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OpenSourceMycetoma / Series-1-Fenarimols

Open Source Mycetoma's First Series of Molecules
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Biological evaluation 2022 #71

Open dmitrij176 opened 2 years ago

dmitrij176 commented 2 years ago

Assay 2022 (Feb) copy

Hello @wwjvdsande. The third batch of UCL compounds has been sent to Rotterdam. The set consists of 17 compounds: 3 Fenarimols from IMSA 14 structures from UCL (9 Fenarimols and 5 Ketoximes (E/Z mixtures)). I will send a separate sheet with MYOS codes and masses via email.

dmitrij176 commented 2 years ago

PS: the parcel is likely to be dispatched by DHL to the Netherlands tomorrow.

dmitrij176 commented 2 years ago

Bio assay 2022.docx

@wwjvdsande @MA-Jjingyi please find attached speadsheet with compound information from the latest batch.

MA-Jjingyi commented 2 years ago

Yep!@dmitrij176 we got all 17 compounds and found the MW file. thank you.

kym834 commented 2 years ago

Hi @OpenSourceMycetoma/corecontrib,

@fantasy121 and I have been working on the SAR for Series 1 and from the in vivo analysis there are a few holes that would be easy to fill and give us matched pairs that will allow us to make some better determinations from SAR. We think we should be able to make some compounds to help fill it in by the end of the month.

Wondering what is the latest possible date we can ship compounds to you @wwjvdsande with time to do in vivo analysis this year? (if in vitro looks good).

Also want check and see if others are happy for us the make these as it may push the paper back a little? Hopefully it will only confirm what we think already and not cause too much of a change.

wwjvdsande commented 2 years ago

@OpenSourceMycetoma/corecontrib @fantasy121 @kym834 @Wilson-Lm @MA-Jjingyi For the tast possible date to ship compounds I would suggest no later than 1 July. Last year we had a lot of issues in the last parts of the larvae season and we need to screen in vitro before. It is simply to labourintensive to screen everything in vivo. @Wilson-Lm has left it is only @MA-Jjingyi able to screen.

@Wilson-Lm is finalising his PhD thesis, this paper will part of it. For him it is necessary to finish it this month. He was already delaying his final defense. However, since the rest of his papers are published we could go for a solution in the middle. If we finish up the paper as far as it is now and just leave the compounds which need to be tested open for now, he could enter it in his thesis in that format and we can add the last data just before we submit it to a journal. The thesis will be published of course and it can be accessed via the website of the university but it is not indexed in pubmed. Since our manuscript is already on github now, would everyone agree to this solution? In the Dutch system, the thesis will need to go to the reading committee first and then to the full committee. After 6 months the defense will be publically held and at that point the thesis is released and published on the university website. It will not be published anywhere else. We will put a disclamer on this chapter in his thesis mentioning manuscript in preparation instead of manuscript submitted or published. In short this would mean:

  1. we finish up the manuscript as far as we can now, it will only be inserted in @Wilson-Lm thesis with the heading manuscript in preparation.
  2. we will work on the other fenarimols this larvae season, add the data and than finish up the manuscript with the latest details
  3. we will submit
kym834 commented 2 years ago

Well I don't want to be holding anyone back from submitting their PhD and I know how much nicer it is to have submitted rather than in preparation!

I'll make the compounds anyhow as I think that they will be useful even if they don't make this paper. @fantasy121 and I have been working on writing up the SAR for the paper that will be added to the draft soon - definitely before our next meeting at the end of the month. In the meeting, it would be great if we can spend a little bit of time discussing the SAR, current draft of the paper and progress etc. I'll add to agenda when the meeting issue is created. Then we can get an idea of if we want/need this compounds to be included which might help us to make this decision.

Thanks @wwjvdsande!

dmitrij176 commented 2 years ago

Assay Results 2022 (Feb) png

Here is an updated scheme of the latest biological assay results (in vitro stage). Several entries were missing in excel table, but that has been fixed now. All MycetOS codes are correct and up to date. Key points from in vitro testing:

wwjvdsande commented 2 years ago

Looks great!

MFernflower commented 2 years ago

Maybe a ketoxime with an phenylethyl side chain might be good? @dmitrij176 phenyl ethyl chloride is cheap

On Tue, May 10, 2022, 9:48 AM Wendy van de Sande @.***> wrote:

Looks great!

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/71#issuecomment-1122422147, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDV4NMRCLAFUXV477E3VJJSJPANCNFSM5PB7LKSA . You are receiving this because you are subscribed to this thread.Message ID: @.*** com>

bebi78 commented 2 years ago

@dmitrij176 @mattodd @MFernflower Excellent. The ketoximes are very promising. I suppose some of them were already described as anti-Chagas compounds in the thesis of Erin Smith. But more (new) derivatives should be definitely prepared. Question: where can I find the excel table/file with the results?

dmitrij176 commented 2 years ago

Maybe a ketoxime with an phenylethyl side chain might be good? @dmitrij176 phenyl ethyl chloride is cheap …

so that substrate would be similar to DM52-1, but longer by -CH2 group. Might worth a shot. I suggest we wait for in vivo performance of DM52-1 and then decide on that one.

