Monthly mycetoma meeting 23rd May 2023

[wwjvdsande]

Time: May 2nd (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: USyd Minute taker: UCL Previous meeting: here Recording: [here] Present: Apologies:

AGENDA

Series 1 - Fenarimols

Final Molecules/SAR Gaps

@fantasy121 completed the selection of Epichem molecules, and the next step is to get them to Wendy.

@fantasy121 shared the list of compounds that have been shipped from Sydney to ErasmusMC.

• [ ] @MA-Jjingyi to evaluate these latest fenarimols and post data to the Master List.

• [ ] @mattodd to email the finalised list to Epichem (was there a query about whether the relationship between Epichem and DNDi still existed?)

• [ ] @meh-cyprian to proceed to try to model fenarimol compounds in potential protein target here, or to clarify what more data are needed. Aim is to better understand the SAR via docking vs homology model of protein.

Paper:

• [ ] @dmitrij176 to upload offline copy of fenarimol lab notebook to UCL respository and provide link (@fantasy121 is https://doi.org/10.25910/CS81-G976).

• [ ] @dmitrij176 to upload his Biological supplemental data (not in Labarchives).

• [ ] @mattodd to review final version of manuscript. Please don't go through the manuscript till @mattodd is finished. After this is done, @MA-Jjingyi and @wwjvdsande will generate an Excel sheet from our current Master List displaying all data on the fenarimols tested.

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)

Siderophores:

New transcriptomic data from @wwjvdsande in the galleria grain model showed that siderophores are produced. These siderophores might be used as a trojan horse to get molecules into the grain. Could we couple fenarimols to siderophores may be to get them in? The idea of the siderophores was of interest and all partners agreed to consider whether this could be done at the different sites. There is also potential relevance to other series.

• [ ] All to report back.

Series 2 - Aminothiazoles

Meeting between the chemistry team and the high schools took place. The contributors now all have their own targets. @KlementineJBS will be the corresponding researcher for this project at USYD (Replacement for @kym834). UCL Masters student cohort begins in late May and will report back.

• [ ] Next meeting of this group needs to be organised, e.g. late June?
• [ ] Best Whitgift sample received to date needs to be included in next shipment to @wwjvdsande from UCL by @dmitrij176 and MyOS code needs generating and adding to the Master List.
• [ ] Whitgift school need help with ordering a chemical: 2-bromo-1-(pyridin-2-yl)ethan-1-one HBr this?. They tried Apollo Scientific and are trying to sort out paperwork for Oakwood, but they are having trouble ordering. They need 1g per group, so 10 g total. They need help with ordering it.
• [ ] Generally we are not doing well at keeping track of who is making what. We need contributors to clarify their targets, and these could be included in the Master List as targets, where the "target" tag can be removed upon synthesis. We need a commitment from all contributors to help with data management on the Master List.

Series 5 - Benzimidazoles

Oxazoles: Good potencies observed for recent compound batches (e.g. https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/82#issuecomment-1325150305). Promising because they resembled the benzimidazoles which showed potent in vivo efficacy. Some oxazoles will be tested against Falciformispora senegalensis too. This series will be evaluated in vivo in the new larval season.

• [ ] @dosreic to try to obtain samples.
• [ ] @alintheopen and Marita Emmanuel would see if they can access them too.

@AndreaOtago has generated a new set of benzoxazoles and these will be shipped to @wwjvdsande

• [ ] @fantasy121 to ask the two new Sydney Hons students (Peiyan and Marita) to join Github and share their IDs (Marita has joined and is @memm0740.
• [ ] Peiyan and Marita to do the Scifinder lit search of the surrounding chemical space: are there other groups making similar compounds whom we could ask for donations?
• [x] Marita to post her synthesis plan for series 5 that was presented last month.

Series 6: ketoximes

[ ] @dmitrij176 to share the figure of the compounds that have been shipped to ErasmusMC for testing (https://github.com/OpenSourceMycetoma/Series-6-Ketoximes/issues/5) Misc

DMPK measurement offer from the Wellcome Centre Anti-Infectives Research (WCAIR) at the University of Dundee, which often hosts trainees from around the world and who could run some 1st tier in vitro DMPK assays for MycetOS compounds as part of the training set for these folks. They have one trainee coming this July for 3 months and they could start doing this, if of interest. Which compounds? Some suggestions have been made

• [ ] All to complete this list of compounds to send to Dundee for DMPK measurements.

MMV Global Health Priority Box screened against Madurella mycetomatis and Falciformispora senegalensis. The data is uploaded in the Master List. Are there any standout hits - yes! MMV1593278, MMV1804559 and MMV020335

Rohan’s contributed compounds: 96 well plate received. To be screened. Data for these compounds here.

• [ ] We need a volunteer to enter the data in Rohan's spreadsheet into the Master List. We have no MyOS codes for them.

