Mycetoma Monthly Meeting 25th October 2022

[mattodd]

Time: 25th October (12 UK, 1 EU, 9 Aus) Location: https://uni-sydney.zoom.us/j/99281549497 Chair: UCL Minute taker: USyd Previous meeting: #80 Recording: here

Apologies: @mattodd

Key things to focus on this month (please add if you'd like to prioritise something):

1. Biological Evaluation (Erasmus)

• [x] @MA-Jjingyi to post powerpoint decks from Sept meeting and from Aug meeting
• [x] @dmitrij176 to summarise (in a new post, with a link to that post from the wiki) latest in vitro and in vivo data from Aug and Sept in advance of the next meeting.
• [x] @fantasy121 and @dmitrij176 to check that all their compounds in the Master List possess molecular weight info (and anything else that is useful/important)

2. New Chemistry (USyd and UCL)

• [x] Update needed from Breaking Good team (@alintheopen @kym834 @KlementineJBS) on which molecules have been made, and which are planned, as well as an updated synthetic scheme.
• [x] @fantasy121 to share the scheme of targets shown in #80 .

3. Other Samples Incoming/Desired

• [x] @dmitrij176 to complete the analysis of the Epichem library to identify compounds useful for closing the SAR gap, and post to a new Issue before the next meeting.
• [x] @fantasy121 to contact Rohan David, to obtain structures for his antimalarial compounds and whether they are intended for a particular biological target.
• [x] @fantasy121 to check the compounds from @AndreaOtago and @csuth22 in OpenSourceMycetoma/series-5-benzimidazoles#3 and ensure these compounds had been assigned MyOS Codes.
• [x] @bebi78 to advise whether all the samples he has recently contributed are in the Master List.
• [ ] @mattodd to pursue metal complexe samples from COADD and report at next meeting.

4. Paper Writing

• [x] @fantasy121 will ask Alice/Peter to complete their review the draft (co-authoring)
• [x] @dmitrij176 to complete his inputs to the experimental section, using the offline editing of Word documents via Dropbox.
• [ ] @fantasy121 and @dmitrij176 to assemble the NMR spectra (images of spectra, and raw data files) for novel compounds - location needs to be decided.

5. Admin

Actions from last time: In the last meeting it was decided to move to a time that is the same each month: 12 noon UK, 1 EU and 9 Sydney. It was also decided that

• [x] @mattodd would generate a back-up Zoom link should USyd not be able to attend (done - https://ucl.zoom.us/j/99789829423), and that
• [x] @wwjvdsande would generate a Teams link as option number 3.
• [x] @wwjvdsande to include these links in a new Outlook invitation for the next 12 months worth of meetings. The meetings are on the 4th Tuesday of each month
• [x] @fantasy121 or @kym834 (whoever made them) to cancel the Outlook invites for the original series of meetings
• [x] Breaking Good compounds @kym834 In meeting: @fantasy121 or @KlementineJBS to provide structures and SMILES for latest Breaking Good compounds, ensure that they are in the Master List (with codes), allowing @wwjvdsande to be able to get logD values.
• [x] @wwjvdsande to chase @MMos2022 for the deck of her presentation and post below.

6. AOB

Next Meeting: Time: November 22nd 12 UK, 1 EU, 9 Aus Who is starting the Issue: UCL Who is chairing: Erasmus MC Who is taking minutes: UCL

Minutes

Apologies: Mat, on vacation

Meeting Starts

1. Biological Evaluation

Action items were all completed.

Bernhard sent additional samples for testing. Drugs for arthritis/inflammation that also have antifungal properties. Package has arrived at Wendy’s lab Metal-complex drugs (Rh- and Pt- complex) also received from IFF

2. New Chemistry

Dmitrij had difficulties distinguishing compounds that have been tested before vs after July as Master List does not contain dates tested

dmitrij176 to summarise (in a new post, with a link to that post from the wiki) latest in vitro and in vivo data from Aug and Sept in advance of the next meeting.

Suggestion: to get Wendy’s team to help with this. Also can cross-check with the manuscript to work out where we are up to.

Dmitrij gave an overview of the summary of recently tested compound. Details see scheme.

