 28 June 2012 - 1:23pm


Request 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).


Looks good, I really like the way that you have presented the compounds. It makes it clear what the aims of this stage of the project are.
My only suggestion would be to take each of the these 17 or so compounds (especially the to be synthesised list) and do a similarity search on to see if there are any more commercially available compounds of interest to you. 

Hi Iain. eMolecules is how we generated the commercially available lists. That is we took the "to be synthesised" list and trimmed by commercial availability to get the commercially available list. There are others of course in the similarity searches but they get quite different, quite quickly. The ones shown are some of the ones that probe the SAR that we're curious about. 

Hi Matt
My thoughts would be to generally keep to small tweaks around the original 123812, along the lines of some targets some of us threw together a while ago (can't find the url on your site but it must be there somewhere ). The reasoning is that at EC50 ca 330nM and multiple membranes possibly to traverse, intracellular target affinity could easily be ca 30nM or if competitive with substrate say 3nM...i.e. pretty tight fit to target and very small exploration of target space required. So 123794 with EC50 54nM but at the cost of a big chunk of added molecule is probably not the way to go: actives that are substantially changed may be introducing new targets (it is actually a bit of a worry how such big changes can also give rise to actives).
We typically find that commercially analogues may provide a little bit of useful SAR but almost always from an early stage we have to make SAR probes in-house....of course I realize chemistry resources are limiting hence a focus on available anlagues initially. But to find early on that e.g. a pyrazole can replace the pyrrole would be nice, the former I regard as a privileged structure. The pyrrole could complicate things but may be stable enough with e-withdrawing groups like ester (like lipitor with a 3-amide) but if one went to replace the ester, may not be a viable progression core...etc etc (actually, the ester may not be susceptible to esterases due to hindrance).
Anyway, just a few thoughts.

Hi Jonathan, was the post you were thinking of this one? I linked to it on the first round of consultation. 
I agree that commercial compounds aren't the best way of probing SAR but in this case the secondary and tertiary amides of TCMDC-123812 are commercially available (eg cB) so they would definitely be worth buying. Some of the larger changes might not be so useful but will help us build more data points without much effort.
In terms of the stability of the ester, we've found that it does seem to be metabolised quite readily, especially in mouse plasma, so the pyrrole methyl groups don't shield it enough. We are looking to nail down if this ester can be replaced with something more stable. We know that we can't use a secondary amide (OSM-S-19 and OSM-S-21 on but we haven't yet tried a tertiary amide for the linker (e.g. sA).
The pyrroles seem quite stable, chemically at least. They stand up to quite harsh treatment without any issues, so I'm not overly worried about them. The pyrazole analogue (sC) is now ready and we'll certainly be investigating it.

MatTodd's picture

An open online consultation about the way forward with this series (i.e. which compounds to make, which to buy) will be held on Wednesday July 25th 2012 at 4 pm Sydney time. Anyone who wants to join and advise can go here to do so: The proceedings will be up online shortly afterwards.

MatTodd's picture

Felix Calderon from GSK Tres Cantos wrote to tell us that none of the compounds above are known inactives for malaria:


"Hi Matt,


From the list of 78 compounds that you sent, only 19 smiles strings are recognized as compound in the GSK collection and none of them have been tested as antimalarials.


The other 59 compounds or either are not in the collection or have either not been recognized for our software.


Hope this helps,




This is very useful advice, and an enormous help to the project from GSK. Thank you Felix. This means that all the compounds listed above on the synthetic and commercial lists are still of interest.

MatTodd's picture

A comment on the series was received from Vrinda Nandi (drug discovery consultant, Bengaluru area, India) on a discussion thread on LinkedIn, which I wanted to repost here (with permission) for the sake of completeness:

"I would say you may have quite a few difficulties with the pyrroles. Being amide bioisosteres, the solubility is expected to be quite poor. And coupled with other amide functionalities would mean poorer solubilities in assays and in vivo. Have you plotted logP with activity? I note that the logP measured / calculated are variable, hence, it may be good to get hold of an ACD package or run a quick assay on a handful to see how lipophilic some of these might be. There may be a correlation of lipophilicity with extent of permeation into the parasite, so the more lipophilic compounds would tend to be more active. However, this can take you down a dubious route. As the program progresses, lipophilicity can markedly affect in vivo absorption and in turn you may fail to see efficacy. 

How are you conducting your oral studies in mice? Sometimes, using cosolvents or solubilizing agents (small percentage of ethanol or a suitable cyclodextrin) may help to get a little more into the bloodstream. It will be challenging however, to demonstrate efficacy with early compounds that have low potency since getting sufficient amounts into the plasma could be difficult. Also do keep in mind that the phenyl ring (unsubstituted at 4-position) is susceptible to hydroxylation. This alongside amide hydrolysis in vivo will give you phenols or carboxylic acids which are poor at traversing membranes and may not have activity against the parasite. Thus, oxazoles and oxadiazoles should be good replacements.

Putting all this into perspective, I would say, test a handful, check in vivo exposures and call for a early "park" if necessary.

I think a sufficient property space has been planned for exploration in the proposed compounds. Good to see that the thiazolidinones have been rejected. 

Good luck. I look forward to the next round of data."


Thank you Vrinda.

I have designed a huge number of potential new antimalarials having great probability of activity predicted by PASS server and I believe these designed molecules will be active against artemisinin resistant strain.I do a PASS activity prediction of above described molecules but it is not showing significant probability of being an antimalarial molecule whereas my designed molecules are showing better and even great probabilty of being antimalrial molecule.
But the main challenge lies with synthesis.If some of these sets molecules can be synthesised then we can overcome the resistancy problem and will ultimately find a new way of treatment.See the attached files for designed molecules.

MatTodd's picture

Soumendranath - thanks, but perhaps you should firm up these arguments a little? If discovery of new medicines was as easy as using the PASS filter, we'd have solved a lot of the world's problems already!

How different are the scores for the molecules above (which you don't give - remember this is open science), and those you mention? Is the difference statistically significant? Perhaps you could enumerate why you think the molecules above are not likely to be antimalarials, and why yours are more likely (i.e. besides the data from the PASS prediction). How well does PASS work on predictions of activity in whole-cell screening (which is what we're doing here) vs isolated target prediction? Specifically why you think they would overcome the resistance problem (and resistance to what?).

If you want to discuss your series further, or request help on something, could you also start a new thread, on a new page? It's important to try to keep discussions focussed and relevant if we can.