Which Compounds To Send to Dundee for DMPK Measurements?

[mattodd]

As mentioned in #7, WCAIR at Dundee (via Dr Lauren Webster) have kindly offered to run several samples from MycetOS for in vitro DMPK measurements as part of one of their training programmes. The assays include kinetic solubility by HPLC, logD by HPLC, toxicity to HepG2 liver cancer cells, microsomal clearance.

By the end of July, we will ship 30-35 molecules, about 5 from each series. This issue is to finalise the list of compounds to be sent.

A meeting was held on June 16th to discuss. @bebi78 has already made suggestions at https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/6#issuecomment-1600655716, and some earlier comments were at https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/5#issuecomment-1538392028.

Requirements of any compounds sent:

• 2-3 mg of highly pure solid (preferred over DMSO solution)
• Unique ID (either DNDiOS ID or unique host Institute ID), SMILES, MW, Amount (mg). Compounds will receive Dundee ID when they are processed there. (@dosreic can provide DNDi IDs if these are desired, but not needed for shipment).
• Have MyOS Codes, which must be included in the shipment details
• Include potent compounds, but can also include less potent if structures address something important, e.g. are designed for improved solubility or include an unusual motif.
• Structurally diverse
• Available now

Status:

Series 1, Fenarimols: @Mattodd has suggested compounds, below. Sources of these need to be identified by @dmitrij176 and @fantasy121
Series 2, Aminothiazoles. @KlementineJBS has suggested compounds, below. Samples available?
Series 3, Phenothiazines. @MFernflower has suggested that these compounds have well-known DMPK, so should not be sent.
Series 5, Benzimidazoles/oxazoles. @csuth22, @AndreaOtago @dosreic to suggest compounds.
Series 6, Ketoximes. @dmitrij176 to suggest compounds.
Niclosamides: @bebi78 has shipped compounds, shown here.
Other: The promising MMV Global Health Priority Box hits (MMV1593278, MMV1804559 and MMV020335). Are in vitro DMPK data already known? Alternatively, could send carbendazim?

Please post suggestions below and any queries.

[dosreic]

Hi Matt,

Re the shipment to Dundee, you can send directly to Lauren, that’s easier. If the compounds are not at the same place, then first get them together and make just one shipment to make it easier for their compound management folks. Let’s also try to coordinate so we all send around the same time, so please keep me in the loop once you have made your selection.

Let me know if you have any questions and thanks for participating 😊

Luiza

Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.**@.> dndi.org

[A picture containing text, clipart Description automatically generated]

De: Mat Todd @.> Enviada em: quarta-feira, 12 de julho de 2023 18:36 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8)

As mentioned in #7https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/7, WCAIR at Dundee (via Dr Lauren Webster) have kindly offered to run several samples from MycetOS for in vitro DMPK measurements as part of one of their training programmes. The assays include kinetic solubility by HPLC, logD by HPLC, toxicity to HepG2 liver cancer cells, microsomal clearance.

By the end of July, we will ship 30-35 molecules, about 5 from each series. This issue is to finalise the list of compounds to be sent.

A meeting was held on June 16th to discuss. @bebi78https://github.com/bebi78 has already made suggestions at #6 (comment)https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/6#issuecomment-1600655716, and some earlier comments were at #5 (comment)https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/5#issuecomment-1538392028.

Requirements of any compounds sent:

• 2-3 mg of highly pure
• Include potent compounds, but can also include less potent if structures address something important, e.g. are designed for improved solubility or include an unusual motif.
• Structurally diverse
• Available now
• Have MyOS Codes, which must be included in the shipment details
• [ ] @mattoddhttps://github.com/mattodd will suggest compounds from series 1, the Fenarimols
• [ ] @KlementineJBShttps://github.com/KlementineJBS will suggest compounds from series 2, the Aminothiazoles
• [ ] @MFernflowerhttps://github.com/MFernflower to suggest compounds from Series 3, the phenothiazines, if suitable.
• [ ] @wwjvdsandehttps://github.com/wwjvdsande, @fantasy121https://github.com/fantasy121, @csuth22https://github.com/csuth22, @AndreaOtagohttps://github.com/AndreaOtago to suggest compounds from Series 5, the Benzimidazoles (if there is some overlap with your DNDi benzoxzole projects let us know to avoid duplication)
• [ ] @dmitrij176https://github.com/dmitrij176 will suggest compounds for series 6, the ketoximes.
• [ ] @bebi78https://github.com/bebi78 can provide at least two of the most active niclosamides from the adjuvant series if suitable.
• [ ] We need to check whether MMV already have such data for the promising MMV Global Health Priority Box hits (MMV1593278, MMV1804559 and MMV020335) – structures available herehttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/6#issuecomment-1567312472. Alternatively, carbendazim would be interesting to look at.