Noteable details: Ketoxime compounds results show similar patterns as observed in Series 1 High log D = poor in vitro (Suggests that also low Log D might = good in vivo)  

3.

dmitrij176 to complete the analysis of the Epichem library to identify compounds useful for closing the SAR gap, and post to a new Issue before the next meeting.

Hung to update master list with his new batch Series 1

SAR gap recheck Dmitrij to post his scheme to GHI to be combined with Hung due end of Oct

mattodd to pursue metal complexe samples from COADD and report at next meeting.

UCL updates Dmitrij gave a brief update on his current batch of compounds being synthesised.

Erasmus update Ma gave an update on biological testing (see below) Ma to upload presentation below.

Currently logD 2.5 gives p = 0.04, Wendy tries to split logD at 3.0 but no statistical significance observed.

Wendy to Request Ben to perform other stat tests (more complex cf log d) to see if new trends emerge Note: Ben will leave DnDi. Contact Dr. Cruz if Ben is no longer corresponding

Paper Writing

• Wendy and Dmitrij have updated manuscript
• Peter has reviewed updated Manuscript V5
• Hung will work on comments addressed to Hung.
• Hung has uploaded NMR spectra to dropbox

Next meeting: UCL minutes Erasmus chair

[kym834]

@OpenSourceMycetoma/corecontrib will also look to tick off the BG relevant task here on the weekend.

[wwjvdsande]

As discussed during the MycetOS group meeting on 27 September 2022, this is the new invite for the monthly MycetOS group meetings. Our main meeting link is:

1. https://uni-sydney.zoom.us/j/99281549497. When nobody from university of Sydney is able to attend and record the meeting, we will meet via the alternative link in the following order:
2. https://ucl.zoom.us/j/99789829423
3. MycetOS meeting teams link

The outlookinvite can be found here: Monthly MycetOS meeting00.zip

[wwjvdsande]

The presentation as given by @MMos2022 in our september meeting Mycetoma Screening Presentation_To share 05.09.2022.pdf

[wwjvdsande]

I added the compounds of Andrea Ortago in the mastersheet and the results of the screening. However there were no smiles. In https://github.com/OpenSourceMycetoma/series-5-benzimidazoles/issues/3#issuecomment-1158804057 the structures are shown can @dmitrij176 or @fantasy121 generate smiles and/or MycetOS codes for them?

[dmitrij176]

I added the compounds of Andrea Ortago in the mastersheet and the results of the screening. However there were no smiles. In OpenSourceMycetoma/series-5-benzimidazoles#3 (comment) the structures are shown can @dmitrij176 or @fantasy121 generate smiles and/or MycetOS codes for them?

Yes Wendy, I will let everyone know when they are added.

[dmitrij176]

@wwjvdsande Master list is now fully updated with information on Benzoxazoles

[dmitrij176]

Hi @kym834. There are only 5 (Series 2) molecules left without SMILES in the Master List: MYOS_00315_00_01 MYOS_00316_00_01 MYOS_00317_00_01 MYOS_00318_00_01 MYOS_00319_00_01 MYOS_00320_00_01

Could you please update these entries so that we can ask Ben to calculate logD values.

[AndreaOtago]

@wwjvdsande Master list is now fully updated with information on Benzoxazoles

Hi, I saw you have updated the Otago compounds etc with your system codes, just a note - the compounds sent in by Otago, the 2-phenylpropanoic derived-compounds (2 compounds) are both the racemic mixture. This was on the sheet I sent in, but Ben may have not/uploaded misleading stereochem, definitely the R/S mixture from Otago. The Imperial team did make some enantiomers, but of different halogen regioisomers.

[mattodd]

@AndreaOtago thanks. Can't remember if that changes the SMILES. @dmitrij176 please check and correct if necessary.

[mattodd]

Hi @alintheopen @kym834 @KlementineJBS I'm getting multiple requests from Schools to get involved in MycetOS this academic year. It'd be very handy to know what you've made in the last academic year and what is planned, so that we can effectively allocate novel structures. Might you be able to post an update (to OpenSourceMycetoma/Series-2-Aminothiazoles#9) on 1) made structures, 2) planned structures and 3) any improvements made to the synthetic protocol?

