Open Source Drug Discovery for Malaria Project Meetings



Project meetings for the Open Source Drug Discovery for Malaria project will be held in the public domain. Meetings will be linked below, with uploads to YouTube. Open to all interested.

Open Source Drug Discovery for Malaria Project Meeting February 26th 2013




Minutes of the OSDDmalaria Online Project Meeting held 26th February 2013
Meeting recording is here.
1. Status of the Arylpyrrole Series
The ether analog had been an obvious analog to make, since it lacks the problematic ester of the hit compound. The analog caused continuing synthetic difficulties (see e.g. here). Various people had provided useful inputs to synthetic design, in particular Frederick DeRoose at Asclepia. During the meeting it was decided to abandon this compound. Anyone reading this who feels they can make it - please give this your best shot! There may be a fundamental issue with this compound's stability, or at least the alcohol precursor of the compound. Either way, for the moment it's dead.
The only other remaining compound of interest was the sulfonamide OSM-S-XX (does this have a number?). The N-methyl analog of this compound has, since the meeting, been made and will be sent for biological evaluation. The method derives from a collaboration between Edinburgh student Patrick Thomson and Sydney student Matin Dean.
2. Status of the Near Neighbour Series
Of the near neighbor compounds so far evaluated, there was a fairly strong correlation between potency and logP. Of the new compounds made, the two most potent compounds (OSM-S-109 and OSM-S-111) had logP values that were not significantly lower than those compounds previously made. The proposed compounds with even lower logP values had proven to be synthetically challenging.
A representative compound (OSM-S-35) had been evaluated by Sue Charman in a glutathione trapping experiment, and there was divided opinion on the results. While the peak areas for Glu-trapped compounds were low, peak areas can sometimes be misleading in such experiments. Nevertheless it was thought the results did not present a red flag for the series.
The two active compounds of remaining interest were:
1. OSM-S-109. This contains an aromatic nitro group, known to cause (usually) genotoxicity issues. It was the intention to reduce this nitro group to the amine, and this should be done if it is trivial, then the potency of this amine should be evaluated. It was thought the amine would be as good as any other compound to evaluate, rather than, for example, acylating the compound first.
2. OSM-S-111, the methoxy-substituted compound. This looks to be a promising compound, and it would be useful to evaluate in vivo. Paul Willis was going to check if there might be an available slot at the Swiss TPH for this, for which about 30 mg would be needed. The experiments would be a Peters Test, in other words 4 days dosing at 50 mg per kg for 4 days, and the taking of blood samples. In the meantime, it was thought a good idea to obtain metabolic data on this compound: i.e. intrinsic clearance in microsomes and solubility. There was no need for another glutathione trapping experiment. Sue Charman would be approached for her availability to do these experiments.
In general, these experiments would represent the remaining experiments for the arylpyrrole/near neighbor paper, at which point these series should be published. A clear description of the reasons for the "kill" decision should be stated. These notes help there, but another post making clear the reasons would be needed. The current draft of the paper was to be resurrected (is here) and Alice Williamson was to be tasked with working on the experimental section.
3. New Thienopyrimidine Series
OSM-S-106 had shown excellent potency in the most recent round of evaluation, indicating the series was an attractive new option. 
At this early stage it makes sense to assess solubility, PK and liver-gametocyte assays - Sue and Vicky for this? This hit compound probably needs resynthesis.
The hit compound is a primary sulfonamide. Such motifs can possess undesirable biological activities, such as carbonic anhydrase inhibition. It was felt desirable to make also secondary and tertiary (methyl) sulfonamides, and this should be incorporated into any short-term synthetic plan.
A shortlist should be drawn up of the compounds in this series seen as either desirable and/or do-able with local synthetic resources. (This has since been done). Paul, Chris Southan and others should be alerted to this list, both to assess suitability and to check for related, available compounds, possibly via passing of the list to the GSK team. At this stage we are looking for maximal potency with minimal logP. Carrying out this consultation in public may help with identifying people able to help with synthesis, as for the last arylpyrrole "Top 10" consultation.