Please post suggestions below and any queries. We also need to decide how to ship to Dundee. My suggestion would be direct, through coordination with Joanne. Any preference on this @dosreichttps://github.com/dosreic ?

— Reply to this email directly, view it on GitHubhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHR4OQR6D4SART4EUCTXP4KCZANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.***>

[MFernflower]

I wonder if working backwards would be useful for the phenothiazine series

• i.e make two new molecules and send them for DMPK before sending them to wendy to screen vs the fungi

@bebi78 perhaps could make the two listed below??

https://opsin.ch.cam.ac.uk/opsin/10%20phenethyl%20phenothiazin.png

https://opsin.ch.cam.ac.uk/opsin/10%20isovaleroyl%20phenothiazin.png

On Wed, Jul 12, 2023, 5:35 PM Mat Todd @.***> wrote:

As mentioned in #7 https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/7, WCAIR at Dundee (via Dr Lauren Webster) have kindly offered to run several samples from MycetOS for in vitro DMPK measurements as part of one of their training programmes. The assays include kinetic solubility by HPLC, logD by HPLC, toxicity to HepG2 liver cancer cells, microsomal clearance.

By the end of July, we will ship 30-35 molecules, about 5 from each series. This issue is to finalise the list of compounds to be sent.

A meeting was held on June 16th to discuss. @bebi78 https://github.com/bebi78 has already made suggestions at #6 (comment) https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/6#issuecomment-1600655716, and some earlier comments were at #5 (comment) https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/5#issuecomment-1538392028 .

Requirements of any compounds sent:

-

2-3 mg of highly pure

Include potent compounds, but can also include less potent if structures address something important, e.g. are designed for improved solubility or include an unusual motif.

Structurally diverse

Available now

Have MyOS Codes, which must be included in the shipment details

@mattodd https://github.com/mattodd will suggest compounds from series 1, the Fenarimols

@KlementineJBS https://github.com/KlementineJBS will suggest compounds from series 2, the Aminothiazoles

@MFernflower https://github.com/MFernflower to suggest compounds from Series 3, the phenothiazines, if suitable.

@wwjvdsande https://github.com/wwjvdsande, @fantasy121 https://github.com/fantasy121, @csuth22 https://github.com/csuth22, @AndreaOtago https://github.com/AndreaOtago to suggest compounds from Series 5, the Benzimidazoles (if there is some overlap with your DNDi benzoxzole projects let us know to avoid duplication)

@dmitrij176 https://github.com/dmitrij176 will suggest compounds for series 6, the ketoximes.

@bebi78 https://github.com/bebi78 can provide at least two of the most active niclosamides from the adjuvant series if suitable.

We need to check whether MMV already have such data for the promising MMV Global Health Priority Box hits (MMV1593278, MMV1804559 and MMV020335) – structures available here https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/6#issuecomment-1567312472. Alternatively, carbendazim would be interesting to look at.

Please post suggestions below and any queries. We also need to decide how to ship to Dundee. My suggestion would be direct, through coordination with Joanne. Any preference on this @dosreic https://github.com/dosreic ?

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDRQHNAIVMOHG7AHAITXP4KCXANCNFSM6AAAAAA2IB5U5A . You are receiving this because you were mentioned.Message ID: @.***>

[bebi78]

@MFernflower Sorry, I don't have the means to prepare these compounds at the moment and within the requested time. I only have N-acetylphenothiazine in stock, which has only weak antifungal activity (see link). https://www.sciencedirect.com/science/article/pii/S1878535217302344

[bebi78]

@mattodd Do you agree that you collect the compounds for DMPK testing from abroad as suggested by @dosreic ? I would dispatch then a package with four compounds next week to your institute (postal address?):

Juglone MYOS_00231_00_01 O=C1C=CC(C2=C(O)C=CC=C21)=O

Naphthazarin MYOS_00232_00_01 O=C1C=CC(C2=C(O)C=CC(O)=C21)=O

4SCF3-Closamid MYOS_00457_00_01 OC1=CC=C(Cl)C=C1C(NC2=CC=C(SC(F)(F)F)C=C2)=O

4SF5-Closamid MYOS_00459_00_01 OC1=CC=C(Cl)C=C1C(NC2=CC=C(S(F)(F)(F)(F)F)C=C2)=O

[MFernflower]

