Open Source Mycetoma (MycetOS) Meeting May 25 2021

[fantasy121]

Hi All, Our next meeting is on 25 May 2021.

We'll be meeting at Zoom ID: 992-8154-9497 https://uni-sydney.zoom.us/j/99281549497.

Times: Sydney - 9 PM, Amsterdam - 1 PM, London - 12 Noon, USA (New York) - 7 AM

Recording of this meeting to go here

Previous meeting are here (#50 )

Agenda

• [x] ISNTD talk event @mattodd @wwjvdsande. Also see #53
• [x] Check Master List for Duplicate compounds with different MYOS codes and merge them accordingly @dmitrij176
• [x] Confirm isomeric forms of MYOS_00004_00_01, MYOS_00010_00_01, MYOS_00117_00_01 and MYOS_00138_00_01
• [ ] Find a way to specify and retain isomer information in Master List
• [x] Kymberley on update of Series 2 compounds @kym834 ---> purification pending - also seems she has finished with series 1 and is now devoting all efforts to S2 compounds
• [ ] @fantasy121 Hung SAR/synthetic update. Upload Chemdraw files for SAR, share with group
• [x] @fantasy121 New roster for host/minute taking by institution. See #52
• [x] Erasmus University, updates on biological evaluation @wwjvdsande @MA-Jjingyi @Wilson-Lm
• [x] UCL synthetic update (for the meeting) @dmitrij176
• [ ] MYOS_00019_00_01 adding missing LogD value to Master List @bendndi
• [x] @dmitrij176 to update (via a new github issue) us on what compounds have shipped and what compounds are planning to be synthesized.
• [ ] Kaitlin will look into developing some materials for her students to start exploring the SAR of some of the Fenarimol analogues. @kbea282

Meeting minutes:

Erasmus Been screening compounds against Falciformispora senegalensis (the second most common causative fungal agent of mycetoma). Benzimidazoles seem to be quite effective, giving good preliminary results, while Fenarimols do not exhibit any good anti-fungal activity against F.senegalensis. Terbinafine (commercial antifungal) is active against F.senegalensis, but not against M.mycetomatis.

Wilsons update on the latest screenning assays: 41 Benzimidazoles tested of which: 11 were from the Patgogen Box 10 were from the Stasis Box 20 were from the Pandemic Box

In vitro/ in vivo results: 6 active in vitro, with one compound giving 20.7% inhibition at 25 micromollar concentration. 6 were carried over to the next phase to determine their MIC 2 tested in vivo

Benzimidazoles should be explored more by MycetOS community as they are potent against multiple strains of mycetoma. There is a need for structural analysis to identify motif similarity within existing mycetoma libraries (such as Pandemic, Response Boxes, Epichem). Recent example: Fenbendazole (with good antifungal potency as showed by the latest screen) has high structural similarity with MMV1782387. Carbamate moiety is of particular interest (eg. Albendazole), therefore additional work is needed in this field.

The larvae season has already started and it is important that project members start sending their compounds as soon as possible to ensure full asssay testing cycle. The absolute deadline for sending novel compounds is the start of July. The best option would be to split deliveries into several parts and start sending analogues that are ready for shipment (if possible).

UCL The first oxime in the new series, Pyrifenox has been synthesised and is currently being characterised. Another molecule is currently in production and involves functional group variation within the main oxime scaffold.

Three more novel Fenarimols have been proposed for synthesis (including P4_A_008 from the Master List). Based on the successful DM7-1 in vivo performance, further pipreridine motif exploration continues with piperidine-4-carbonitrile substrate. Another heterocyclic addition to the existing series 1 library will involve fenarimol with pyrrolidine moiety. DM23-6 has been deprotected into DM36-1, giving a new analogue for testing. The precursor showed good potency at the in vitro stage, so further investigation was considered useful.

For the 2021 in vivo testing season, UCL has got 5 new compounds that are almost ready for shipment (currently 3/5). DM27-1 and DM28-1 havent been tested last time and it needs to be checked whether they are still in London or in Rotterdam. It is anticipated, that other proposed analogues (at least 3 fenarimols and 2 oximes) will be sent for evaluation as well.

University of Sydney

As part of the SSP 2021 project and based on the previously discovered hit compound 2-aminothiazole which has formed Mycetoma's Series 2, 12 new molecules have been synthesised by a joint effort of students (10) and demonstrators (2). See here for details. All of the analogues are novel. Purity checks and structure characterisations are currently in progress.

Closing remarks

ISNTD talk event: more information to follow from @mattodd in due course. Mat: will speak to ISNTD and DNDi on the subject and update everyone soon.

@OpenSourceMycetoma/corecontrib, please add anything you wish to discuss to the agenda

[fantasy121]

I've worked out the isomeric forms of the following ( I've added a note on the master list of their isomeric identity):

MYOS_00004_0001 (S)_ enantiomer version of EPL-BS1246 MYOS_00010_00_01 racemate version of EPL-BS1025 MYOS_00117_0001 (S)_ enantiomer version of EPL-BS1246 MYOS_00138_00_01 DM16-1 ?

