Mycetoma Monthly Meeting 22nd Nov 2022

[fantasy121]

Time: November 22nd (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: Erasmus MC Minute taker: UCL Previous meeting: #82 Recording: here

Attendees: new today were Luiza Cruz (DNDi), Rohan Davis (Griffith Uni), Saina Eslami Torbati (UCL undergrad)

Apologies:

Key things to focus on this month (please add if you'd like to prioritise something)

---

AGENDA

1. Outstanding items from previous meeting

• [x] @dmitrij176 to summarise (in a new post, with a link to that post from the wiki) latest in vitro and in vivo data from Aug and Sept in advance of the next meeting. (Suggestion: to get Wendy’s team to help with this. Also can cross-check with the manuscript to work out where we are up to.)

• [ ] @dmitrij176 to complete the analysis of the Epichem library to identify compounds useful for closing the SAR gap, due end of Oct. To be combined with Hung's list to lead to a set of compounds to request from Epichem in order to close the SAR gaps. Update: initial analysis posted, but this needs to be distilled to a set of compounds that should be ordered to complete the current paper. Action remains with @fantasy121 and @dmitrij176

• [ ] @mattodd to pursue metal complex samples from COADD and report at next meeting.

• [x] @MA-Jjingyi to upload biological evaluation presentation for #82 October meeting

• [ ] @wwjvdsande to equest Ben to perform other stat tests (more complex than, new, or orthogonal to Mann-Whitney) to see if new trends emerge (Note: Ben will leave DnDi. Contact Luiza Cruz if Ben is no longer corresponding)

• [ ] @fantasy121 will work draft of manuscrip Re: comments addressed to Hung. Due end of Oct

2. Discussion points for this meeting

• Rohan's contribution of compounds from Griffith University QLD: Numbers of compounds, screening capacity, costs and motifs of interest, to be discussed. @rohandavis to ship 10 compounds to @wwjvdsande - which? Rohan has the 512 compounds in an SDF file. Shipping from Compounds Australia, DMSO 5 mM stocks, can be plated. Costs: sending to Netherlands is tricky. Send smaller number of dry stocks is easy. $300 to send some dry ones. $3-4000 to send the DMSO. No dedicated support from a grant. A decision is needed on what to send.
• Crowdsourcing update - incoming contributions from e.g. Whitgift school, Hampton school, Julia Sarju (@JuliaSarju, York Uni). Others @kym834 ?
• USYD update. @fantasy121 is shipping a set of compounds to @wwjvdsande - what are these structures? Also some Series 2 compounds from Breaking Good incoming - again, what are these? (Since @wwjvdsande is away, these compounds should be sent directly to @MA-Jjingyi). @fantasy121 to update Master List when compounds have been sent.
• UCL update
• Erasmus update
• Paper Writing discussion: @fantasy121 has addressed all compounds relevant to him. SI data for SAR diagrams are in one document. It is not clear whether the Si document is ready for submission: @fantasy121 and @dmitrij176 to advise. The relevant raw data also needs to be available, e.g. NMR data or offline copies of the lab notebooks. Wendy updated figures of survival curves and the screening data. @mattodd to have a look next.
• In meeting: the importance was mentioned of keeping the Master List up to date, with all new biological data entered as soon as it is received. The Master List is currently up to date.
• Note that this repository is for fenarimols. There are other repositories that cover other series of molecules, and new data/discussions relevant to those should ideally be placed there. e.g. ketoxime, aminothiazole data.
• When entering data, it is important to include provenance - who made the molecule.

3. Any other businesses?

• Mat is trying to work with a group of Cameroonian scientists to carry out some homology modeling of M. mycetomatis Cyp enzymes to understand the fenarimol SAR and assist with future planning.
• Dmitrij to send current compounds for in vitro testing, including separated E and Z ketoxime isomers.
• LogD should be kept in mind as a design criterion for all series.

• Someone mentioned this paper: https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00960

  Jan 24th 12 noon UK, 1pm EU

[dmitrij176]

SAR gap analysis Fenarimols SAR gap analysis (final).zip

[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). Please let me know in the coming few days if you want to contribute using a 100% voucher. I will send you an official invitation then. If Mat and Wendy don't have interest, I can provide the 100% voucher to other interested PIs of this github group. The same for the malaria OSN.

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

[wwjvdsande]

@OpenSourceMycetoma/corecontrib @bebi78 would this be something for our fenarimol manuscript?

[bebi78]

@wwjvdsande @mattodd I suppose the fenarimol article is already written in J Med Chem style. But maybe the ketoximes would fit. @dmitrij176 Submission of a review article is also possible using the 100% waiver.

[dmitrij176]

That would be great. The ketoximes would definitely have to be in n future publication(s).

[bebi78]

@mattodd OK for you to plan with a ketoxime manuscript for the special issue?

[dmitrij176]

For the outstanding assigned objective on the latest in vitro and in vivo data from Aug and Sept screening, would using Blue and Orange box lists (from Mimis September presentation) as a reference for the potency scheme creation be accurate? Do these 2 lists cover all molecules for the latest potency scheme? @MA-Jjingyi @wwjvdsande could you please advise on this? Thank you in advance.

