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.
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: http://www.youtube.com/watch?v=toUcn4t-ddA
The compounds discussed in this meeting are shown here:
Meeting - October 19th 2012
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.
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.
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.
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
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.