Sadly I dont have acess to a lab either

@mattodd maybe could see if can find some first year college students to make them? starting materials are isovaleric anhydride, phenothiazine powder, and a phenethyl halide + solvent + base + workup

@bebi78

On Thu, Jul 13, 2023, 11:03 AM bebi78 @.***> wrote:

@MFernflower https://github.com/MFernflower Sorry, I don't have the means to prepare these compounds at the moment and within the requested time. I only have N-acetylphenothiazine in stock, which has only weak antifungal activity (see link). https://www.sciencedirect.com/science/article/pii/S1878535217302344

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1634406315, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDXT2H5WOYECUL2TEMLXQAE2LANCNFSM6AAAAAA2IB5U5A . You are receiving this because you were mentioned.Message ID: @.***>

[MFernflower]

i think the four compounds you are willing to send seem good @bebi78

On Thu, Jul 13, 2023, 11:19 AM bebi78 @.***> wrote:

@mattodd https://github.com/mattodd Do you agree that you collect the compounds for DMPK testing from abroad as suggested by @dosreic https://github.com/dosreic ? I would dispatch then a package with four compounds next week to your institute (postal address?):

Juglone MYOS_00231_00_01 O=C1C=CC(C2=C(O)C=CC=C21)=O

Naphthazarin MYOS_00232_00_01 O=C1C=CC(C2=C(O)C=CC(O)=C21)=O

4SCF3-Closamid MYOS_00457_00_01 OC1=CC=C(Cl)C=C1C(NC2=CC=C(SC(F)(F)F)C=C2)=O

4SF5-Closamid MYOS_00459_00_01 OC1=CC=C(Cl)C=C1C(NC2=CC=C(S(F)(F)(F)(F)F)C=C2)=O

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1634436223, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDQETC25XCJ3ZCZUTVLXQAGYPANCNFSM6AAAAAA2IB5U5A . You are receiving this because you were mentioned.Message ID: @.***>

[mattodd]

OK, so my Series 1 (fenarimol) suggestions are:

1 and 2. MyOS_00008 and MyOS_00167 as representative members of the triaryl scaffold that are in vivo active.

3. MyOS_00016 as an in vivo active piperidine.
4. MyOS_00001 as an in vivo active piperazine.
5. MyOS_00004 as one of the original in vivo active compounds with an alternative connection to the core. Pure S enantiomer if we have it, otherwise rac. 6 and 7. MyOS_00009 and MyOS_00017 as active compounds with alternative core substituents.

cLogP (chemdraw) ranges from 2.7 to 4.8.

Suggestions/comments welcome, obviously.

(As a side note, I found searching the master list for these structures (to get the MyOS codes) useless when using SMILES strings. The strings chemdraw gave me and the strings in the master list were both correct, but different. InChI usually worked.

Fenarimols for Dundee DMPK.zip

For shipping, I don't know. If Dundee are happy to receive packages from multiple places, it makes sense to me to send directly, to reduce cost. Is someone willing to reach out to Lauren?

[bebi78]

@mattodd Also agree to send directly. Anyway, the proper postal address of Lauren is needed @dosreic

[mattodd]

Have written to check address, amounts, submission deadline and whether we can ship separately.

[dosreic]

Thanks Mat!

Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.**@.> dndi.org

[A picture containing text, clipart Description automatically generated]

De: Mat Todd @.> Enviada em: sábado, 15 de julho de 2023 10:01 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8)

Have written to check address, amounts, submission deadline and whether we can ship separately.

— Reply to this email directly, view it on GitHubhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1636759584, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHSX4Z24C7NZF3IMQDTXQKIATANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.***>

[mattodd]

We can ship separately to Lauren and I have the address, which I'll email to those needing it. I've also received some extra requirements re the shipped compounds, which I've added to the original post in this issue above (Unique ID (DNDiOS) (am checking whether this is needed), Host Institute ID, SMILES, MW, Amount (mg). Solid preferred to DMSO stock.

[dosreic]

Hi Mat,

I don’t think the DNDI number is needed, just a unique ID that you use in the project. But if it is, I’m happy to provide you with that.

Best, Luiza

Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.**@.> dndi.org

[A picture containing text, clipart Description automatically generated]

De: Mat Todd @.> Enviada em: segunda-feira, 17 de julho de 2023 18:18 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8)

We can ship separately to Lauren and I have the address, which I'll email to those needing it. I've also received some extra requirements re the shipped compounds, which I've added to the original post in this issue above (Unique ID (DNDiOS) (am checking whether this is needed), Host Institute ID, SMILES, MW, Amount (mg). Solid preferred to DMSO stock.