Synthetic Chemistry of the Thienopyrimidine series:
1. Suzuki. The coupling of various bromothienopyrimidines with boronic acids and esters is proving to be much more difficult than anticipated. There is little precedence for this coupling, but it is not clear why the reactions so rarely generate the desired products or what can be done about it. A summary of successes and failures will be constructed (has now been started here) and an appeal will be sent to the community for help with this step.
2. CRO input to starting material synthesis. It would be a time saving if the central starting material for this synthesis, chlorothienopyrimidine, could be provided in bulk to the project from the CRO sector. The synthesis is well-behaved and low risk. Representative procedures will be posted (now here and here) and advice from the CRO community will be sought.
Project Tools
1. Knime: There had been some discussion of automating workflows using Knime. There was little expertise in the group with this, but advice from others was being sought as a way of making the compound data in the project more usable.
2. The lack of notifications on ELN entries was still seen as a major problem, since this prevented the ELN being used as a discussion area, or as a place for summaries. It was felt by some that there was an increasing number of pages in the project generally, which was requiring an increasing amount of time for curation. The landing page was also seen as a major need. Mat was in touch with Intersect NSW about a quote for such a page and would pursue this. 
3. Continuing problems were seen with The Synaptic Leap platform, mainly with regards broken notifications and difficulties in making posts. While the name recognition of the site helped with knowledge of the project, the barrier to entry represented by the Drupal platform behind the Synaptic Leap webpage was seen as a continuing problem. (In a subsequent meeting at the Open Data Institute on March 4th, it was suggested to Mat that we should look into Github itself as a project coordination site.)
4. Having one SD file as the master list of all compounds was seen as being an attractive way forward. The location of the file was not thought to be important, but was currently on Github.
1. The last meeting was attended by someone from Roche, and this person should be recontacted as a possible source of project input.
2. The next meeting should be at the end of April, in order to allow for a couple of rounds of synthesis and evaluation on the thienopyrimidine set.
3. The osddmalaria data have been posted to ChEMBL here. It will be important to try to integrate the SD file with a continual import of the data to ChEMBL, but this is not currently simple. Discussion with George and John at ChEMBL to continue about how to do this.
1. Have the aryl pyrrole sulfonamide biologically evaluated (Patrick Thomson, but Mat and Paul Willis to organize UK lab). Resynthesise this compound to check method (Matin).
2. Reduce OSM-S-109 to the amine and evaluate potency (Murray).
3. For the methoxy-substituted near neighbor compound (OSM-S-111), check whether Swiss TPH has an available slot for this to be evaluated in vivo (Paul). Check available stocks of this compound (thought to be 30 mg) (Murray). Sue Charman to be approached for metabolic data (Mat).
4. Summary for the reasons for the "stops" on the arylpyrrole and the near neighbor set needs to be written (Mat). Work to be continued on the experimental section of the paper (Alice).
5. Check on need to resynthesise OSM-S-106 (Murray). Sue Charman to be asked about possibility of basic metabolic stability/solubility (Mat). Vicky to be asked about possibility of late stage gametocyte assays (Mat).
6. Post shortlist of thienopyrimidine derivatives with SMILES and request input from community (Murray and Mat).
7. Post summary of Suzuki reactions trialled to date in the thienopyrimidine series (Murray and Althea). Request input from community (Mat).
8. Post procedures for synthesis of chlorothienopyrimidine (Murray and Althea), and begin to explore CRO sector involvement (Mat and Paul).
9. Explore use of Knime with project data (Murray with online help).
10. Obtain quote for development of project landing page (Mat).
11. Explore whether github could be used in a project coordination role (Mat to request input from developer community).
12. Re-contact previous attendee from Roche (Alice).
13. Misc: Post meeting recording (Mat). Done.
14. Misc: Explore involvement of undergraduate communities in the synthesis of compounds (Mat).
15. Misc: Re-contact Mike Pollastri for possible involvement (Mat).
16. Misc: Consider new sources of possible synthetic chemistry input on thienopyrimidine series (all).