[dmitrij176]

@wwjvdsande Master list is now fully updated with information on Benzoxazoles

Hi, I saw you have updated the Otago compounds etc with your system codes, just a note - the compounds sent in by Otago, the 2-phenylpropanoic derived-compounds (2 compounds) are both the racemic mixture. This was on the sheet I sent in, but Ben may have not/uploaded misleading stereochem, definitely the R/S mixture from Otago. The Imperial team did make some enantiomers, but of different halogen regioisomers.

Hi @AndreaOtago. Can you please specify which entries you are referring to (codes from the scheme)? We do have enantiomers and racemates in the Master List. The way we mark that is by adding this extra information in the E column. Alternatively, each isolated isomer, enantiomer gets a separate MYOS code.

[AndreaOtago]

Hi @dmitrij176 sorry I was just going off the visual chemdraws above, I can't find the link/where to get to the master list, and also I am unsure where the biological data file/info link is, it would be interesting to see the activity of the compounds.

[mattodd]

@dmitrij176 it's the two compounds with the stereocentres, 398 and 399. According to our convention "Different stereoisomers (or mixtures thereof) should have different MYOS codes" so these racemates can keep their codes, but the drawing needs to be altered and the SMILES/InChI/InChIKEY codes need to be re-done if they are different for racemates vs single enantiomers. @AndreaOtago the link is on the front page of this repository - http://tinyurl.com/MycetomaMols

[kym834]

Hi @kym834. There are only 5 (Series 2) molecules left without SMILES in the Master List: MYOS_00315_00_01 MYOS_00316_00_01 MYOS_00317_00_01 MYOS_00318_00_01 MYOS_00319_00_01 MYOS_00320_00_01

Could you please update these entries so that we can ask Ben to calculate logD values.

Have now updated the SMILES etc for these compounds in the master list.

[kym834]

Hi @alintheopen @kym834 @KlementineJBS I'm getting multiple requests from Schools to get involved in MycetOS this academic year. It'd be very handy to know what you've made in the last academic year and what is planned, so that we can effectively allocate novel structures. Might you be able to post an update (to OpenSourceMycetoma/Series-2-Aminothiazoles#9) on 1) made structures, 2) planned structures and 3) any improvements made to the synthetic protocol?

Hey @mattodd,

1) I've updated the repository for series 2 with

• the compounds that were successfully made and have been shipped by the schools in May/June. https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/9
• the compounds that SSP have been working on this year. They are currently completing the characterisation and we'll know in the next week or so if they have successfully made them. https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/10

I have also updated the wiki with some extra pages that now show compounds which have been evaluated, those awaiting evaluation and those that are currently being synthesised. Hopefully this will help avoid overlap but we either need to get people to update these pages themselves or get people posting issues in the repository with what they are planning so we can keep it updated.

2) In terms of planned structures, the nitro compounds USyd has hopefully made this year https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/10 will be used to expand the structure through reduction of the nitro and subsequent substitution in 2023. As we are waiting on characterisation data though this isn't set in stone. I've also indicated that the 2,3 and 4-chloro compounds made last year (MYOS_00180_00_01, MYOS_00181_00_01 and MYOS_00182_00_01) and those hopefully made this year (not confirmed so no MYOS numbers yet) could be used in coupling reactions to further expand the structure. I'm working on added a story to the home page of the wiki that expands the logic behind the compounds made so far and these possible future directions.

I'm also very happy plan an administrative role and engage in discussions with people about what we make and help direct the series as well as keep the GitHub repo up to date.

3) No improvements to the synthetic protocol. I've put the detailed protocol (example from SSP 2021) into the wiki. So hopefully now visitors will find it easier.

[PaulMcKeatingSevenoaks]

Thank you, @kym834 !

[dmitrij176]

Updated Benzoxazoles

@mattodd @wwjvdsande the Master List is now fully updated. @bendndi would you please generate logD values for us.

[mattodd]

OK, @dmitrij176 out of interest did the chemical strings (SMILES etc) change between single enantiomer and racemate?

[wwjvdsande]

@OpenSourceMycetoma/corecontrib I updated the spreadsheet with the logD values etc. @bendndi was so kind to calculate the missing values

[wwjvdsande]

@OpenSourceMycetoma/corecontrib we are in the sydney zoom link. Is anyone from sydney joining? @fantasy121?