— Reply to this email directly, view it on GitHubhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1638895933, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHTNIMGSXDJ6HMFC7TDXQWTYFANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.***>

[KlementineJBS]

Suggested compounds from Series 2:

Lead is MYOS176 / MMV006357. MYOS535 was made recently and has not yet been sent for in vitro testing but was chosen for the interesting structural motif.

[bebi78]

@mattodd @dosreic Here is the info about the adjuvant series compounds sent to Lauren (delivered today according to the postal service): MycetOS.Adjuvant.DMPK.2023.xlsx

[bebi78]

@dmitrij176 Have you finalized your list of ketoximes/series 6 compounds? Was the salt preparation successful?

[mattodd]

Hi @KlementineJBS Thanks for your selection. Are the numbers potencies in uM, or...

Makes sense to send the lead compound. I also like the adamantane. The CF3 makes sense as a test of the liability of the lead compounds methyl.

The other two? They are quite similar to each other and to the other compounds. Do you have a sense of which compounds are predicted to be more soluble, via logP calculations? Maybe we should aim for compounds that span the range. How about the nitro-substituted compounds? How about MeO as an electron-donating group? Are there any from the UCL set that might suit?

[mattodd]

Update on Series 5, via email correspondence with @csuth22 @AndreaOtago @dosreic:

@dosreic has selected a range of benzoxazoles from the compounds @csuth22 and @AndreaOtago students made over the last few years. Picked based on the DNDi measured activity and also to include a range of FGs regardless of good activity (correct @dosreic?) Selected not necessarily because of potenct vs M. mycetomatis. <-- we need to know which compounds have been selected.

If there are any Otago-generated benzoxazoles we would like DMPK for from MycetOS we need to let @AndreaOtago know and she can check stocks. (@AndreaOtago is not 100% sure what numbers in the Master List represent significant biological activity) @AndreaOtago has 7 benzoxazoles ready to send to Dundee, which are being posted this week, but can add in more. <-- we need these structures to avoid duplication.

@csuth22 is also sending compounds this week. Spreadsheet of these is attached:

OSN P5 DMPK from Charlotte.xlsx

To make an effective decision here we ideally need to know the potency of all compounds in this series to date (the wiki is blank), and then which of those are not already in the sample sets being sent to Dundee as described above. Any volunteers to collate these data, quickly?

[dosreic]

Hi Mat, thanks for summarizing the info.

It’s all correct and the attached spreadsheet contains compounds from both Charlotte (Imperial) and Andrea (Otago) from P5 series, according to activity against Leishmania, Tcruzi and FG.

Please, let Charlotte and Andrea know if they should include any other compound from their stocks, if interesting fro mycetoma.

Best wishes, Luiza

Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.**@.> dndi.org

[A picture containing text, clipart Description automatically generated]

De: Mat Todd @.> Enviada em: terça-feira, 25 de julho de 2023 10:01 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8)

Update on Series 5, via email correspondence with @csuth22https://github.com/csuth22 @AndreaOtagohttps://github.com/AndreaOtago @dosreichttps://github.com/dosreic:

@dosreichttps://github.com/dosreic has selected a range of benzoxazoles from the compounds @csuth22https://github.com/csuth22 and @AndreaOtagohttps://github.com/AndreaOtago students made over the last few years. Picked based on the DNDi measured activity and also to include a range of FGs regardless of good activity (correct @dosreichttps://github.com/dosreic?) Selected not necessarily because of potenct vs M. mycetomatis. <-- we need to know which compounds have been selected.

If there are any Otago-generated benzoxazoles we would like DMPK for from MycetOS we need to let @AndreaOtagohttps://github.com/AndreaOtago know and she can check stocks. @.***https://github.com/AndreaOtago is not 100% sure what numbers in the Master List represent significant biological activity) @AndreaOtagohttps://github.com/AndreaOtago has 7 benzoxazoles ready to send to Dundee, which are being posted this week, but can add in more. <-- we need these structures to avoid duplication.

