Prospective Compounds for Screening (Antimalarial and Natural Products) from Griffith University (Rohan Davis)

[fantasy121]

Hi @OpenSourceMycetoma/corecontrib

Rohan has gotten back to us Re: potential compounds for screening A few points:

1. Can we work with sdf's for chemical structure analysis, or do we want ChemDraw file or SMILES?

2. Are only antimalarial compounds of interest? I have a small library of 512 pure natural products that is housed at Compounds Australia (5 mM stock solutions). (Free but needs to pay for plating and shipping). See attached paper which gives an overview of Rohan's open access library on a kinetoplastid drug discovery project: DOI: 10.3390/molecules22101715

3. Are any of the OSM Series 4 compounds active in your mycetoma assay? I have a few OSM analogues that I could also send, see attached paper. DOI: https://doi.org/10.3390/molecules26092421

[fantasy121]

For point 1, I guess we should ask Rohan to send ChemDraw file or SMILES string? That'd be what I use, not sure about SDF.

[fantasy121]

@mattodd Point 3. Have we had any OSM series 4 compounds screened for mycetoma?

[fantasy121]

Point 2. What do we think of this offer? @OpenSourceMycetoma/corecontrib

[mattodd]

My quick responses (to this very nice offer of help)

1) Don't mind - sdf works fine for e.g. Datawarrior if that's simplest

2) The more the merrier. How much?

3) That would also be very good. I'm afraid I'm not sure if any OSM S4 compounds have been tried - I would hope that had that happened the OSM codes would be in the MycetOS Master List. Bit of a punt unless M. mycetomatis has an ATP4 ion pump, anyone?

[MFernflower]

That library contains Thiaplakortone a very unusual phenothiazine (series 3) like natural product isolated from a sea sponge

On Thu, Nov 3, 2022, 7:06 AM Mat Todd @.***> wrote:

My quick responses (to this very nice offer of help)

1.

Don't mind - sdf works fine for e.g. Datawarrior if that's simplest 2.

The more the merrier. How much? 3.

That would also be very good. I'm afraid I'm not sure if any OSM S4 compounds have been tried - I would hope that had that happened the OSM codes would be in the MycetOS Master List. Bit of a punt unless M. mycetomatis has an ATP4 ion pump, anyone?

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/84#issuecomment-1301940988, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDQ4RRACMFMTHH2CRCDWGOMEZANCNFSM6AAAAAARVXU3SQ . You are receiving this because you are on a team that was mentioned.Message ID: @.*** com>

[MFernflower]

@bebi78 being our resident natural products chemist does anything in the library look interesting to you?

On Thu, Nov 3, 2022, 3:07 PM MFernflower @.***> wrote:

That library contains Thiaplakortone a very unusual phenothiazine (series 3) like natural product isolated from a sea sponge

On Thu, Nov 3, 2022, 7:06 AM Mat Todd @.***> wrote:

My quick responses (to this very nice offer of help)

1.

Don't mind - sdf works fine for e.g. Datawarrior if that's simplest 2.

The more the merrier. How much? 3.

That would also be very good. I'm afraid I'm not sure if any OSM S4 compounds have been tried - I would hope that had that happened the OSM codes would be in the MycetOS Master List. Bit of a punt unless M. mycetomatis has an ATP4 ion pump, anyone?

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/84#issuecomment-1301940988, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDQ4RRACMFMTHH2CRCDWGOMEZANCNFSM6AAAAAARVXU3SQ . You are receiving this because you are on a team that was mentioned.Message ID: @.*** com>

[bebi78]

@MFernflower @fantasy121 @wwjvdsande Seems to me that three of the natural products presented in the paper are especially interesting because of their high selectivity/low toxicity (Lissoclinotoxin E/1, chalcone analog/13, and chelerythrine chloride/15). Is it possible to get these three compounds from Rohan for free? Mefloquin is a widely applied synthetic antimalarial showing some selectivity. Might also be considered for mycetoma testing unless it has already been tested (DNDi pandemic response box?).
Gambogic acid/4 also showed moderate selectivity in the paper. It is structurally related to the already tested garcinol. But garcinol was not very active against M. mycetomatis.

[MFernflower]

lissoclinotoxin e and thiaplakortone share some resemblance to the series 3 phenothiazines so might be interesting to open up series 3 a bit perhaps time to synthesize a few n alkyl phenothiazines?

