DNDi Open Synthesis Network

[bendndi]

The first two participating institutions from the DNDi Open Synthesis Network have recieved the preliminary data for the MycetOS project and ahole to initiate work over the Summer:

Illinois Mathematics ans Science Academy (IMSA) https://www.imsa.edu/site_section/discover/ Augusta University https://www.augusta.edu/

Hopefully representatives from both locations will join in on our Github discussions soon!

[MFernflower]

@fantasy121 I assume lithium addition to the relative ketones is going to be the main synthetic route?

[MFernflower]

@fantasy121 Added a link to your PHD eln in the wiki

[fantasy121]

@MFernflower For the most part I think nBuLi would be the route I’ll be using. For the halogenated versions which I’m planning to synthesise, it is a little bit more tricky. I am having some difficulties in coming up with a strategy to synthesis the asymmetrically substituted anthracenone (in red) which is a precursor to the final product with the six-member ring lock. I played around with a few different combinations, I came up with a possible solution (in the red box), essentially it’s a double Friedels-Craft reaction to get to that ketone. I still feel that I haven’t got to the most reliable route yet though.

[fantasy121]

@MFernflower I've also added a link to my PhD note in the new post I just made. Both notebooks are also hyperlinked together as well so you can easily jump from one to the other

[MFernflower]

I really cannot find any of the ketones needed for sale from suppliers other than the Butyrophenone, Fluorenone and Anthrone @fantasy121 How would you plan to make the ethoxy compound?

[drc007]

@fantasy121 Not an area of chemistry I am familiar with but how stable will the tertiary alcohol be?

[MFernflower]

Might be wise to just make the nonhalogenated six-lock and check stability - I don't think this mechanism will cause any issues with the five-locks however! @fantasy121 @drc007 @mattodd

[fantasy121]

@MFernflower Do you mean the ethoxy as in MXF006? I'm thinking of applying the same nBuLi route I've been using for many previous molecules I made. I would just need to brominate the ethoxy side group first and I have a few candidate for that. If unfortunately nBuLi starts attacking my ether, I've got this back-up plan as well, although this reaction is for diphenyl ethoxy tertiary alcohol. Might need to tweak reaction condition to incorporate that pyridyl group. Maybe down the bromobenzene ratio down to 1 equiv and then adding bromopyridine as 1 equiv ratio after the benzene addition. Also I could shorten the reaction time and/or lower temperature to make the diphenyl species less favourable. It might take some experimentation.

[fantasy121]

The paper reporting that Barbier-Grignard reaction: https://www.sciencedirect.com/science/article/pii/S004040391302128X

[drc007]

I think that some of those routes will result in an extra carbon in the side-chain?

[fantasy121]

Might be wise to just make the nonhalogenated six-lock and check stability - I don't think this mechanism will cause any issues with the five-locks however! @fantasy121 @drc007 @mattodd

I would definitely make the unhalogenated version first to test the robustness of the synthetic route. That would also give the product P4_D_MXF009

[fantasy121]

I think that some of those routes will result in an extra carbon in the side-chain?

Thank you. You caught me in a moment of blindness. It seems I've miscounted one of the carbons. It does make thing surprising more affordable though.

[mattodd]

@drc007 the concern about the elimination you mention above - not sure it's such a risk. The big R group goes axial, to avoid the clash, meaning the OH is pseudo-eq, meaning it's hard to eliminate because of bad overlap of that sigma* with the pi system. Not impossible, just harder than you might think, I'd wager.

[MFernflower]

@mattodd I'd love for further MD studies to be done on MXF009 but even a simple tool like molview really shows the clash well: http://molview.org/?q=OC1(C2=CN=CC=C2)C2=CC=CC=C2CC2=C1C=CC=C2

[dmitrij176]

@bendndi DM6-1/ P4_C_001 and DM7-1/ P4_C_003 have been synthesised, purified and sent for biological evaluation. Remaining 4 will be finished soon. Could you please update the OSN master list.

[luxsika]

Hi! The compounds that I have synthesized have been sent for biological evaluation.

[bendndi]

Updated OSN list

White: Not Started Yellow: Ongoing Green: Completed

[MFernflower]

@bendndi can you add C1(CCC1)C(O)(C1C=NC=CC=1)C1CCC1 as MXF_012

and OC(C1CCCC1)(C1CCCC1)C1=CC=CN=C1 as MXF_013

Had to repost because github chewed up my smile strings

[dmitrij176]

@wwjvdsande the Excel file with the latest information on biological testing of novel Fenarimols is missing data on MIC50. Could you please provide us with that and the method information as well ? Thank you in advance.