@csuth22https://github.com/csuth22 is also sending compounds this week. Spreadsheet of these is attached:

OSN P5 DMPK from Charlotte.xlsxhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/files/12161374/OSN.P5.DMPK.from.Charlotte.xlsx

— Reply to this email directly, view it on GitHubhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1649799862, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHX6ETIIEC6CX6NT6QTXR67QBANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.***>

[MFernflower]

update on series 3 is here

https://github.com/OpenSourceMycetoma/Series-3-Phenothiazines/issues/6

[AndreaOtago]

Hi all, yes as Luiza said the file you have attached link to above (OSN P5 DMPK from Charlotte.xlsx) includes both Imperial and Otago DNDi 'OSN P5' compounds that Luiza suggested. I am shipping (as have stock) 7 of the 8 suggested by Luiza, so all the 'Otago' ones in that sheet but NOT DNDI0004042513. I am happy to add more/check stocks of more if there are others people want to send because of Mycetoma activity, please let me know and I will check the freezer.

[KlementineJBS]

Hi @KlementineJBS Thanks for your selection. Are the numbers potencies in uM, or...

Makes sense to send the lead compound. I also like the adamantane. The CF3 makes sense as a test of the liability of the lead compounds methyl.

The other two? They are quite similar to each other and to the other compounds. Do you have a sense of which compounds are predicted to be more soluble, via logP calculations? Maybe we should aim for compounds that span the range. How about the nitro-substituted compounds? How about MeO as an electron-donating group? Are there any from the UCL set that might suit?

Oops, you're right, the potencies should be uM not uL.

We have various nitros on hand to send but none have showed good activity so far - the compound here, MYOS427, had a mean percentage growth of 96 at 100 uM concentration. Of course happy to send if you think it's worthwhile.

We have a few OMe compounds on hand but I'm not sure whether it's better to send MYOS422 (activity ok but not great) or MYOS536, which hasn't been tested yet.

[mattodd]

@KlementineJBS I would send compounds with a range of logPs and FGs. So a methoxy and a pyridine. 422 and 427 would be good. Yes 421, 535 and lead. What do you think? For compound optimisation we probably don't want MeO or NO2, but here we're getting a sense on impact on in vitro DMPK only.

[mattodd]

So it would seem that there are already a good range of benzoxazoles going to Dundee from @csuth22 and @AndreaOtago, meaning that for Series 5 (which is a mixture of benzoxazoles and benzimidazoles) we would only really need to send benzimidazoles. Many of the better-known compounds may already have in vitro DMPK data, but are there others we might like to send? @memm0740 ? or from https://github.com/OpenSourceMycetoma/series-5-benzimidazoles/issues/1

[AndreaOtago]

@mattodd great, I will push go on sending the Otago benzoxazoles Luiza selected to Dundee next week :)

[mattodd]

If we had a sheet, extracted from the Master List, of all the Series 5 compounds (with SMILES, so we can import to data warrior) and the MYOS codes, and the potencies, then we could quickly figure out if there were some benzimidazoles that we might want to send. With this list we could also figure out if, in fact, @MA-Jjingyi already has samples in the lab that could be shipped to Dundee. @memm0740 given that you're working on this series, I wondered if you might already have such a list? Ideally the benzimidazoles minus the oxazoles.

[dmitrij176]

@dmitrij176 Have you finalized your list of ketoximes/series 6 compounds? Was the salt preparation successful?

Yes, the finalised list looks like this:

Few important points in selections: DM114-1 is a pyrifenox analogue, but only with 2,4-diF substitution. It not a novel compound and its potency is currently unknown. Selection reason: According to literature reading, fluorine is supposed to enahnce the general safety profile of the molecule. It is currently the only Pyrifenox-like analogue in Series 6 library available as two separate E and Z isomers. DM49-1 is a E/Z mixture. Second in preference line candidate with the same IC50 potency (of 0.1 micromollar) as Pyrifenox. Plus cyclic moiety which adds to structural diversity. DM50-2 mixture is a compound with good potency and extended alkyl chain. DM52-1 structurally different, potent compound with benzyl ring.

On the other hand there are several unresolved issues with series 6

Pyrifenox/DM34-1 (separate E and Z isomers) originally was the first choice, but the problem is that its a commercial compound. While a lot of data is available, i still could not find information on HepG2 toxicity or microsomal clearance. Say solubility is available, but other specific DMPK parameters are missing. The most up to date information is probably from this source: http://sitem.herts.ac.uk/aeru/ppdb/en/Reports/572.htm Sigma specification sheet which is usually very detailed and informative, lacks a lot of information. It also states the commercial formulation as being a E/Z mixture, meaning that no DMPK were performed on separate isomers. https://www.sigmaaldrich.com/GB/en/sds/sial/45737 Similar for PubChem profile: https://pubchem.ncbi.nlm.nih.gov/compound/Pyrifenox Should we still include it @mattodd?