[mattodd]

Our new contact at DNDi, following Ben Perry's departure, is Luiza Cruz @dosreic. Welcome Luiza!

[MFernflower]

@dosreic to see if she can send this compound from a DNDI paper to Wendy:

https://github.com/OpenSourceMycetoma/Series-2-Aminothiazoles/issues/11

[dosreic]

@MFernflower Awesome, I checked with my colleague, and this would be possible indeed.

@wwjvdsande how much compound do you need and to whom I send?

[mattodd]

Rohan Davis is also now on Github - @rohandavis. Welcome!

[mattodd]

As I mentioned, I want to post something simple about how students at e.g. schools and unis can get involved, and the current needs of the project. This can go on the wiki somewhere, in this case for Series 2. Feeback please @kym834 @fantasy121

MycetOS has now run several experimental open science projects with schools and other cohorts of junior students. The project has molecules that need to be made, and if students participate then they have the satisfaction of making new molecules that are actually needed in a live drug discovery endeavour, and which are biologically evaluated.

If you are at a school and reading this, then you can get involved. Typically speaking what you'll need is as follows:

1) A good teacher willing to manage the project in your school. 2) Some time - typically some hours each week for a term, or something like that. 3) The ability to order in chemicals, including organic solvents, and handle them. 4) Some equipment, typically a fume cupboard, some glassware, a balance.

At the moment we're making these molecules, which can be purified by crystallising them. For advanced methods of purifying molecules (like chromatography) and for characterising the molecules at the end (using NMR and MS) we (the MycetOS team) can help with that, so don't worry if you can't do it locally.

This is an open science project, meaning you would need to record what you're doing in an online electronic laboratory notebook. We can provide one if you don't have somewhere where you can write your work and record your data.

The current molecules are shown here. The first slide shows molecules that have recently been made, and the second slide shows what we're hoping you'll do - the same chemical synthesis, but varying the red "aniline" bit.

If you're interested, get in touch. There is a team at the University of Sydney in Australia and one at University College London. But you can take part from anywhere.

We're also very interested in hearing from students who might want to get involved in other ways - for example in helping other student groups to get involved by being a point of contact between those groups and the scientists who are driving the research at the contributing universities.

[kym834]

RE schools contributing compounds - Barker College (@katieterrett) has planned to run a synthesis of some Series 2 compounds in their Science Extension early next year. I'm yet to confirm if any students have showed interest in the project (they get to choose what they want to do) but looking likely they will contribute couple of compounds. I'll add to Series 2 repo once confirmed :)

@mattodd looks good. I think really pushing for them to get in touch to discuss what is possible given their resources e.g. maybe they only do one step or something if they don't have time. Home page of the Wiki or the Code tab be the best place I reckon.

[mattodd]

Whitgift school are now also on here @Whitgift. Welcome!

[MFernflower]

@dosreic and @MA-Jjingyi to communicate and figure out shipping of the DNDI anthelmintic aminothiazoles as Wendy is currently unavailable

[dosreic]

@MFernflower @MA-Jjingyi I might have to wait for @wwjvdsande because we need to setup an MTA beforehand. I will follow up with the Discovery team at DNDi about this next week and keep you updated.

[PaulMcKeatingSevenoaks]

Hello. Think we are getting ready to go in January, so are making a shopping list. Any particularly suitable molecules to target at the moment? e.g. groups on rings? Also don't want to repeat work that @Whitgift might be doing at a similar time... Otherwise will see if there are other easy-ish derivatives based on USYD work. @kym834 @mattodd

[MFernflower]

Perhaps this compound could be worth making? https://pubchem.ncbi.nlm.nih.gov/compound/745760

Message ID: <OpenSourceMycetoma/Series-1-Fenarimols/issues/83/1333902502@ github.com>

@kym834 @mattodd

[mattodd]

Why that one, @MFernflower ? @kym834 as you mentioned in OpenSourceMycetoma/Series-2-Aminothiazoles#12 did you have an update to the recent biological data, and which molecules might make most sense to order? And @Whitgift - did you make a decision on target? We don't have a general MycetOS meeting planned this side of Xmas, but we could maybe organise a special one just to plan for this series, sometime in the week commencing Dec 12th? e.g. 10 a.m. UK time Dec 13th, 9 p.m. Sydney that day? Any use @PaulMcKeatingSevenoaks ?

[MFernflower]

@mattodd the compound I found in pubchem has some resemblance to a compound made and tested recently:

[kym834]

Hey @mattodd, results on the Series 2 Wiki are up to date. A couple gave similar growth inhibition to the hit at 25 µM and 100 µM but their IC50s weren't as good.

@MFernflower and @mattodd, the 2-pyridyl has so far shown to be important for activity so I'm reluctant to make compounds without this in place as in the compound suggested. As for the other ring, MYOS_00317_00_01 shown above and MYSO_00315_00_01 (fluoro para to amine linker) show that the 4-methyl-2-pyridyl rings system of the hit compound is not entirely essential and if we kept the 2-pyridyl of the first ring and paired this with the rest of the compound suggested would only be probing this same question, so I don't think there is much value in just changing the trifluoromethyl to a methyl.

