Biological Results for Second Set of Compounds

Published by MatTodd on 4 March 2012 - 3:02am

In January the first biological data for compounds from the open source drug discovery for malaria project came through. The compounds were based on two hits identified in the GSK Tres Cantos set (TCMDC-123812 and TCMDC-123794). The two originals performed well, and we also identified two other compounds that looked promising (PMY 14-1 and PMY 14-3-A). Biological data were obtained from three labs (the original GSK lab, Stuart Ralph's lab in Melbourne and Vicky Avery's lab in Brisbane) and compared to known antimalarials.

Since then Paul and Zoe have been making a second set of compounds, which we shipped last month. Details of those compounds are in this spreadsheet. They are intended to explore the most promising compounds from the first set.

The first biological data are now back - from Vicky Avery's lab. We have some super-potent compounds, which is very exciting. One is picomolar (the data below are the average of two runs on 3D7). The data are posted raw here, and are summarized below (direct link to picture file).

A few obvious points:
1) We're eagerly awaiting the data from the other two labs, to see if the activity is confirmed.
2) The QSAR isn't flat - i.e. changes to the structure of the molecules make a difference to the bioactivity.
3) The aryl pyrrole appears to be needed in all sets.
4) Replacement of the ester with an amide in the original GSK compounds is seriously deleterious.

What's needed:
1) The most potent compounds have high logP. We're going to need to make them more aqueous soluble.
2) The best four from the first round and four from this second round are going to be shipped for basic metabolism assays to Sue Charman at Monash.
3) We're hoping to send 2-3 compounds for in vivo evaluation. Possibly the two originals, plus one of the super-potent compounds. Awaiting confirmation that we can do that.
4) The work that Sanjay Batra at CDRI is doing on installing sterically demanding groups on the aryl ring in place of F will be an important addition here.

1) What do we do to decrease logP?
2) There have already been some good suggestions on how to change these compounds by modification of/introduction of other heterocycles. We think this is still the way to go for round three. Everyone agree?
3) Does the lack of activity for compound ZYH 23-1, and its laughable lack of reactivity towards hydride reduction, suggest we need not worry about these compounds being PAINS?

If you've any other gut feelings about these compounds, or if you'd like to play with them in your lab, or if you spot some chemistry you'd like to do to make a related scaffold, please say.

To re-state the obvious: this is open source, meaning you can join the project, or take what we've done and use it in your own research, with attribution (CC-BY-3.0).


Very encouraging results. Looking forward to see GSK data to confirm this outstanding activity. However the molecules are far away from a developability point of view (CYH-7-2 presents a clogP of 8.1). I have found really interesting the result of CYH-18-1, around 300nM. This means that pyridines or even heterocycles are tolerated, so, from my point of view, it would be worthy to check what is the most convinient position for the N of the pyridine. I will avoid the use of the CF3 groups or any other group for the moment.

Absolutely. The most active compounds have suboptimal logP. The polar surface area also is on the low side as we don't want these compounds to end up in the brain. We discussed these with Paul Willis last week and the next compounds will seek to rectify the solubility/logP. Thanks!

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Yes, we're currently thinking about (and asking for advice on) the next round. Ultimately it's going to be a good idea to play with the "upper" heterocycle to try to decrease logP. Advice seems to be that logP should now become a feature of the design process. Your suggestion, Felix, of making the other two isomers of the pyridine substituent on the pyrrole is an interesting one that had not come up - does that make a difference to the logP, I wonder?

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This second set of compounds has now been assayed by GSK. Data posted here.

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The 3-fluoro "near neighbour" analog has been evaluated by Sanjay Batra, and found to possess low activity. The assay was carried out vs. chloroquine and also to one of the original GSL compounds synthesized by Paul (TCMDC-123812) - the control data came back consistent, implying that TCMDC-123812 is a good compound for the project to agree on as a second standard. The compound is commercially available, is in the Malaria Box, and we can ship it out to contributors.
Raw data:
Original G+ thread where data first appeared is here.

Dear Mat,
We do the cytotoxicity assay in Vero Cell Lines via MTT assay.

James S. Pham at Bio21 has also evaluated these compounds and I've posted the data on labtrove. His results confirm high activity for the near neighbours.