DM104-1 is a novel compound available as 2 separated isomers, but the Bromo halogens are probably not good for DMPK in general. The potency is currently pending.

Finally, the salt formulation has not been done due full occupancy for series 6 list. Again, wasnt even sure which potent candidate to select here, especially with Pyrifenox removal. The salt can still be prepared very quickly.

Of course, there are many more molecules which have been synthesised for the project, but not tested in vitro. We can make some selections from there as well if needed (i.e structurally interesting motif etc)

@mattodd @bebi78 please let me know your thoughts on theses suggestions. Thank you in advance

[mattodd]

Hi @dmitrij176 can you please post the structures of all the other Series 6 compounds that are available with logP and potency (if available). We can then finalise the decision.

[dmitrij176]

Hi @dmitrij176 can you please post the structures of all the other Series 6 compounds that are available with logP and potency (if available). We can then finalise the decision.

Thats everything what has been evaluated in vitro/in vivo. Other two batches are pending. Should I post them for consideration?

[mattodd]

Yes, we need all Series 6 molecules for which we have samples, whether evaluated or not.

With logP values. You've provided logD values, but the ones for the red structures above (bottom 4) don't look right. I would expect MYOS325 to have good predicted solubility, but let's see.

[bebi78]

@mattodd @dmitrij176 The inactive MYOS322 with the naked oxime group might be useful to compare with pyrifenox and the other active alkyloximes.

[dmitrij176]

Yes, we need all Series 6 molecules for which we have samples, whether evaluated or not.

With logP values. You've provided logD values, but the ones for the red structures above (bottom 4) don't look right. I would expect MYOS325 to have good predicted solubility, but let's see.

Tested batch with added logD values

Second batch

Latest batch

[dmitrij176]

@mattodd @bebi78 for the second and third schemes, the logP values were generated using ChemDraw. For MycetOS project (and data consistency) we use StarDrop software to calculate logD values. I will ask Louiza to perform the calculation soon. Mat, MYOS325 result is what we got back from assay testing. Potency values were provided by Wendy.

[dmitrij176]

@mattodd @bebi78 I have rechecked the 2 Fenarimols (MYOS01 and MYOS16) from UCL library and can now confirm that the compounds are stable after 4 years since their synthesis. The samples are ready for DMPK shipment. MYOS04 unfortunately is not available anymore, while the other entries on Mats suggested Fenarimol list are from Sydney. @fantasy121 do you still have them?

DM4-3B DMPK check.pdf DM7-1 (3,4) DMPK check pdf.pdf

[dmitrij176]

We can ship separately to Lauren and I have the address, which I'll email to those needing it. I've also received some extra requirements re the shipped compounds, which I've added to the original post in this issue above (Unique ID (DNDiOS) (am checking whether this is needed), Host Institute ID, SMILES, MW, Amount (mg). Solid preferred to DMSO stock.

@mattodd could you please post Dundee address for the shipment.

[dmitrij176]

UCL compounds for DMPK studies have been dispatched and should arrive today in Dundee. For Series 1 Fenarimols, I have found a third compound in my library which was on original wanted list. Thats MYOS00010, but as a racemate.

Finalised list:

[dosreic]

Hi Dmitri, can you please forward the email re shipment to Dundee to me? @.***

Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.**@.> dndi.org

[A picture containing text, clipart Description automatically generated]

De: dmitrij176 @.> Enviada em: quinta-feira, 10 de agosto de 2023 10:12 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8)

UCL compounds for DMPK studies have been dispatched and should arrive today in Dundee. For Series 1 Fenarimols, I have found a third compound in my library which was on original wanted list. Thats MYOS00010, but as a racemate.

Finalised list:

[Imagem removida pelo remetente. Fenarimols for Dundee DMPK jpeg]https://user-images.githubusercontent.com/44785501/259751113-b73a1787-8ab8-4148-938f-bec4970e8fdd.jpeg

— Reply to this email directly, view it on GitHubhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1673193466, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHXSURN5CTYORG6LZLTXUTMZFANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.***>

[dmitrij176]

Hi Dmitri, can you please forward the email re shipment to Dundee to me? @. Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @*.**@*.> dndi.org [A picture containing text, clipart Description automatically generated] De: dmitrij176 @.> Enviada em: quinta-feira, 10 de agosto de 2023 10:12 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8) UCL compounds for DMPK studies have been dispatched and should arrive today in Dundee. For Series 1 Fenarimols, I have found a third compound in my library which was on original wanted list. Thats MYOS00010, but as a racemate. Finalised list: [Imagem removida pelo remetente. Fenarimols for Dundee DMPK jpeg]https://user-images.githubusercontent.com/44785501/259751113-b73a1787-8ab8-4148-938f-bec4970e8fdd.jpeg — Reply to this email directly, view it on GitHub<#8 (comment)>, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHXSURN5CTYORG6LZLTXUTMZFANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.>

Hello Luiza. Can you provide me your email. Just to clarify, you need the word documents with compound information (SMILES, MW etc)?