This assignment is based on the result of our initial screen where EPL-BS1246 and EPL-BS1025 are different isomers of each other:

Can you confirm that 00138 is a racemate? @dmitrij176

I think we need a better solution to retain isomer information in our Master List as this mistake keeps happening. You can also see that the isomers have different efficacy as well so best not to mix them up in the long run. Any thoughts on how to do this efficiently? @mattodd @dmitrij176

@dmitrij176 Can I also put you in charge of finding instances where the same chemical structure is assigned multiple unique MYOS_00000.... codes? If you can group each of these duplicates under the one 00000 code and assign batches or some other way to denote that they're the same chemical structure. My understanding is that new 00000 numberings are meant to be assigned to unique chemical structures only. You can download my chemdraw zip file at #51 to view all the structures so far (otherwise let me know so I can give you PNG versions of these files to view)

[mattodd]

Yes @fantasy121 this looks important to sort out - we can't have duplicative numbers. The codes we're using do not have something for enantiomeric excess, so it's easiest to give racemate and enantiomer separate codes. So those ones you highlighted above need correcting, and any other instances of this need to be identified.

[dmitrij176]

@fantasy121 @mattodd MYOS_00138 is definitely a racemate. So I though that we all agreed that isomers/enantiomers would be noted in the aka section, because we havent devised any MYOS convention in the context of the MYOS code.

Regarding duplicates, yes @fantasy121 no problem. I will check the list.

[mattodd]

"Different stereoisomers (or mixtures thereof) should have different MYOS codes (i.e. a difference in the first 5 numbers)" was how we have it in the numbering convention. Obviously if we have to delete a number because it's a duplicate then we just delete it and we don't renumber all the later compounds. It doesn't matter if a MYOS code that was deleted is not then taken up by another compound.

[mattodd]

Hi all @OpenSourceMycetoma/corecontrib - any update on the date/time of the meeting (https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/50#issuecomment-839665973)? Currently assuming 25th at 10 pm London?

[Wilson-Lm]

If I recall what was agreed in the last meeting, we will now stick to the same time for the next few meetings or until changed. The meeting will be on 25th on this time:

Times: Sydney - 9 PM, Amsterdam - 1 PM, London - 12 Noon, USA (New York) - 7 AM.

[fantasy121]

Date and time for our May meeting is now confirmed, please look at OG post @OpenSourceMycetoma/corecontrib @alintheopen @pedrochemical @kbea282 @MA-Jjingyi

[MFernflower]

@kym834 Perhaps one of the students you are working with could prepare the oxime I proposed?

[MFernflower]

@kym834 The student could perhaps try making the oxime by grinding: https://orgmedchemlett.springeropen.com/articles/10.1186/2191-2858-1-12

[fantasy121]

@OpenSourceMycetoma/corecontrib sorry I’m an apology for tonight. I was filming for a science communication project but went overtime. I won’t make it in time for our meeting. I will work on finishing the rest of my SAR this week and post on GHI

[MFernflower]

https://wi.knaw.nl/page/fungal_display/8589

@wwjvdsande @Wilson-Lm

Boydii is commercially available from an NL supplier

I think the strain supplied is a white grain eumycetoma isolate from the southern US.

[MFernflower]

@dmitrij176

finished oxime proposal list:

[dmitrij176]

@kym834 could you please add some additional information that you think might be relevent to the minutes section, under the university of Sydney paragraph. You will see several brackets as you go through it. Just 1-2 sentences with details on group variation and the hit compound. Also, could you send me the info/links on the synthesis that we talked about last time. Thanks in advance.

[kym834]

@kym834 could you please add some additional information that you think might be relevant to the minutes section, under the university of Sydney paragraph. You will see several brackets as you go through it. Just 1-2 sentences with details on group variation and the hit compound. Also, could you send me the info/links on the synthesis that we talked about last time. Thanks in advance.

Synthesis Step 1 - lithium halogen exchange and substitution (KRS_015) https://github.com/TheBreakingGoodProject/ELN-Kymberley-Scroggie/issues/24 Step 2 - TEMPO oxidation (KRS_003) https://github.com/TheBreakingGoodProject/ELN-Kymberley-Scroggie/issues/11. Note that this oxidation is dependent on pH and temperature. If you keep the ratio of buffer to solvent to bleach you shouldn't have any problems. TEMPO decomposes rapidly at 25 °C so keep at 10°C (lower is fine but reaction slower).

I will post an update with all the chemical structures and details into the Series 2 repo and link the minutes above to this and update the brackets.

Thanks for your write up of the minutes @dmitrij176!

[dmitrij176]

@kym834 could you please add some additional information that you think might be relevant to the minutes section, under the university of Sydney paragraph. You will see several brackets as you go through it. Just 1-2 sentences with details on group variation and the hit compound. Also, could you send me the info/links on the synthesis that we talked about last time. Thanks in advance.

Synthesis Step 1 - lithium halogen exchange and substitution (KRS_015) TheBreakingGoodProject/ELN-Kymberley-Scroggie#24 Step 2 - TEMPO oxidation (KRS_003) TheBreakingGoodProject/ELN-Kymberley-Scroggie#11. Note that this oxidation is dependent on pH and temperature. If you keep the ratio of buffer to solvent to bleach you shouldn't have any problems. TEMPO decomposes rapidly at 25 °C so keep at 10°C (lower is fine but reaction slower).

I will post an update with all the chemical structures and details into the Series 2 repo and link the minutes above to this and update the brackets.

Thanks for your write up of the minutes @dmitrij176!

Thank you Kymberley.

[dmitrij176]

@MFernflower Oxime 1. Ketone (3-(4-Chlorobenzoyl)pyridine) has already been ordered.