Kinase inhibitor library. The updated KCGS library was ordered on 1st of May. Bio-informatical analyses have been carried out by Mickey. @bebi78 can send some 10 targets

Bioinformatics: Waleed requested information on which aspect of bioinformatics should be prioritised to work on first. @wwjvdsande corresponded offline with him. This will include a 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

AOB Other Updates: USYD UCL Erasmus Other sites

[wwjvdsande]

@OpenSourceMycetoma/corecontrib I made the agenda item for tomorrow. Can either USyd or UCL update the agenda? It is now displaying the minutes from the 2nd of may

[bebi78]

@wwjvdsande @dosreic Maybe the compounds for DMPK testing by Dr. Lauren Webster (WCAIR) in Dundee can be discussed.

[AndreaOtago]

Sounds like an interesting meeting and I hope to join in one month :) However tomorrow (Wed NZ time) I have an 8am lecture so a late night meeting not great this evening, hopefully meet some of you next month.

[KlementineJBS]

Can't come to the meeting unfortunately but these are the targets that we'll be attempting to make in early June. We should be able to update on these by next meeting.

I thought I'd also share these ChemDraw files which attempt to sum up the compounds made in Series 2 - I'll add them to the Series 2 wiki later too, but please tell me if I've missed a compound that's in progress/planning.

Thiourea alterations

Bromoketone alterations

[memm0740]

My post on my honours project including research update and synthetic plan- https://github.com/OpenSourceMycetoma/series-5-benzimidazoles/issues/2#issuecomment-1558989625

[dmitrij176]

@wwjvdsande https://docs.google.com/spreadsheets/d/1YhK-3i2KwuVabo1GbZSgVjAUbavEICCMKi5v-EhNq80/edit#gid=1917346673 Bio assay SI (excel file)

[MA-Jjingyi]

@all sorry for poor connection. the ZOOM is closed suddently. and i can not open it again. @dmitrij176 4 days per week are for in vivo test. so, i really have no time for in vitro susceptibility test recently.

[MFernflower]

@wwjvdsande said something about three drugs from an mmv box being good

can we get mmv codes and maybe structures?!?

@MA-Jjingyi

[wwjvdsande]

@MFernflower They were MMV1593278 MMV1804559 MMV020335

[bebi78]

@mattodd @wwjvdsande @dmitrij176 @fantasy121 I asked @dosreic to contact Dr. Webster about the DMPK tests and we are waiting now for a response. I suppose that four or five compounds can be tested definitely, and I suggest to make a list of up to 5 compounds of highest priority. In my opinion, this includes in vivo active compounds intended for the coming papers such as fenarimols and ketoximes, for example. I suppose that DMPK data is already available/published for the known drugs of the drug collection boxes. In case more than five compounds can be sent we can still fill the list with suitable compounds from the other compound series 2-5 and the adjuvants. If not we can wait until there are capacities in Dundee again.

[MFernflower]

@mattodd or @bebi78 or @cdsouthan or @dmitrij176 to post drawings of the three MMV drugs Wendy found:

MMV1593278 MMV1804559 MMV020335

[dmitrij176]

@mattodd or @bebi78 or @cdsouthan or @dmitrij176 to post drawings of the three MMV drugs Wendy found: MMV1593278 MMV1804559 MMV020335

COc1ccc(cc1)c2cc3ncnc(N4CCN(CCN5CCCC5)CC4)c3s2 Cn1nc(c2cccc(CNC3CCc4ccc(O)cc34)c2)c5cnc(NC6CCCC6)nc15 Cc1nc(NCc2ccc(F)cc2)nc(NCC(C)(C)C)c1C

[wwjvdsande]

@MFernflower @mattodd @dmitrij176 @fantasy121 for us non-chemists, do these molecules belong to certain chemical classes?

[MFernflower]

they all seem novel but one does look kind of like a malaria drug @mattodd @wwjvdsande

[bebi78]

@MFernflower Seems to me not surprising since they are MMV compounds. But I think you mean that especially the middle pyrazolopyrimidine looks like some active open source malaria compounds. Thus, it might be a promising source for MycetOS, too @mattodd Thienopyrimidines are interesting bioactive compounds (anticancer, antiviral, antibiotic, etc.). It is a prospering class because the starting thiophene compounds are either commercially available or can be easily prepared by the Gewald reaction. I'm working on anticancer active and tubulin binding thienopyrimidines (see link), and can provide a few active compounds when there are test capacities again. https://www.sciencedirect.com/science/article/abs/pii/S0223523420300271

[bebi78]

@wwjvdsande Because of the pyrimidine rings of the compounds I assume quinine-type mechanism(s) or a DHFR inhibitory effect.