@bebi78

[bebi78]

@MFernflower I can organize expired quetiapine pills.

[MFernflower]

I don't know if quetiapine was already tested in the MMV boxes - I think for now we should see if we can get the natural products box from Rohan Davis @mattodd @bebi78

On Wed, Nov 9, 2022, 11:52 AM bebi78 @.***> wrote:

@MFernflower https://github.com/MFernflower I can organize expired quetiapine pills.

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/84#issuecomment-1309049753, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDTY7NGECRHV3SLMBADWHPJDRANCNFSM6AAAAAARVXU3SQ . You are receiving this because you were mentioned.Message ID: @.***>

[bebi78]

@mattodd @wwjvdsande I launched a new special issue about infectious tropical diseases in Int J Mol Sci (IF 6.2, deadline May 2023, see link below). I can provide a 100% voucher (no APC). Let me know within the next few days, if there is interest to contribute. If Mat or Wendy don't have interest, I can also provide other interested PIs of this github group with a 100% voucher, the same for the malaria OSN.

https://www.mdpi.com/journal/ijms/special_issues/9NC2P6QH33

[wwjvdsande]

@MFernflower @bebi78 @fantasy121 for me it is fine if we screen a few compounds more but it needs to be doable for @MA-Jjingyi. It might be good to focus a bit on the series we are interested in to get some new lead compounds. I myself would be most interested in series5 compounds if they are there as well. They seem to have the best in vivo activity so far and are active against multiple mycetoma causative agents. With the diagnostics currently still not optimal many physicians have to start treatment without knowing the exact causative agent. To have a treatment which works equally well for multiple causative agents would then to be preferred. @MA-Jjingyi developed this year a Galleria mellonella model for Falciformispora senegalensis which we could include for series5, as they were active against that causative agent as well.

[MFernflower]

@wwjvdsande were the molecules from @AndreaOtago tested?

[wwjvdsande]

@MFernflower, yes the results are in the masterlist

[MFernflower]

@wwjvdsande sorry for not being up to date but have any compounds been tested in the caterpillars infected with Falciformispora? Indeed targeting microtubules seems like a good strategy however this basically automatically makes pregnancy a contraindication for treatment (although I think no antifungal is safe during pregnancy because animal and fungal cells are so similar)

[wwjvdsande]

@MFernflower yes we tested amphotericin B, terbinafine and itraconazole. This was simply to characterize the model. We did not test any mycetOS molecules yet. It is quite some work to set up these models and get them reproducible. Amphotericin B did prolong larval survival, like it does when the larvae are infected with Madurella mycetomatis, however the effect was less pronounced. The other two drugs did not prolong larval survival.

[MFernflower]

@wwjvdsande Did niclosamide kill the Falciformispora? @bebi78 is offering to send you some more analogues of niclosamide with the problematic nitro group deleted

[MFernflower]

@bebi78 @wwjvdsande there is also another analogue of niclosamide called "TFM" that can be purchased at TCI

https://www.tcichemicals.com/NL/en/search/?text=4-Nitro-3-%28trifluoromethyl%29phenol

https://www.sciencedirect.com/science/article/pii/S0166445X1830674X

[MFernflower]

@rohandavis to perhaps ship around 10 compounds over to @wwjvdsande

Including the S3 like natural product thiaplakortone A

[mattodd]

@rohandavis has shipped the compounds in the attached Excel file. Received by @wwjvdsande. These compounds need to be added to the Master List (and Mycetos codes generated). I have asked Rohan if he might have someone willing to do this. Update - he doesn't, so this needs doing by a volunteer. Do we have one?

Note Rohan says "Note that 4 compounds have NOT had their structures determined, we beleive they are pure by LCMS (part of an undergraduate research project in my lab - ongoing), haven't run the 1D/2D NMR yet as these are minor compounds from a plant extract so will need more sample to do that. Will pursue if active in your assay."

Davis Group Pure compounds Screening Plate_Erasmus_FINAL.xlsx

This file really ought to be backed up to an ELN somewhere too, if anyone would like to vounteer to post it there?

[KlementineJBS]

I finally finished adding Rohan's compounds to the masterlist, sorry that took so long. Is there existing testing data that can now be added from the biology team @wwjvdsande ?