Monthly MycetOS meeting - 26th November 2024

[KlementineJBS]

26th Nov 2024

Will be at 9 AM EU/7 PM AU (see your timezone here)

The Outlook invite can be found https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/2#issuecomment-1905476888

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: USyd Minute taker: UCL Previous meeting: #27 Recording of today's meeting: https://youtu.be/v4eq_fP8YUc Present:

Housekeeping

• all tabs remaining on masterlist as of 22-10-24 are to be kept, as they represent various compound libraries
• no meeting next month (happy holidays)

Series 1 - Fenarimols

• Mat is finishing off a few fiddly bits on the paper but it will be submitted soon
• [ ] @mattodd to capture on wiki pages the desirable compounds identified in the Fenarimol paper, e.g. the meta-substituted derivatives
• has @fantasy121 been able to share his thesis/other relevant work on the wiki?

Series 2 - Aminothiazoles

• Uni of York hits 771 and 772 have IC50s around 0.1 - 1 uM
• Klementine to update SAR page with results, Bernhard's compound and molecules-in-progress from Whitgift + U of York --> this has been done, see here
• Whitgift is working on the fluoro analogue listed in the SAR and their next target can be found here - essentially an N-methylated version of MYOS605, which is the unsubstituted "skeleton" of our lead
• Peter has shared the compounds currently being made by Uni of York here
• @dosreic has been in contact about sending compounds of interest. While one was not available, she sent a few extras described here
• Klementine has contacted Prof Marco Pieroni and he seemed keen to share some molecules, but nothing has been finalised. More about this here

Series 3 - Phenothiazines

• Do we still need the MYOS626-628 compounds for in vivo testing? We previously discussed having some of the Uni of York students re-make these compounds if Lori cannot provide them

Series 5 - Benzimidazoles and benzoxazoles

• Andrea, Ma and Charlotte have been working on the draft of their benzoxazole manuscript here
• Klementine searched the MMV boxes for benzoxazoles and they can be found here

Series 6 - Ketoximes

• Dmitrij still working on SAR and paper, will share when it is completed

Other business

please add any other business you'd like to discuss next meeting

[eloizidou]

Reza (UCL MSc student) searched the PDB database for structures of aminothiazoles bound to proteins and he also used Swiss Target Prediction. The results are attached here. I believe Reza will join the meeting tomorrow and can talk about this further. LIST OF AMINOTHIAZOLE TARGETS_pdb_database.xlsx

[mattodd]

Latest update on what's left for the paper submission. Let me know if I've missed anything!

Current draft is on Dropbox. "Fenarimol Paper July 29th MHT HPD". Please don't change anything without noting the change below.

1) References are still a problem.

There are phantom (not numbered) references between 3 and 4, and between 6 and 7 etc etc. Some of the DOIs are not right (e.g. for ref 23. In other words, I think this needs a reformat. At this stage is it easiest to do this manually, or would someone in @wwjvdsande team like to reformat? --> @wwjvdsande will do that when the manuscript is complete

2) Diagrams

I have changed what was Table 1 into new Figure 8 @fantasy121. This makes it more consistent with the rest of the paper.

• [x] @fantasy121 @dmitrij176 Could any remaining chemdraws please be deposited in the Dropbox/Drafts folder?

• [x] @fantasy121 Fig 9 - the aromatic system for compounds 73 and 74 needs to be made consistent (double bonds, not circles).

• [ ] I still think Fig 12 could be in colour. One compounds number (14) needs bolding. @fantasy121 I see you've provided the chemdraw, so I will do this. @mattodd

• [ ] @fantasy121 @dmitrij176 - Figure 13: so 4 and 10 were reported in the first paper, but 310 was found for this paper. Shouldn't it appear somewhere else, like Figure 10? It just comes out of nowhere. Let me know, and I can add it.

• [x] @fantasy121 P61 Fig 12 - check that compound 14 is a thiophene and not thiazole (as originally stated in the text).

3) Supporting info

• [x] @mattodd to check that the potency spreadsheet (which will be Supplementary File S1, (mentioned on pages 47 and 53 and 58)) is ready and includes all relevant compounds in the paper, with in vitro and in vivo data . Can someone please remind me where this file is located? It needs to be on Dropbox. --> @wwjvdsande made that so she will copy it to dropbox @fantasy121 added this SI File into the SI folder for dropbox (file link here)

• [x] Also mentioned is Supplementary file X (page 53) which is the list of contributors. Do we have? Contribution details also in File above

• [x] @fantasy121 @dmitrij176 the big SI file for the NMR spectra for novel compounds in the paper. Is this complete file now "SI NMR sample July 25th MHT HPD" on Dropbox? i.e. all the spectra we need?

• [ ] In open science projects/papers we like to make a point about the lab notebooks being available. This includes links to the actual lab notebooks, but also offline archived notebooks that are uploaded to university repositories. Are we able to do that here? I know there was some complexity about @dmitrij176 ELN, but @fantasy121 is this something that is possible?