[dosreic]

lcruz at dndi.org

Yes, compound & shipment information, please

Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.**@.> dndi.org

[A picture containing text, clipart Description automatically generated]

De: dmitrij176 @.> Enviada em: quinta-feira, 10 de agosto de 2023 10:18 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8)

Hi Dmitri, can you please forward the email re shipment to Dundee to me? @. Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.@.> dndi.org [A picture containing text, clipart Description automatically generated] De: dmitrij176 @.> Enviada em: quinta-feira, 10 de agosto de 2023 10:12 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Which Compounds To Send to Dundee for DMPK Measurements? (Issue #8https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8) UCL compounds for DMPK studies have been dispatched and should arrive today in Dundee. For Series 1 Fenarimols, I have found a third compound in my library which was on original wanted list. Thats MYOS00010, but as a racemate. Finalised list: [Imagem removida pelo remetente. Fenarimols for Dundee DMPK jpeg]https://user-images.githubusercontent.com/44785501/259751113-b73a1787-8ab8-4148-938f-bec4970e8fdd.jpeg — Reply to this email directly, view it on GitHub<#8 (comment)https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1673193466>, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHXSURN5CTYORG6LZLTXUTMZFANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.>

Hello Luiza. Can you provide me your email. Just to clarify, you need the word documents with compound information (SMILES, MW etc)?

— Reply to this email directly, view it on GitHubhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/8#issuecomment-1673202621, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHWRWMQMGWXTD34WLVTXUTNO5ANCNFSM6AAAAAA2IB5U5A. You are receiving this because you were mentioned.Message ID: @.***>

[fantasy121]

OK, so my Series 1 (fenarimol) suggestions are:

1 and 2. MyOS_00008 and MyOS_00167 as representative members of the triaryl scaffold that are in vivo active. 3. MyOS_00016 as an in vivo active piperidine. 4. MyOS_00001 as an in vivo active piperazine. 5. MyOS_00004 as one of the original in vivo active compounds with an alternative connection to the core. Pure S enantiomer if we have it, otherwise rac. 6 and 7. MyOS_00009 and MyOS_00017 as active compounds with alternative core substituents.

cLogP (chemdraw) ranges from 2.7 to 4.8.

Suggestions/comments welcome, obviously.

(As a side note, I found searching the master list for these structures (to get the MyOS codes) useless when using SMILES strings. The strings chemdraw gave me and the strings in the master list were both correct, but different. InChI usually worked.

Fenarimols for Dundee DMPK.zip

For shipping, I don't know. If Dundee are happy to receive packages from multiple places, it makes sense to me to send directly, to reduce cost. Is someone willing to reach out to Lauren?

@mattodd @dmitrij176 I have ample supply of MYOS0001_00_01 (re-characterised and stable) and potentially some MYOS00167 (needs double-check to confirm).

I think MYOS0001_00_01 is the one that @dosreic already has this, according to correspondence above? If not I can send more of this compound.

I can ship MYOS00167 early next week if it's not too late to do this.

I unfortunately have run out of MYOS0009 and MYOS00017 at the quality required for the analysis.

[fantasy121]

@mattodd @bebi78 I have rechecked the 2 Fenarimols (MYOS01 and MYOS16) from UCL library and can now confirm that the compounds are stable after 4 years since their synthesis. The samples are ready for DMPK shipment. MYOS04 unfortunately is not available anymore, while the other entries on Mats suggested Fenarimol list are from Sydney. @fantasy121 do you still have them?

DM4-3B DMPK check.pdf DM7-1 (3,4) DMPK check pdf.pdf

@dmitrij176 I do not have MYOS0004 as it was not a target of synthesis for my Honours/PhD project

[mattodd]

OK @fantasy121 @dmitrij176 could one of you please summarise which of my Series 1 list we do not have samples for, and could you suggest some replacements that we do have samples for (either USyd or UCL) that we could perhaps substitute in? I've no time today/tomorrow, and we need to get these final fenarimols to Dundee ASAP.

