Monthy mycetoma meeting 21 March

[wwjvdsande]

Time: March 21st (12 noon UK, 1pm EU, 11pm Aus) Timezones.

The Outlook invite can be found here

Location: https://uni-sydney.zoom.us/j/99281549497. In case of failure, use https://ucl.zoom.us/j/99789829423 and in case of double failure use MycetOS meeting teams link Chair: EMC Minute taker: USyd Previous meeting: here Recording: here Present:

1) Fenarimol Paper Writing

• [x] @dmitrij176 @fantasy121 to complete SAR gap analysis on the Epichem library and finalise the list of compounds to request. A refinement of https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/1#issuecomment-1427065305 is needed so that we know whether to request compounds from Epichem for the current paper, or not. i.e. which matched pairs would be instructive in answering questions we have for the current SAR. We need to be clear on which current actives are the comparators. ACTION: @fantasy121 share the diagram shown in-meeting, clarifying that the known compounds are active. Then we select ca. 10 compounds to request from Epichem.

• [x] @fantasy121 @dmitrij176 Is the chemical experimental section complete (in main paper and in SI document)? Looking at the current draft it looks like there are still remaining issues on the experimental section on the chemistry. If @fantasy121, @dmitrij176 @kym834 could take a look at it and go through it to check the issues highlighted and remove comments when solved. The ppt looks fine. Action: @fantasy121 @dmitrij176 (and ideally @kym834) meet to finalise, and generate copies of these files that are ready to submit to a journal.

Supplemental files for the manuscript:

• [x] Labarchives offline notebooks (not PDF) are needed as supplemental files that contain all chemistry experiments. Action on @fantasy121 @dmitrij176. New ELNs can be made by copying over entries of relevance. The offline versions can be posted to university repositories.

• [x] Biological supplemental data (not in Labarchives), an Excel sheet can be generated from our current Master List displaying all data on the fenarimols tested. Action on @MA-Jjingyi and @wwjvdsande.

• [x] @mattodd @fantasy121 @dmitrij176 @MA-Jjingyi @wwjvdsande need to double check that all fenarimols made are tested in vitro/vivo and all noteworthy/relevant compounds are included in the manuscript - to ensure we don't accidentally miss key data generated since the first draft of the paper. If @fantasy121 @dmitrij176 can check if all their molecules are entered in the spreadsheet and sent then @MA-Jjingyi and @wwjvdsande will check if they are screened and are in the manuscript if they are important.

• [ ] @mattodd to review current paper draft once the above are done.

2) Series 2: aminothiazoles

• [ ] Rohan's contribution of compounds from Griffith University QLD: Numbers of compounds, screening capacity, costs and motifs of interest, to be discussed. Have these been shipped? What were they?

Crowdsourcing update - incoming contributions from e.g. @Whitgift, @JuliaSarju, @PaulMcKeatingSevenoaks, Hampton School. Others @kym834 (e.g. Barker College (@katieterrett))? Update on meeting held is https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/13#issuecomment-1401059202. Needed: a check on compound novelty, and the provision of targets for @Whitgift and @PaulMcKeatingSevenoaks.

• [x] Meeting is needed to make sure every school has a different target @mattodd @kym834 Did this happen? Does it need to?

Looking likely that a group of students at UCL will work on this series in the summer.

3) Series 5

Actions based on potencies observed for most recent compound batches_ - e.g. oxazoles https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/82#issuecomment-1325150305 were selected because they resembled the benzimidazoles which showed potent in vivo efficacy. The oxazoles were validated _in vitro against Madurella mycetomatis and appeared to be very potent. They will be tested against Falciformispora senegalensis too. This series will be evaluated in vivo in the new larval season.

Are there more oxazoles out there? Could check with DNDi. @bebi78 said: @AndreaOtago and @csuth22 were generating more compounds this year and would be happy to share (which is fantastic).

• [ ] @fantasy121 to ask the two new Sydney Hons student to join Github, share their IDs and do the Scifinder lit search of the surrounding chemical space: are there other groups making similar compounds whom we could ask for donations?

  @wwjvdsande mentioned that the benzimidazoles had been found to be active in vivo (@MA-Jjingyi to share any data?)

4) Series 6: ketoximes

19 compounds designed. Most of them are synthesized by UCL. [ ] @dmitrij176 to share the figure (below, in this issue) of the compounds that have been shipped.

5) AOB

Other Updates: USYD UCL Erasmus Other sites

Was there a discussion needed around the DNDi project described in this paper?

Another possible source of molecules https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/1#issuecomment-1401932450? And also https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/1#issuecomment-1445713185?

Series https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/82#issuecomment-1325157545. [ ] Compounds tested in vitro. @bebi78 to go over them to see if there might be interesting leads. Any action?

[MFernflower]

https://www.mmv.org/mmv-open/global-health-priority-box/about-global-health-priority-box

MMV released a new box of fun

Might be worth screening? @bebi78 @mattodd @wwjvdsande

it contains some unusual molecules

[wwjvdsande]

@MFernflower @bebi78 @mattodd yes we know. MMV had notified us. @MA-Jjingyi has screened the box already against Madurella mycetomatis, she is now screening it against Falciformispora senegalensis. NOt sure if we added the data we have already in the spreadsheet. If not we will do so. We did upload the MICs and MIC50s for the MycetOS compounds last week.