• [X] @fantasy121 Offline notebook on the USYD library repository is here https://ses.library.usyd.edu.au/handle/2123/30280

• [ ] @dmitrij176 notebook link

Hung's notebook is available as an offline copy in USYD library repository. Link here

4) Experimental

• [x] Synthetic procedure F - "ACl3" in fig needs to be "AlCl3". Could someone please fix?

• [ ] Int3 molecule size and typo N-methyl-2-pyrrolidone is supposed to be N-methyl-2-pyrrolidinone, right? @dmitrij176

There are some pretty simple molecules that don't have any reference to lit data. e.g. compound MYOS_00164. There are a number of lit 1H NMR spectra of this molecule reported, and one in acetone (same as us): link here. (It matches, thankfully).

• [ ] Sorry, but @fantasy121 @dmitrij176 I need you to check that none of your compounds that have no statement about matching lit don't have lit references that we ought to be citing ("Spectroscopic data matched those in the literature"). I'm not expecting many, but we need to be sure. Please just plug them in to SciFinder and look for experimental spectra and let me know when done.
• [X] @fantasy121 has updated literature references for his compounds.
• [ ] @dmitrij176

5) Acknowledgements

• [ ] Acknowledgements section - LAST CHANCE to add people and funders etc. @fantasy121 have the Sydney team signed off?

• [ ] @mattodd to deal with the important IMSA authorship/acknowledgements issue, including running this past John Thurmond there: "Six compounds were synthesised by students from the Illinois Mathematics and Science Academy (IMSA)" are these people suitably acknowledged? Thanks @fantasy121 for clarifying which compounds, above. Compounds were sent to us in 2021 @dmitrij176 and we carried out LCMS, which I will add to the SI.

6. Misc

• [ ] @mattodd check capitalisation of logD and capitalisation of Figure titles.

• [ ] In the section "In vitro screening of fenarimol analogues" there are a bunch of concentrations mentioned in the mM range. Am I right in thinking these are typos and that they should read micromolar?

• [x] Throughout MIC50 units should be micromolar? @wwjvdsande --> correct

• [X] P66 I've highlighted a repetition in red @fantasy121 can you please resolve? Re p66: the highlighted sections talked about two different compounds and referred to different literature sources. These two sentences supported two different claims. So please keep them as they are.

• [ ] What is our conclusion re logD? Lower or higher than 2.5? Fig 1 in vitro suggests > 2.5 is better. Fig 3 suggests lower is better for in vivo. Do we just need to emphasise in the conclusions that we appear to need a balance? --> action @wwjvdsande

• [x] Cover Letter - done. It's going to ACS Infectious Diseases.

• [x] Potential Referees - I have a list ready.

[mattodd]

Hi all - I'll be on the school run during the meeting, I'm afraid, so please excuse any delays in responding or bad connections.

[wwjvdsande]

Potential interesting (fungal specific) targets: woronin body, the fungal specific kinases, the trehalose pathway

[fantasy121]

My Offline notebook on the USYD library repository is here https://ses.library.usyd.edu.au/handle/2123/30280

[fantasy121]

@KlementineJBS I thought recording was done on my end but I think it's actually on Wendy's computer @wwjvdsande. Can you check and upload this onto YouTube?

@mattodd

[eloizidou]

We could try homology modelling and docking of aminothiazoles and the fungal kinases. Maybe Reza can help with this.

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Potential interesting (fungal specific) targets: woronin body, the fungal specific kinases, the trehalose pathway

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[mattodd]

Hi @eloizidou the mention of new protein targets was more so that we could get them into an ASMS screen. But definitely homology modelling of likely targets of aminothiazoles, based on what's known of the chemotype in the PDB, would be v useful for that paper.

[KlementineJBS]

Hey Hung @fantasy121 , the recording was via my laptop :) I've just uploaded the video and added it to the top comment.

[fantasy121]

@mattodd I have addressed all of corrections you noted above for the manuscript which were assigned to me. Re: Fig 12. I leave this to you to colourise. Re: Fig 13 compound 3, 4 and 310. These compounds didn't fit into the flow of the in vitro analysis as they are not quite piperidyl (Fig 9) or piperazyl (Fig 10). In a much more primitive SAR analysis, I used to have these compounds under "linker/spacer" motifs that "space out" the right ring (which would be a piperidyl/piperazyl). Even then 310 still wouldn't fit as it is not spacing out a piperidyl/piperazyl. @mattodd any thought on where to fit these? I could maybe make a case to add 3 and 4 into Fig 9. @dmitrij176 made 310, so maybe understanding the thought process to justify the synthesis of this compound could help add this into Fig 10 (which is where most of @dmitrij176 compounds reside).

[fantasy121]

@wwjvdsande As I have updated the experimental section, there are now new references added. I have provided the DOI. Please add these into the bibliography in your next updating of it.