[MFernflower]

Message ID: <OpenSourceMycetoma/Monthly-zoom-meetings/issues/6/1568497817@ github.com>

@mattodd maybe we can get a few open source malaria actives and inactives s3 and s4 drugs over to wendy?!?

[bebi78]

@mattodd @wwjvdsande @dmitrij176 @fantasy121 There will be a teams meeting about the planned DMPK tests with Dr. Lauren Webster, Dundee, next week Friday June 16th at 13.00 BST/14:00 CET (see info below, organized by @dosreic).

Reunião do Microsoft Teams

Ingressar no seu computador, aplicativo móvel ou dispositivo de sala

Clique para ingressar na reunião

ID da Reunião: 387 461 365 409 Senha: jgT5Lc

Baixar o Teams | Participe na web

Ingressar em um dispositivo de videoconferência

178736985@teams.bjn.vc

ID de Vídeo Conferência: 126 602 426 4

Instruções VTC Alternativas

Saiba mais | Opções de reunião

[bebi78]

In terms of the DMPK testing (kinetic solubility by HPLC, logD by HPLC, toxicity to HepG2 liver cancer cells, microsomal clearance), @dosreic gives us/MycetOS a contingent 30-35 compounds (at least 2 to 3 mg, powder) we can send to Dr. Lauren Webster's lab in Dundee by August. So I think 4 to 5 compounds can be provided from each compound series. I beg the following group members to provide a list of suitable compounds from the following series (maybe by next week and the coming June meeting) based on activity and availability: Series 1, fenarimols: @dmitrij176, @mattodd, @fantasy121 (in particular, compounds mentioned in your manuscript draft) Series 2, aminothiazoles: @kym834
Series 3, phenothiazines: @MFernflower Series 5, benzimidazoles: @wwjvdsande, @fantasy121, @csuth22, @AndreaOtago (if there is some overlap with your DNDi benzoxzole projects let us know to avoid doubles) Series 6, ketoximes: @dmitrij176, @mattodd As mentioned earlier, I can provide at least two of the most active niclosamides from the adjuvant series. @MA-Jjingyi @wwjvdsande Are there news from the in vivo assays, which can be considered for compound selection? Are compounds from the compound boxes available for DMPK testing?

[mattodd]

Thanks for that @bebi78 - I agree. We can run through this next week. Clearly we should focus on compounds that are active and for which we have samples, but there is also utility in obtaining data on compounds that are predicted to be more soluble even if they exhibit lower potency. Since I'm looking at the fenarimol manuscript at the moment, I'm expecting selection of those compounds to be simple. @dmitrij176 can you pick about 5 structurally diverse ketoximes - maybe this is a good time to update the chemdraw of all compounds that have been evaluated, so that we can quickly compare.

[wwjvdsande]

@OpenSourceMycetoma/corecontrib next week during the MycetOS meeting I will be teaching the whole afternoon so I cannot attend. I did the convening next time for USyd. Can USyd do it this time for me? Alternatively if we will have the meeting two hours earlier I will be able to make it.

[mattodd]

Yes, I'm also meant to be at a funding event for most of the day. Maybe we should reschedule, particularly if others can't make it, e.g. from Sydney? Could do same time July 6th? @OpenSourceMycetoma/corecontrib

[wwjvdsande]

@OpenSourceMycetoma/corecontrib 6th July would be OK for me.

[bebi78]

@mattodd @wwjvdsande Thursday 6th July is OK for me.

[mattodd]

OK, let's go for July 6th at 12 noon. @OpenSourceMycetoma/corecontrib

@wwjvdsande it looks from my Outlook calendar that you sent out the invites. Are you happy to alter only tomorrow's meeting to move it to the new date (not the whole series)?

I can set up the new meeting Issue. @wwjvdsande you shouldn't do this job again!

Sydney Uni is down as minute taker - will someone from Sydney Uni be in attendance? @fantasy121 @kym834 @KlementineJBS?

[KlementineJBS]

Yep, a few of us should be attending but I definitely will be so will gladly either take minutes or convene. Thank you @wwjvdsande for picking up our slack last month!

[wwjvdsande]

OK, let's go for July 6th at 12 noon. @OpenSourceMycetoma/corecontrib

@wwjvdsande it looks from my Outlook calendar that you sent out the invites. Are you happy to alter only tomorrow's meeting to move it to the new date (not the whole series)?

I can set up the new meeting Issue. @wwjvdsande you shouldn't do this job again!

Sydney Uni is down as minute taker - will someone from Sydney Uni be in attendance? @fantasy121 @kym834 @KlementineJBS?

@OpenSourceMycetoma/corecontrib the calender invite was changed. You should all have received the updated invite. Remember, we will join in the zooms link not the teams link!

[mattodd]

Hi @OpenSourceMycetoma/corecontrib - I just posted the issue for the meeting on the 6th. Agenda is not yet done properly. Will update, but feel free to edit up to the start of the meeting.