MycetOS Meeting 31st May 2022

[wwjvdsande]

Open Source Mycetoma (MycetOS) Meeting May 31st 2022

Recurring Meeting Zoom link: https://uni-sydney.zoom.us/j/99281549497

Time: 12 noon UK time (other time zones)

Chair: UCL (is it?)

Minute taker: Sydney (is it?) MycetOS Meeting Minutes May 2022.docx

Recording:

Previous meeting: #74

Agenda

1. Paper writing (Files are here. Everyone is encouraged to post relevant files in this location, e.g. schemes).

• [ ] @fantasy121 @kym834 @dmitrij176 To work towards a complete experimental section with the same style employed throughout as per #75. Required also for @Wilson-Lm thesis submission.

A reminder about raw data files (e.g. raw NMR data, other spreadsheets). The paper we submit needs to be self-contained at the journal. All raw data needs to be submitted either to the journal or to a Uni repository. No data for the published paper can be housed only on an ELN or Github (which are not as permanent as a publisher/uni).

Destination: Something like ACS Infectious Diseases, Med Chem etc. (we will need to ensure we have an agreement for open access).

2. Potency Data

• [ ] @MA-Jjingyi to check and update the in vitro potency list with correct compound classes (mainly series 6 ketoximes; DM48-52). P4_A/B 3 entries are from Series 1 Fenarimols.
• [ ] @MA-Jjingyi to report on any new potency evaluations
• [x] @dmitrij176 to share diagram showing results discussed in #74 - i.e. correlating the structures with the potencies.
• [ ] @MA-Jjingyi to advise on the location of the data derived from the samples sent in from Kenya.

A reminder: all shared molecules need MyOS codes. Local codes are OK only locally. A reminder: In vivo compound evaluation submission deadline is 1st of July 2022.

3. Mechanism of Action of the Fenarimols and Ketoximes

• [ ] @dmitrij176 to update wiki page with what is known of fenarimol MoA (e.g. campaigns vs other pathogens) and ketoxime MoA.
• [x] @wwjvdsande to update on conversations related to MoA with Japanese group (which?) and SSGCID on protein crystallisation
• [ ] Can we use alphafold structure to make sense of our SAR data? @mattodd is in discussion with new collaborator who is interested in doing this with homology models.

4. Kinases

• [x] @wwjvdsande has submitted an application for funds to XXX (buy the kinase inhibitor library, correct?)

5. Other Series

• [x] @kym834 is doing a high school workshop on May 31st with 200 students on Series 2, where the students will do the final synthetic step. @kym834 to post about these targets so that there is no unintentional overlap with what @AndyBishopSevenoaks is doing. Update on targets here

• [ ] Updates to perfume compounds @bebi78 ?

6. AOB

• [ ] @mattodd @wwjvdsande @bendndi to coordinate submission to UNESCO call by July 15th.
• [ ] Ayan (last meeting guest) to set up Issue on potential relevance of E. coli screening platform for mycetoma targets.

Minutes

[wwjvdsande]

@OpenSourceMycetoma/corecontrib we will be away on the 24th and not be able to join the meeting. Do you want to proceed this meeting without the ErasmusMC team or do you want to move it one week (either earlier or later).

[kym834]

Happy to meet either the week before or later :)

[bebi78]

Sure. One week earlier or later is OK for me.

[dmitrij176]

I am good with both options.

[wwjvdsande]

Shall we say the 31st of may then?

[mattodd]

@kym834 - would you be able to alter the Outlook invite (if you were the one that sent it?).

[mattodd]

@OpenSourceMycetoma/corecontrib hopefully everyone on for the meeting tomorrow. Am I right in thinking UCL is chairing and Sydney is minuting (where is the rota for this?). Could everyone please take a look at the above and try to complete actions assigned to them? Has the last meeting recording been uploaded?

[MA-Jjingyi]

Hi, everyone. The MIC data have been updated in the spreadsheet. you all can check it easily.

@dmitrij176 because I received the compounds noted as DM41-2 and DM44-1, i changed the name in the spreadsheet and updated these data for them.

[dmitrij176]

Hi, everyone. The MIC data have been updated in the spreadsheet. you all can check it easily.

@dmitrij176 because I received the compounds noted as DM41-2 and DM44-1, i changed the name in the spreadsheet and updated these data for them.

Thanks

[AndyBishopSevenoaks]

Good to make it to the meeting today. @dmitrij176 @mattodd the molecule is in the post and is due to be delivered tomorrow before 1300. @fantasy121 @kym834 it would be good to get in touch and see how we can make high school student involvement most effective.

[bebi78]

@wwjvdsande @mattodd @MFernflower It is good to have computer chemistry experts from Cameroon in the team now. Aside Cyp51, further suitable docking targets of certain compound series can be tubulin (benzimidazoles), HDAC (Ptero-Hepam), and kinases. Maybe docking calculations can lead to a pre-selection of kinase inhibitors in case there won't be funding to buy a complete library of kinase inhibitors. @mattodd I asked Ben if benzoxazoles of his P5 project are available for testing (I put you into cc).

[dmitrij176]

Good to make it to the meeting today. @dmitrij176 @mattodd the molecule is in the post and is due to be delivered tomorrow before 1300. @fantasy121 @kym834 it would be good to get in touch and see how we can make high school student involvement most effective.

@AndyBishopSevenoaks the parcel has arrived. Thank you. Could you please provide me with additional information. I need:

1. Name (does the molecule has any assigned MYOS/other internal code?)
2. The diagram of the structure (can be Chemdraw file).

Also, what is the status of the mixture? I was told that there would be Aq and Org phases sent out separately. Correct me if I am wrong. The parcel contains only one vial. Does the mixture still require work up? Could you please clarify these things for me. Thank you in advance.