[dmitrij176]

OK, so my Series 1 (fenarimol) suggestions are:

1 and 2. MyOS_00008 and MyOS_00167 as representative members of the triaryl scaffold that are in vivo active. 3. MyOS_00016 as an in vivo active piperidine. 4. MyOS_00001 as an in vivo active piperazine. 5. MyOS_00004 as one of the original in vivo active compounds with an alternative connection to the core. Pure S enantiomer if we have it, otherwise rac. 6 and 7. MyOS_00009 and MyOS_00017 as active compounds with alternative core substituents.

cLogP (chemdraw) ranges from 2.7 to 4.8.

Suggestions/comments welcome, obviously.

(As a side note, I found searching the master list for these structures (to get the MyOS codes) useless when using SMILES strings. The strings chemdraw gave me and the strings in the master list were both correct, but different. InChI usually worked.

Fenarimols for Dundee DMPK.zip

For shipping, I don't know. If Dundee are happy to receive packages from multiple places, it makes sense to me to send directly, to reduce cost. Is someone willing to reach out to Lauren?

@mattodd we currently dont have MYOS008, 009, 017, 167,

[dmitrij176]

If we have remaining 4 slots, may I suggest the following:

DM10-2 and DM25-1 were other most potent Fenarimols in my assays with good performamce. DM88-4 definitely adds structural diversity. Dioxolane ring is present in many marketed antifungals (including ketoconazole), so if possible I would include that entry Regarding, DM114-1,it is almost identical to Pyrifenox, but analysing it would allow critical analysis of 2 structurally close molecules in the context of minor changes (Question being asked here: how substitution of Cl with F at the 2,4 position affects DMPK). I think that would be useful. @mattodd

[dmitrij176]

If we have remaining 4 slots, may I suggest the following:

DM10-2 and DM25-1 were other most potent Fenarimols in my assays with good performamce.

DM88-4 definitely adds structural diversity. Dioxolane ring is present in many marketed antifungals (including ketoconazole), so if possible I would include that entry

Regarding, DM114-1,it is almost identical to Pyrifenox, but analysing it would allow critical analysis of 2 structurally close molecules in the context of minor changes (Question being asked here: how substitution of Cl with F at the 2,4 position affects DMPK). I think that would be useful.

@mattodd

@fantasy121 can you please clarify whether you are sending anything from USYD to Dundee DMPK study? If not then, we will fill the remaining slots with the above suggestions. Please let us know asap. Thanks

[dmitrij176]

The reserve batch from UCL has been dispatched to Dundee. Due for delivery today.

[fantasy121]

@dmitrij176 That's good with me. I don't have enough to form a batch for shipment. Thanks for filling the rest of the slots.

[dmitrij176]

Hi @mattodd. Can you please post the DMPK results from Dundee. I have attached Chemdraw and Word files with the relevant compound information. Thanks

DMPK (UCL).docx DMPK combined list.zip](https://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/files/13519013/Fenarimols.for.Dundee.DMPK.combined.list.zip)

[mattodd]

Results from the Dundee DMPK analysis are as follows:

DNDi compound results - MycetOS summary_Oct2023 Edited.xlsx

(@bebi78 I've removed your original post because we did not have permission to share the other compounds in the sheet)

Here's how it was all done:

DNDi_Gisele.Project_Nov2023.pptx

@dmitrij176 can you please check the correspondence between what was shipped and what was tested? It looks like 11 compounds tested, but more in the Word file you shared?

For anyone who has relevant data in this sheet, please make a diagram for those molecules so we can see what has been learned.

[dmitrij176]

Results from the Dundee DMPK analysis are as follows:

DNDi compound results - MycetOS summary_Oct2023 Edited.xlsx

(@bebi78 I've removed your original post because we did not have permission to share the other compounds in the sheet)

Here's how it was all done:

DNDi_Gisele.Project_Nov2023.pptx

@dmitrij176 can you please check the correspondence between what was shipped and what was tested? It looks like 11 compounds tested, but more in the Word file you shared?

For anyone who has relevant data in this sheet, please make a diagram for those molecules so we can see what has been learned.

@mattodd I have checked the updated spreadsheet and indeed a number of entries are missing. These include: MYOS_00322_00_01 MYOS_00001_00_03 (EPL-BS0495) MYOS_00016_00_01 MYOS_00136_00_01 MYOS_00145_00_01 MYOS_00583_00_01 MYOS_00589_00_01

Could you please enquire with Dundee on these results. Then we can generate a scheme.