Open Source Drug Discovery for Malaria Project Meeting Oct 19th 2012



This meeting was the first of what will become regular monthly meetings for the OSDD malaria project. Open to all, so please feel free to come along to them.

Wiki pages:

Software for the meetings is Adobe Connect run from the University of Sydney.

Webcam feeds are from Mat Todd, Paul Willis (MMV) and Sanjay Batra (CDRI). Other participants present and contributing by audio or chat.

In case the embed functionality is not working, here's the direct link to the video:



The compounds discussed in this meeting are shown here:

Recent biological data

Compounds currently being made

Meeting - October 19th 2012

Items discussed:

Agenda Item 1:
New preliminary biological data from Vicky Avery:


Indicates a very high sensitivity to changing the ester of the first hit TCMDC 123812 (OSM-S-5). Lack of activity from others is interesting. Might support prodrug hypothesis. But the obvious half (carboxylic acid) was inactive.

Compounds of remaining synthetic interest.

Question arose about whether controls were included in Vicky's data. Checked later: yes, controls were included.

Paul Willis suggested a compound that was more truncated:


This has now been made and sent for evaluation.

Sanjay Batra suggested a urea replacement in place of the amide.

We will wait for final data from Avery before planning other compounds.

Agenda Item 2
Synthesis of Remaining Compounds

Triazolourea series: initial compounds have been made and evaluated too (data link above) showing that the hit compound and a precursor analog are active. There is a concern that these are acylating agents. Have chemists seen any enhanced lability of these compounds? Comments welcome on these structures.

Initial GSK screen for TCMDC 134395 (OSM-S-56): 767 nM vs 3D7. These new data have slightly better numbers (e.g. 333 nM).

Commercial compounds: On their way from Molport (have since arrived and been sent on). Thienopyrimidines to be coupled with compounds from arylpyrrole series and others. See the relevant ELN page.

Arylpyrrole compounds still to make (main page)

sA - now found to be inactive
sB - in progress by Paul Y - see e.g. PMY 60-4
sC - amino acid derivs - parked for the moment until we have data on the other compounds, to make sure it's worth it.
sD - Ether linked compound. Awkward to make. Not clear why.

Relevant attempts

This compound could be of interest to CROs. Frederik Deroose from Asclepia was present in the meeting and expressed interest. Depends entirely on timing and cost. Paul Willis was skeptical on the need for the compound if it was going to take a lot of input. This was followed up subsequently between Frederick and Mat, and we're now deciding whether to contract out the synthesis of this compound. We could send 500 mg of the aldehyde or grams of the precursor to the aldehyde.

sE - sulfonamide. Matin still pursuing this. Will be following (by NMR) the subsequent functional group manipulations.
sF - oxadiazole - ugly EDC coupling involving a hydrazine. Isomer hopefully to be made by student working with John Wallis.
sG - Matt Tarnowski's compound - nearly there. Murray will be stepping in to finish this off most likely. Matt successfully made a precursor

sH - Couple of these compounds now made and included in new compounds sent to Vicky.
sI - Fused ring compounds - now generating ideas for the central ring. Whether this compound is made depends on what's quick and available.
sJ - done and sent to Vicky Avery October 27th.

One of Sanjay's students making one of the pyrazoles, but the group is waiting for delivery of starting materials. Timeframe needs to be 2-3 weeks for synthesis.

Arylpyrrole completion:
Want final data from Vicky by next meeting (i.e. late November)

Agenda Item 3
CRO inputs. Working on this. Background

To date approached 7-8, but with little interest. Continuing.

There has been useful input from Kevin Lustig at Assay Depot, who has commented on the above post. Possibly a major push on CROs if we start on a new series.

Agenda Item 4
The thienopyrimidine series has not been completed. Jimmy Cronshaw soon finishing his Honours project but will not have time to complete this molecule. Will probably bring in someone else to finish the synthesis. Will depend on activity of commercial compounds that have been sent to Avery on October 27th.

Agenda Item 5
Current weaknesses of ELN and Synaptic Leap websites. Both require work. Some paid, some volunteer. This work needs to be done ASAP (probably over the long break). e.g. alerts for the ELN, and a landing page for TSL. Possible level of interest from people working Ginger Taylor, TBC.
Willis: landing page, needs a simple project description and getting up to speed. How does one do that? To catch people coming along and conveying project status. Mike suggested progress bars for sub-goals. A need for a separate landing page that's highly visual.

This aspect of the project needs significant input from non-scientists.

Agenda item 6


- Need to recontact Frey's team at Labtrove, and migrate data over to Nectar.
- Paul Willis to look into possible other series, in case we park the arylpyrroles. Want series that other people are not working on. Anyone else can suggest series. Paul and Mike did some filtering - which we should resurrect.
- To do: recontact Nislow lab for biodata
- To do: recontact GSK for DHODH assay

Not discussed:

First malaria paper being written, and is now posted on Github, which we'll be using more, and which will require a little bit of coordination/instruction. It's possible that there could be a split of this paper into two, since the new emphasis on the arylpyrroles means the near neighbor set seems slightly out of place.

Related to this: the near neighbor set were promising-looking, in the sense of potency but also late stage gametocyte assay. They are not being pursued by us at present, but perhaps we could re-discuss them again later?


1. Arylpyrrole set to be completed, with biological evaluation, by next meeting

2. We are hoping for synthetic input from the Batra and Wallis labs in that timeframe

3. Thienopyrimidine and arylpyrrole sets of commercial compounds have been sent for evaluation

4. Software people need to be engaged for improvements in website design

5. To do: chase Nislow and GSK for bio data, and Paul W to consider which series might act as back-ups if we were to park the arylpyrroles owing to their narrow SAR.