[bebi78]

@wwjvdsande @MA-Jjingyi You mentioned that naphtharazin is non-toxic. Was juglone toxic in previous tests?

[MA-Jjingyi]

Hi,@bebi78. in our test, juglone's IC50 is beyond 8uM. we didn't select it as a promising one to do larvae test. but as for naphtharazin, it is non-toxic in our larvae toxic test.

[bebi78]

@MA-Jjingyi Thanks. This is very interesting. @wwjvdsande I think you mentioned in a previous meeting that juglone was tested by you some years ago and found to be toxic.

[dmitrij176]

Good to make it to the meeting today. @dmitrij176 @mattodd the molecule is in the post and is due to be delivered tomorrow before 1300. @fantasy121 @kym834 it would be good to get in touch and see how we can make high school student involvement most effective.

@AndyBishopSevenoaks the parcel has arrived. Thank you. Could you please provide me with additional information. I need:

1. Name (does the molecule has any assigned MYOS/other internal code?)
2. The diagram of the structure (can be Chemdraw file).

Also, what is the status of the mixture? I was told that there would be Aq and Org phases sent out separately. Correct me if I am wrong. The parcel contains only one vial. Does the mixture still require work up? Could you please clarify these things for me. Thank you in advance.

@AndyBishopSevenoaks ?

[AndyBishopSevenoaks]

We only sent through the organic phase, happy to also send on the aqueous phase but not sure there is anything useful in there. How did the extraction go for @fantasy121? PDF of synthetic route and final structure below. Sevenoaks Synthesis #1.pdf

[wwjvdsande]

b

We tested juglone previously. It was indeed toxic to the larvae. The paper can be found here: https://pubmed.ncbi.nlm.nih.gov/35064672/ The toxicity data were published in a supplemental figure:

[bebi78]

@wwjvdsande Thanks a lot for sharing the paper! Maybe naphtharazin can also inhibit melanin synthesis or act synergistically with azoles. I just want to add that one of my cancer research partners found out that naphthazarin inhibits c-Myb activity in human cancer cells. Maybe that can become a suitable antifungal target, too.

[bebi78]

@mattodd @wwjvdsande @kym834 Seems that a group in Otago can provide benzoxazoles from the DNDi leishmaniasis project.

[bebi78]

@mattodd @bendndi @wwjvdsande @MFernflower Just repeating my today's mail to Ben for the members of this group: Some companies of the DNDi NTD Drug Discovery Booster Hit-to-Lead program, e.g., Takeda and Daichii-Sankyo, have published or patented various benzoxazoles as kinase inhibitors or antifungals. Booster S05 project also deals with some interesting azabenzimidazoles. Maybe they can share some of their compounds for mycetoma testing.

[fantasy121]

We only sent through the organic phase, happy to also send on the aqueous phase but not sure there is anything useful in there. How did the extraction go for @fantasy121? PDF of synthetic route and final structure below. Sevenoaks Synthesis #1.pdf

@kym834 should be able to answer this question better as she is more familiar with this series. Thanks.

[dmitrij176]

Hi Kymberley (@kym834 ). I am purifying a thiazole type compound for Sevenoaks School. Could you please advise me on purification; I am particualry interested in gradient and solvent system choice. Maybe you could redirect me to one of your ELN pages which would have close structures to my thiazole.

I used MeOH: DCM gradient, but could only pull out most of the crude mass components in high MeOH percentages which is not ideal.

The semi-pure mixture still has multiple components and I dont believe running it with the same solvents will do the job. EtOAc:Hex system is not polar enough; tried Et3N in MeOH: DCM, but it gives spots with traces on TLC.

Let me know if you have any suggestions. Thanks in advance.

[kym834]

@dmitrij176 - we were able to isolate all these compounds by the addition of water which formed clean pure precipitates. Simple wash with water and then hexanes was all that was needed.

I have done columns of some of the compounds but they are really limited by solubility. Have you been able to get it to dissolve? If not, dissolve the sample in DCM or ethyl acetate and then add ~5 drops of DMF to help get them dissolved (should go from cloudy to transparent) and then loaded onto a column and eluted with ethyl acetate:hexanes. You'll get a small elution of the DMF within the first to second column volume but if you've set the collection limit to 40 mAu it shouldn't collect if you've only use this small 5 drop amount.

I had no need to increase polarity and use methanol but maybe you do need it for this compound.

[dmitrij176]

@dmitrij176 - we were able to isolate all these compounds by the addition of water which formed clean pure precipitates. Simple wash with water and then hexanes was all that was needed.

I have done columns of some of the compounds but they are really limited by solubility. Have you been able to get it to dissolve? If not, dissolve the sample in DCM or ethyl acetate and then add ~5 drops of DMF to help get them dissolved (should go from cloudy to transparent) and then loaded onto a column and eluted with ethyl acetate:hexanes. You'll get a small elution of the DMF within the first to second column volume but if you've set the collection limit to 40 mAu it shouldn't collect if you've only use this small 5 drop amount.

I had no need to increase polarity and use methanol but maybe you do need it for this compound.

Thank you Kymberley. Indeed solubility was an issue. Very useful information for future isolations. Lastly, would you mind posting the URL adress of the website with C13 coupling database. Other sources for C-F coupling were not as good and informative as the one you showed to us before. Really would appreciate that to finish the remaining experimental for the paper. Thanks

[kym834]

@dmitrij176 sorry I only just saw this now. Here is the website https://organicchemistrydata.org/hansreich/resources/nmr/?index=nmr_index%2F19F_coupling#f-data10