[MFernflower]

i will likely not be able to attend tommrows meeting

i did not see any new mmv box data on the google sheet however

@wwjvdsande

[fantasy121]

MINUTE

Series 1: Manuscripts

SAR Gap compounds Current SAR targets need potency data @Hung to add.

@ Hung to narrow down to 10 compounds from 17. Re-up diagram to March Meeting

@ Matt will email the finalised list to Epichem correspondent

@ dmitrij to update 2 sig fig Ready for review

@ Hung to upload offlines notebook to USYD respository and provide links @ dmitrij to upload his

Biological supplemental data (not in Labarchives), an Excel sheet can be generated from our current Master List displaying all data on the fenarimols tested. Action on @ MA-Jjingyi and @ wwjvdsande.

The cut-off for in vivo data is end of larva season 2022 In vitro data will continue to be collected in 2023 (In vivo data 2023 season might be added to later revisions of manuscript but don’t wait for this before submission)

Series 2: The meeting needs to happen. (Kym) @ Hung double check with Alice and Peter about correspondent to task BG project as replacement for Kym

A group of HS students will be working with UCL to synthesise more targets on Series 2.

Series 5: Erasmus has tested some of compounds, not having IC50 yet.

Search for new Oxazoles: new targets to be synthesised Spring/Summer

Bernhard has new compounds to be sent to Wendy

New Honours Students USYD. @ Hung to ask Peter and Alice Re: the students progress into the project

Series 6: Dmitrij sent some samples for testing. Isomer information is updated

Rohan’s contributed compounds 96 well plated or glass vials? List of compounds unknown, to be shared before being shipped Mat has sent an email to follow-up

Latest MMV Global Health Priority Box acquired Tested against Mycetoma 100uM and 25uM Master List to be updated

Asking Dr. Cruz for new LogD values updates

Bioinformatics: Computational studies Waleed requested more information on the priorities of which aspect of bioinformatics should be prioritised to work on first.

Phylogenetic tree to work out relationships of various species were identified as high priorities so that we can search the literature for closely related species to Mycetoma, and for the potential structures of the drug target, which would enable us to simulate our data/estimation/computational models @ wendy to link the resources for phylogenetic tree

Kinase inhibitor library A new library (most likely KCGS library) will be screened against mycetoma.

Bernhard can send some 10 targets

[wwjvdsande]

@MFernflower @OpenSourceMycetoma/corecontrib the data of the global health priority box plus all screening data on Falciformispora senegalensis are added to the spreadsheet. Have fun exploring it. Thanks for @MA-Jjingyi for screening and updating it.

[MFernflower]

@wwjvdsande were there any drugs in the box that seemed useful?

On Tue, Apr 11, 2023, 8:52 AM Wendy van de Sande @.***> wrote:

@MFernflower https://github.com/MFernflower @OpenSourceMycetoma/corecontrib https://github.com/orgs/OpenSourceMycetoma/teams/corecontrib the data of the global health priority box plus all screening data on Falciformispora senegalensis are added to the spreadsheet. Have fun exploring it. Thanks for @MA-Jjingyi https://github.com/MA-Jjingyi for screening and updating it.

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/4#issuecomment-1503276102, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDRGWXMQGZZUKARPNR3XAVHY3ANCNFSM6AAAAAAV6OHGQM . You are receiving this because you were mentioned.Message ID: @.***>

[bebi78]

@mattodd @wwjvdsande The covid response box also contains some kinase inhibitors (already tested, see spreadsheet), and some phenothiazines with promising activity @MFernflower

[wwjvdsande]

@MFernflower there were many hits against Madurella mycetomatis but only a few against Falciformispora senegalensis. The ones active against both will be tested further. Ma is going to do the IC50 soon.

[MFernflower]

@bebi78 can you post the structures of the series 3 phenothiazines that interested you to the s3 github

[bebi78]

@MA-Jjingyi @wwjvdsande Two more series 2 and series 5 compounds were dispatched today by DHL.

[MFernflower]

@bebi78 do not know if you are willing to make more compounds but of the phenothiazines i always had something like this in mind https://opsin.ch.cam.ac.uk/opsin/10%20isovaleryl%20phenothiazin.png

should be easy to make from acid anhydride + phenothiazin powder + solvent + DIPEA base

[bebi78]

@MFernflower I already have made about 1 g the N-acetyl derivative (nice crystals) I planned to use for the synthesis of cinnamoyl derivatives in the coming months. Of course, I can already send some mg of the acetamide for testing. The synthesis of more N-acyl derivatives like the one you suggested might be a good project for schools. @mattodd @PaulMcKeatingSevenoaks @Whitgift @mattodd @wwjvdsande @fantasy121 Meeting tomorrow?

[kym834]

Just ticking off that the meeting with the schools has happened. Agenda and minutes here. All the schools have different targets and we discussed what targets they will look at in the future - especially USyd and UCL who will be starting the synthesis of new compounds in the next few months.

[kym834]

@dmitrij176 @fantasy121 - have you had a meeting yet to work on the fenarimols paper?

[dmitrij176]

Hi @kym834. Yes, we finalized everything and the latest version is up to date and ready for Mat to review.

[kym834]

@dmitrij176 awesome! Sorry I wasn't keeping up with the meeting minutes and didn't chip in. Let me know if there is anything else you'd like me to do to get this one over the line :)