dmitrij176 commented 2 years ago

@dmitrij176 @mattodd @MFernflower Excellent. The ketoximes are very promising. I suppose some of them were already described as anti-Chagas compounds in the thesis of Erin Smith. But more (new) derivatives should be definitely prepared. Question: where can I find the excel table/file with the results?

https://docs.google.com/spreadsheets/d/1YhK-3i2KwuVabo1GbZSgVjAUbavEICCMKi5v-EhNq80/edit#gid=954203120

@MA-Jjingyi could you please uopdate the following entries: MYOS_00310- MYOS_00314. These were missing in the speadsheet and I added them yesterday.

bebi78 commented 2 years ago

@dmitrij176 Thanks for sharing the link to the excel file. @wwjvdsande @MA-Jjingyi Now that I see the results I would like to ask you if I can use the 100 and/or 25 µM activities for my planned paper of the Zimt compounds with you as co-authors?

@bebi78 yes you can add the Zimt compounds to your paper

bebi78 commented 2 years ago

@dmitrij176 In addition, some substituents (halo, methoxy) at the benzyloxy ring of DM52-1 might lead to interesting derivatives.

MFernflower commented 2 years ago

p-Methoxybenzyl bromide is a reagent you should have in the lab might be useful to make a ketoxime from @dmitrij176

On Wed, May 11, 2022, 11:35 AM bebi78 @.***> wrote:

@dmitrij176 https://github.com/dmitrij176 In addition, some substituents (halo, methoxy) at the benzyloxy ring of DM52-1 might lead to interesting derivatives.

— Reply to this email directly, view it on GitHub https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/71#issuecomment-1123939315, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDTRCONNUPYGQXYWEALVJPHVVANCNFSM5PB7LKSA . You are receiving this because you were mentioned.Message ID: @.***>

MA-Jjingyi commented 2 years ago

Hi, @dmitrij176 , I tested the compounds noted DM44-1, not DM44-2. please double check the compounds name which you sent to me. the others 4 compounds MIC data will be added into speadsheet soon.

@MA-Jjingyi could you please uopdate the following entries: MYOS_00310- MYOS_00314. These were missing in the speadsheet and I added them yesterday.

wwjvdsande commented 2 years ago

@dmitrij176 Thanks for sharing the link to the excel file. @wwjvdsande @MA-Jjingyi Now that I see the results I would like to ask you if I can use the 100 and/or 25 µM activities for my planned paper of the Zimt compounds with you as co-authors?

@bebi78 yes you can add the Zimt compounds to your paper

bebi78 commented 2 years ago

@wwjvdsande @MA-Jjingyi Thanks. I will keep you updated about the manuscript.

bebi78 commented 2 years ago

@wwjvdsande @MA-Jjingyi What isolate are you using for your tests? Somalian, Sudanese?

dmitrij176 commented 2 years ago

Bio assay (June 2022 ) jpeg

Good day Wendy (@wwjvdsande ) and Ma (@MA-Jjingyi). I am sending another batch of UCL compounds to Rotterdam. The parcel is due for delivery tomorrow (8th of July). All supporting information is enclosed in the package. Let me know if you need anything else. Thank you

MA-Jjingyi commented 2 years ago

Hi,@dmitrij176. we will pay attention to the package. when we get the compounds , we will let you know.

dmitrij176 commented 1 year ago

Good day Wendy. I am preparing a poster and a flash oral presentation on Mycetoma project for the upcoming RSC symposium that I will be attending next week. I would like to ask your permission to use some of the larval survival data graphs from the performed assays. Would that be ok? @wwjvdsande

wwjvdsande commented 1 year ago

@dmitrij176, sorry I was in Sudan without access to internet. For me it is ok to use the data.

dmitrij176 commented 3 months ago

@wwjvdsande @MA-Jjingyi looking back at the in vivo data for Fenarimols, is there a particular reason why the survival rates in successful molecules never exceeded the 25-30% mark? Even with hit compounds it always stayed at similar levels. Is there a specific reason? If so, what numbers should we be aiming for in these performances (eg. above 50% or 70-75%)? Upon control injection to larvae, it's obviously 100%.

MA-Jjingyi commented 3 months ago

@wwjvdsande @MA-Jjingyi looking back at the in vivo data for Fenarimols, is there a particular reason why the survival rates in successful molecules never exceeded the 25-30% mark? Even with hit compounds it always stayed at similar levels. Is there a specific reason? If so, what numbers should we be aiming for in these performances (eg. above 50% or 70-75%)? Upon control injection to larvae, it's obviously 100%.

Hi @dmitrij176 ,Wendy is on summer holiday. So, I'm writing to reply to you here.

the injection control group is injected PBS only without infection, considered as blank control. the survival rate is 100% to make sure larvae quality is good. amphotericin B is the treatment control because it has been proven that AMB works well in infected larvae. but its survival rates are around 27%-33%. after checking survival data, it has been proven that not many compounds show same/higher survival rates with/than AMB in the larvae model. we aim to find more efficacy compounds without limitation of survival rate I think. higher is better.

dmitrij176 commented 3 months ago

Thank you Ma.