[bebi78]

@dmitrij176 @fantasy121 Fatty alkyl pyridinium salts (e.g., cetylpyridinium chloride/CPC) can have considerable antifungal activity (see link). I used N-alkyl salts of 4-picolin for the synthesis of various stilbazolium dyes as part of finished a material science project. But can be repurposed for mycetoma testing. @wwjvdsande

https://www.mdpi.com/2309-608X/6/4/218

[MFernflower]

@bebi78 maybe a few of those stilbazolium compounds could be sent for antifungal testing - they kind of resemble the known antifungal Miltefosine

[MFernflower]

@bebi78 @wwjvdsande

All though if I'm not mistaken miltefosine was tested and found to not prolong larval survival

[MFernflower]

@dmitrij176 I was wondering if you could make one of the non commercially available phenothiazines (series 3) if you had time to do so - something like N-isovaleryl phenothiazine might be interesting to screen

[bebi78]

@MFernflower Yes, I will check if I still have the stilbazolium compounds and the corresponding N-alkylpicolin precursors. Maritima might also be a suitable starting compound to prepare pyridinium salts. Cetylpyridinium might be prepared analogously.

[MFernflower]

@bebi78 should just be as easy as refluxing maritima, dmf, ethyl iodide and potash together - Although these type of compounds tend to have toxicity issues that limit there use to topical formulations (with the exception of miltefosin)

On Wed, Oct 26, 2022, 12:14 PM bebi78 @.***> wrote:

@MFernflower https://github.com/MFernflower Yes, I will check if I still have the stilbazolium compounds and the corresponding N-alkylpicolin precursors. Maritima might also be a suitable starting compound to prepare pyridinium salts. Cetylpyridinium might be prepared analogously.

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[bebi78]

@MFernflower Often you don't need potash and can use ethanol as solvent, the pyridine is reactive enough to be alkylated by alkyl bromides in hot ethanol. I still have six or seven N-cetylpicolines and cetylstilbazolium dyes I can provide for testing.

[dmitrij176]

@dmitrij176 I was wondering if you could make one of the non commercially available phenothiazines (series 3) if you had time to do so - something like N-isovaleryl phenothiazine might be interesting to screen

We will see.

[mattodd]

Hi @OpenSourceMycetoma/corecontrib - sorry to miss the meeting. Three Q's where I think we need clarification:

1) I'm having trouble figuring out from the minutes if there are new action items that we need to add to next meeting #83. Please could the minute taker check through the above minutes to see whether all actions from Oct are inluded in Nov?

2) What's the next things needed on the paper? Who is next to read the manuscript (there are still a lot of comments outstanding) and what's remaining to be done for the experimental Word file?

3) We've previously mentioned ordering compounds from Epichem to close SAR gaps, e.g. in #79 "Hung has made his list of potential compounds for gap, @dmitrij176 indicated that he still is to go through the epichem library to find compounds for SAR gap. When both @fantasy121 and @dmitrij176 have made their lists they need to be compared and ordered via Martine to ship the compounds in one shipment." After checking the main SAR Issue #51 I can't see the diagram of your SAR gap analysis @fantasy121 though I'm sure we saw it in a meeting. Can you please link to where this is (i.e. the list of compounds we should evaluate, based on SAR to date) or post it again somewhere?

[bebi78]

@MFernflower @wwjvdsande @mattodd @MA-Jjingyi Please find below a list of cetylpyridinium compounds including the new cetyl-maritima, and new niclosamide derivatives (inspired by Wendy's niclosamide paper) I can share for testing anytime.

Niclosamide.Cetyl.docx

[MA-Jjingyi]

20221025myctOS meeting -MA.pptx the slides from last month are here. please check.