[bendndi]

@MFernflower Updated OSN list

[dmitrij176]

@bendndi with respect to the OSN list, would it be possible to show which compounds have already been made, including their potencies as well ? This will keep everyone updated on the latest developments in the chemical library.

[bendndi]

@dmitrij176 The compounds in green are the ones which have already been made from the list (white for "not started", orange for "In progress", Green for "Completed". Biodata for these componuds are still under evaluation.

For looking at biodata for other compounds in the series (i.e. ones from the series but not made via the OSN) there is a master google docs table here:

and also images of some of this data here

The data set is also available as an sd file here

Personally I think this last file is the best one to use if you're interested in assessing the biodata - just open the sdf file in datawarrior

[bendndi]

Updated OSN list 20Sep 2019

[MFernflower]

@bendndi I came up with another analogue that might be worth adding to the list:

CC(C)(C)OC(=O)N1CC(C1)OC(C1=CN=CC=C1)C1=C(F)C=C(Cl)C=C1

tert‐butyl 3‐[(4‐chloro‐2‐fluorophenyl)(pyridin‐3‐ yl)methoxy]azetidine‐1‐carboxylate

[MFernflower]

Matrix sells needed precursor for like 20 dollars!!! http://www.matrixscientific.com/024669.html

[MFernflower]

@bendndi if possible can you update list to mark tested compounds as so and to include the new ideas me and few others were throwing out?

[dmitrij176]

MycetOS project update

I would like to reserve the following compounds from the OSN list:

DM17-1/ P4_C_MXF003: ClC(C=C1F)=CC=C1C(N2CCC(CC2)=O)C3=CN=CC=C3

DM18-1/ P4_A_007: ClC(C=C1F)=CC=C1C(N2CCN(CCN(C)C)CC2)C3=CN=CC=C3

DM19-1/P4_C_MXF001: ClC(C=C1F)=CC=C1C(N2N=CC=C2)C3=CN=CC=C3

DM22-1/ P4_C_MXF002: ClC(C=C1F)=CC=C1C(N2N=CN=C2)C3=CN=CC=C3

DM23-1: CC(C)(OC(N1CC(OC(C2=C(C=C(C=C2)Cl)F)C3=CN=CC=C3)C1)=O)C

@bendndi DM23-1 is a newly proposed analogue by @MFernflower which currently does not have an assigned OSN code. Could you please add the structure to the updated scheme.

DM4-3B and DM16-1 will be used as positive controls in biological testing. Unfortunately, DM9-1 synthesis was unsuccessful. Project update.zip

[MFernflower]

@dmitrij176 I'd assume that DM9 might be too sterically hindered - perhaps making the version with the two tert butyl groups lopped off might be worthwhile if time permits?

[bendndi]

@dmitrij176 @MFernflower Thanks, I'll update sometime later this week once I'm back in the office! B

[bendndi]

Hi all, the OSN list is now updated:

Green - Completed Orange - synthesis ongoing White - not started

@dmitrij176 @MFernflower

[MFernflower]

@bendndi @dmitrij176 OSN update looks good but if I am not mistaken it is missing two compounds?

[bendndi]

Hi all, the OSN list is now updated:

Green - Completed Orange - synthesis ongoing White - not started

@MFernflower

[MFernflower]

@bendndi Thank you Dr.Perry! Could you upload a CSV file containing all this data for users of datawarrior? I think the old files and the zips on the github are out of date!

[bendndi]

@MFernflower Done

[MFernflower]

@bendndi Might not be a bad idea to somehow mark the di-tert-butyl as being difficult or impossible (steric bulk?) to synthesize as @dmitrij176 could not complete it

[dmitrij176]

MycetOS project update

DM24-1: ClC(C=C1F)=CC=C1C(NC2=CC=CC=C2)C3=CN=CC=C3 DM25-1: ClC(C=C1F)=CC=C1C(N(C)C2=CC=CC=C2)C3=CN=CC=C3

Following a number of attempts to synthesise DM9-1 analog, a series of reactions with aniline based substrates were carried out. The assessment of the following synthetic route showed that both aniline (DM24-1) and N-methylaniline (DM25-1) can be added to the Fenarimol core. Reaction with diphenylamine in DM26-1 (which is the most structurally related reagent to the tert-butyl substrate in the original DM9-1 experiment) generated trace amounts of the desired product. The results suggest that extra aromatic rings along with tert-butyl groups do lead to steric hindrance in these reactions. It was decided not to include DM26-1 in the OSN list as the product could not be characterized due to its very small percentage in the product mixture. Therefore, I would conclude that the outcome of the two aforementioned reactions is the same.

DM23-6 experiment with 1-Boc-3-hydroxyazetidine produced the desired Fenarimol analog after the introduction of several key changes to the original reaction protocol. Results were achieved by first deprotonating the substrate with NaH, followed by the addition of DMAP catalyst to promote reaction completion. Under standard conditions (triethylamine and KI), the product did not form.