I have a meeting with Barker College (@katieterrett) today so will be able to get confirmation on if and what compounds they will be working on for Series 2.

I'm also on leave the week suggested for a meeting and unlikely I'll be able to join. Not back until the following week.

[MFernflower]

@kym834

Thanks for the information: here's a few other compounds I found on pubchem

• thoughts?

https://pubchem.ncbi.nlm.nih.gov/compound/155924610

https://pubchem.ncbi.nlm.nih.gov/compound/873000

[kym834]

@MFernflower Yes, but aniline isn't suitable for schools, and I'd be pretty reluctant to use cyclohexylamine in schools too. I'd be interested to see what other starting materials we could source that have substitution on the phenyl and cyclohexane rings so we had some functional groups that we can further use to build out the structure. And that are suitable for school students.

For example, USyd did make some with chlorines around both ring structures. These were made with the intention of being great starting materials for coupling reactions with some boronic acids. I just don't know about robustness of the reaction conditions nor suitability for schools as I've not looked into it from this perspective before.

[PaulMcKeatingSevenoaks]

Interesting.

Yes, @mattodd @Whitgift, I could do a 10am UK meeting on Tuesday 13th to look at some possibilities for series 2 which are school-friendly.

[MFernflower]

@kym834 would starting with 4-Pyridin-2-yl-thiazol-2-yl-amine and doing a reductive amin with acetophenone work?

https://user-images.githubusercontent.com/3164942/205701261-8fbd5bd7-b95b-4e6a-9204-1d0ad6da6d6b.png

[mattodd]

@Whitgift @PaulMcKeatingSevenoaks @kym834 @katieterrett so that we can be sure that we're targeting distinct structures, could we please either set up a quick TC or post current target structures below?

Based on the current data, shouldn't we explore variations in the 5-methyl-2-pyridyl moiety? Keep the 2-pyridyl but explore other substituents? Walk the pyridine N around the ring? Try 5-membered rings there? Seems like a nice route if we can just vary the red "aniline" in the general route?

[MFernflower]

@Whitgift @PaulMcKeatingSevenoaks @kym834 @katieterrett

I think one of the issues was that reagents like aniline and cyclohexyl amine might be too toxic

I had the idea of having someone make or buy 4-(pyridin-2-yl)thiazol-2-amine - And then have the students do reductive Amination with 2-picoline-borane and an aldehyde or ketone (E.G acetophenone or benzaldehyde)

@mattodd

(Reposted to include more people)

https://www.organic-chemistry.org/chemicals/reductions/picoline-borane.shtm

[bebi78]

@MFernflower Simply use NaBH4 for the reduction step. There is a DNDi project with similar pyrazole compounds (P1Tc) and I also have prepared one pyridylthiazole derivative for comparison purposes for that project (but the thiazole was less active against T. cruzi than the analogous pyrazole). I'm not sure if that DNDi project started with such thiazoles in 2018 but was abandoned because of toxicity concerns of the thiazole ring by Ben. I think he has commented somewhere on this github group about the thiazole problems some years ago.

[JuliaSarju]

Hello! Julia from the Uni of York here. We have a group of 6 very interested year 3 chem undergrad students who are keen to contribute. We are planning to follow @mattodd suggestion to vary the aniline. Could we have some help identifying the first few options to try or what to avoid?

[bebi78]

@MFernflower Nobody from DNDi commented, so I suppose such reductive amination compounds (from Schiff base reaction followed by NaBH4 reduction) would be new and of relevance, and your suggestion would fit well for students or pupils (I could provide then one analog from the DNDi P1Tc project). Several amides were already published, which showed activity against tuberculosis (C.C. Aldrich et al. Bioorg Med Chem 2013, 21, 6385, also describes a simple synthesis of the starting 2-aminothiazole from commercially available compounds). Should antitubercular amides be synthesized for repurposing? Might then also be done by students.

[dosreic]

Hi everyone! Sorry, I'm still new to GitHub and did not notice the subject around the P1Tc project. I'm also new to the project, and wouldn't be able to say if it started with a thiazole ring. But this project has originated from this one, https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5b01456, if helps...

[bebi78]

@dosreic Thanks for posting the link and the clarification. Maybe we can discuss it in the next meeting in January. @MFernflower @mattodd @JuliaSarju @kym834

[kym834]

Hello! Julia from the Uni of York here. We have a group of 6 very interested year 3 chem undergrad students who are keen to contribute. We are planning to follow @mattodd suggestion to vary the aniline. Could we have some help identifying the first few options to try or what to avoid?

Started a new issue in Series 2 to discuss with a few options for @JuliaSarju to consider.

[bebi78]

@MFernflower @mattodd @dmitrij176 @fantasy121 @kym834 @dosreic Ben's new paper published by JMC. Maybe some clues for amine modification. https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00775