[wwjvdsande]

Hi Ma,

Didn't we present this already last time? If so, no need to present now

Wendy

From: MA-Jjingyi @.> Sent: maandag 21 november 2022 14:30 To: OpenSourceMycetoma/Series-1-Fenarimols @.> Cc: Wendy Laureijssen - van de Sande @.>; Mention @.> Subject: Re: [OpenSourceMycetoma/Series-1-Fenarimols] Mycetoma Monthly Meeting 25th October 2022 (Issue #82)

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20221025myctOS meeting -MA.pptxhttps://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fgithub.com%2FOpenSourceMycetoma%2FSeries-1-Fenarimols%2Ffiles%2F10056904%2F20221025myctOS.meeting.-MA.pptx&data=05%7C01%7Cw.vandesande%40erasmusmc.nl%7Ca5841b8457a84841d2ab08dacbc48db7%7C526638ba6af34b0fa532a1a511f4ac80%7C0%7C0%7C638046344199692611%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=TrSoEBSvs%2BVjg6lHytgW8qO6AL%2BXQoeaTehb1mHBwvQ%3D&reserved=0 the slides are here. please check.

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[MA-Jjingyi]

Hi Ma, Didn't we present this already last time? If so, no need to present now Wendy From: MA-Jjingyi @.> Sent: maandag 21 november 2022 14:30 To: OpenSourceMycetoma/Series-1-Fenarimols @.> Cc: Wendy Laureijssen - van de Sande @.>; Mention @.> Subject: Re: [OpenSourceMycetoma/Series-1-Fenarimols] Mycetoma Monthly Meeting 25th October 2022 (Issue #82) Waarschuwing: Deze e-mail is afkomstig van buiten de organisatie. Klik niet op links en open geen bijlagen, tenzij u de afzender herkent en weet dat de inhoud veilig is. Caution: This email originated from outside of the organization. Do not click links or open attachments unless you recognize the sender and know the content is safe. 20221025myctOS meeting -MA.pptxhttps://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fgithub.com%2FOpenSourceMycetoma%2FSeries-1-Fenarimols%2Ffiles%2F10056904%2F20221025myctOS.meeting.-MA.pptx&data=05%7C01%7Cw.vandesande%40erasmusmc.nl%7Ca5841b8457a84841d2ab08dacbc48db7%7C526638ba6af34b0fa532a1a511f4ac80%7C0%7C0%7C638046344199692611%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=TrSoEBSvs%2BVjg6lHytgW8qO6AL%2BXQoeaTehb1mHBwvQ%3D&reserved=0 the slides are here. please check. - Reply to this email directly, view it on GitHubhttps://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fgithub.com%2FOpenSourceMycetoma%2FSeries-1-Fenarimols%2Fissues%2F82%23issuecomment-1322068723&data=05%7C01%7Cw.vandesande%40erasmusmc.nl%7Ca5841b8457a84841d2ab08dacbc48db7%7C526638ba6af34b0fa532a1a511f4ac80%7C0%7C0%7C638046344199692611%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=j1G2dFVdgt0s3qnYzfEhTWZPvV30yeFSiE9r3D%2FKyz4%3D&reserved=0, or unsubscribehttps://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fgithub.com%2Fnotifications%2Funsubscribe-auth%2FAIVWIOTQ4RVK2AJL6SCC5ADWJN2PFANCNFSM6AAAAAAQW6AR3Y&data=05%7C01%7Cw.vandesande%40erasmusmc.nl%7Ca5841b8457a84841d2ab08dacbc48db7%7C526638ba6af34b0fa532a1a511f4ac80%7C0%7C0%7C638046344199692611%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=0IFDZ61Ge5caWer3%2FUT8X6IUmFDJzaTONLQNtJya00g%3D&reserved=0. You are receiving this because you were mentioned.Message ID: @.**@.>>

@wwjvdsande we did present it last month. and I forgot to upload them last month. so, i upload them now.

[AndreaOtago]

Finally getting around to having a look at the biological results from the Otago benzoxazoles out of interest, and I see a few are quite good, and also looks like the best here were some of the worst/inactive in the OSN/DNDi/parasite screen, so interesting!

[dmitrij176]

Finally getting around to having a look at the biological results from the Otago benzoxazoles out of interest, and I see a few are quite good, and also looks like the best here were some of the worst/inactive in the OSN/DNDi/parasite screen, so interesting!

Hi @AndreaOtago. Yesterday during MycetOS meeting, we discussed the assay results covering July-September 2022. I generated a potency scheme which might be of further help to you if interested. Otago benzoxazoles are included. Attaching the files below.

Potency results (July-Sept 2022)  Blue Box.zip

[dmitrij176]

Potency results (July-Sept 2022) Orange Box.zip