@bendndi could you please add DM24-1 and DM25-1 to the OSN list and update the status of the completed molecules.

Project update March 2020.zip

[MFernflower]

@dmitrij176 @bendndi I think it would be wise to not add DM26 to the OSN list

Lovely work however!

[MFernflower]

@wwjvdsande @Wilson-Lm Just curious how long it takes for the assay to be done - Fungi can have variable growth times from fast to agonizingly slow - I remember having to culture Hericium for a buddy's culinary mushroom farm and it took forever to take hold

[MFernflower]

@dmitrij176 When you get a chance can you split the compounds you send to Wendy up into a new issue?

[bendndi]

Updated OSN list: Green - completed Pale orange - synthesis ongoing Dark Orange - problem (synthesis difficult or impossible) White - not started

Great work @dmitrij176 ! I added in the benzyl analogues to DM24 and DM25, could be worth a look too if you have a chance.

[wwjvdsande]

@wwjvdsande @Wilson-Lm Just curious how long it takes for the assay to be done - Fungi can have variable growth times from fast to agonizingly slow - I remember having to culture Hericium for a buddy's culinary mushroom farm and it took forever to take hold

@MFernflower unfortunately, M. mycetomatis is one of those slow growing fungi. One MIC takes 2-3 weeks due to the culture time and we always test in duplicate or triplicate. We will do an initial screening with high concentrations of the compound hopefully in two weeks time from now. We will initiate the starter culture this week. The initial results we will deposit here and those who seem to have some activity will be tested further. In case anybody want to add some compounds in the screen it would be nice if we can add them all in one go.

[alintheopen]

Cc @fantasy121

[fantasy121]

@wwjvdsande As a point of reference, could you also give everyone here a preferred miminum amount of each compound to send to you for biological evaluation?

[wwjvdsande]

@fantasy121 we need at least 2 mg for the initial screenings. If the compound is weighed and the weight is on the tube that would be great. It needs to be able to be dissolved in DMSO or water or culture media for the in vitro screenings. In case a compound is very potent and we want to proceed to larvae work it is preferred if the compound can be dissolved in normal saline, water or PBS. However in case we need to dissolve in DMSO, we can only inject a maximum of a 5% DMSO solution into the larvae.

[wwjvdsande]

Dear all, due to the COVID-19 outbreak many research facilities in Europe closed their laboratories for now. Also we are working from home. That means that it will take a bit longer before we can test the compounds generated. We hope that the COVID-19 outbreak will not disrupt all our lives to long. When we will return we will start the cultures up and test all compounds received. Any compounds not sent to us yet can be sent then. Madurella is a slow grower it will take at least 2 weeks till a month till it is ready to be used for in vitro testing.

[dmitrij176]

@bendndi I have noticed that the OSN list in issue #29 is an outdated version. The updated scheme https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/13#issuecomment-596427111 with the latest compound status was posted on the 9th of March

[bendndi]

@bendndi I have noticed that the OSN list in issue #29 is an outdated version. The updated scheme #13 (comment) with the latest compound status was posted on the 9th of March

Yep, I've updated it now -I didn0't have the most recent one to hand but I needed to put i a placeholder since @fantasy121 wanted it to be the top commment in the thread he had opened. Will update again once I've compiled the list.

[dmitrij176]

@dmitrij176 Any chance you're able to share this as a SMILES list e.g. an excel table with smiles column, status colum and ID column? It is much easier and quicker to handle SMILES than having to resketch compounds by had each time. (I can help you get the SMILES strings if you can tell me which drawing package you're using)

@bendndi apologies for this misunderstanding. All the compounds from todays update are already in the OSN list. This includes the 2 molecules that are currently in development (DM27-1 and DM28-1). I have double checked the lists, its all correct. DM4-3B and DM16-1 are positive controls, but DM4-3B has been synthesised before and therefore should not be included. I am using Chemdraw, so no problems with generating SMILES. Whenever new molecules are being proposed, I will provide the SMILES codes. In addition to that, would you still prefer me to create a list with all SMILES ?

Lastly, I have noticed that DM24-1/P4_C_DM24 and DM27-1/P4_C_014 structures were drawn incorrectly. Both are missing a H atom. Could you please correct that.

[bendndi]

@dmitrij176 The software I'm using (Stardrop) uses implied hydrogens on heteroatoms (you'll notice that the hydroxyls are also missing hydrogens). Unfortnately I'm not able to change this setting.

[dmitrij176]

@Wilson-Lm would you be able to share any up to date biological data for my analogues ?

I need it for my upgrade report R&D section.