Poll to decide which compounds to synthesise next as 'Pfizer phenol' analogues

[david1597]

Intro

This post is about which series 4 compounds we should make next based on the phenol, #525, from the Pfizer biosynthesis, #513, but also how best to use polls to do this as suggested by @mcoster in #551. Posting in this To Do List repo as although it specifically relates to series 4, it's a trial run at how we may run such polls across any of our work.

Background

Following on from @JoshMaxwell's introductory post #554, we're keen to continue exploring this chemistry which now appears to be working well, and applying it to make further anologues of the phenol compound, OpenSourceMalaria/Series4/issues/3.

The general scheme towards these final compounds is as follows where we now wish to look at SAR around the phenol and bioisosteres:

@mattodd and I had some ideas, @MFernflower had a suggestion and @mcoster a number of great suggestions over at that link (If you have fresh suggestions, they're welcome in the comments below). We're going to do a final Combi-Blocks order from our lab early next week and not wait till January, so we can include more starting materials for this particular project in that. Time and $ restraints mean we can't make everything we can possibly think of. I've looked through the catalogue at some iodo precursors that are available, and I'm asking for some help from the OSM community in deciding which to aim for. Which do we think are essential and a top priority? Which compounds do we think would be neat to have, and should make once the priority list is addressed? And which are probably best not bothering with?

Trialling Google Forms for this, as suggested by @miike in #551. Does that sound good, @mcoster? Any discussion relating to how well the poll works in general terms is probably best continued in #551. Lets see how it works out. Use this issue for any discussion relating to this specific question and to discuss any of the proposals.

The Question

Which of the following precursors should we use? If no price is listed, we already have it in stock.

[mcoster]

Awesome! Just got back from a couple of days away, so didn't get a chance to say that I really like the Google forms suggestion of @miike

It will be interesting to see if the results from the survey are helpful, and whether clear trends or suggestions are present. Good luck!

[drc007]

You might want to check the tautomer of the hydroxypyridines, I suspect L will be 2-pyridone. 2-halopyridines are chemically reactive, might be an issue. Halogen substitution will have interesting effects on the pKa of the phenol which might be informative. Not sure SF5 has a benefit of simple CF3

[MFernflower]

I agree with @drc007 I don't like the look of the hydroxy and halo pyridines As for why I recommended to @david1597 SF5 is because it's a good mimic of t-butyl/CF3/Isopropyl - You know I think we should scrap the SF5 and go for isopropyl instead (it's a a lot cheaper!) --> see https://www.alfa.com/en/catalog/B25476/

[drc007]

I've added a link to this on LinkedIn https://www.linkedin.com/feed/update/urn:li:activity:6345889115766079488 will hopefully gain exposure to more drug discovery scientists.

[mcoster]

Just had a thought - maybe a tinder style interface would be good for next generation compound selection/prioritising! Swipe left if you don't think it's worth the effort, swipe right if you do. Aggregate responses and, voila!

[holeung]

My collaborator (Alan Aspuru-Guzik)'s lab implemented a Tinder-like interface for materials chemistry.

Towards a better screen

[mcoster]

Very interesting! Seems to have worked well for them. It would be great to have the computed properties for the compound, and perhaps a link to the github issue discussing the hypothesis being tested, on the molecule profile. I don't suppose your collaborator's code is open source? Or would he be willing to share with OSM?

[holeung]

I'll follow up with Alan on whether their code can be shared and get back to the group. I remember the molecular Tinder profiles showed calculated properties.

[MFernflower]

SwissADME would be a nice service to add into our "Drug Tinder'

[mattodd]

Votes: D, H, P, S, T, U. And an (acetate) ester of the parent compound. Have submitted via the Google Form also.

[holeung]

Unfortunately, the Aspuru-Guzik lab molecular Tinder code is licensed to a company and cannot be shared at this time.

[maratsydney]

As I am working on Buchwald-Hartwig coupling, I see possibility to play with structure R towards C-N coupling to make structures as presented below. I assume it should be possible to install C-N bond at the last step and this way relatively easy explore this area. And I guess it will be interesting molecules to test.

[mcoster]

@holeung - ok, no problem

[david1597]

Thanks for all the comments, and responses so far. I'll leave the poll open for a while longer as we will not be starting the synthesis until after our Christmas shutdown.

@maratsydney Yes, I think this is a good idea - we can give you the final compound from 'M', and you can explore this.

@holeung Thanks for checking that! It's a good idea @mcoster. I feel I may have included too many options (in a single batch) in this poll and a Tinder style would be a way around that. Although on the other hand, seeing all options concurrently maybe allows comparisons and prioritisations easier to decide.

@drc007 Thanks a lot, both for the useful comments and for helping gain exposure. Much appreciated.

[mcoster]

Very much an aside... The more I hear about blockchain technology, the more relevant it seems for open science projects. An ELN on the blockchain would be ideal. Also, transparent voting (eg. for target compound selection) - I just heard on a STEM education podcast about an a blockchain voting implementation at an Australian Primary school. Turns out even 10 year olds can create their own cryprocurrencies. I don't suppose any OSMers know a tame blockchain expert who would be interested in creating and maintaining an entire blockchain ecosystem for a friendly open source drug discovery initiative?.. :grin:

[mattodd]

Interesting question @mcoster but yes, I'd start a new issue with it! Starting with: how does such a system differ from a highly inter-linked, machine-readable set of ELNs?

[cdsouthan]

Could @holeung do some 3D overlays to add another rational dimension to new compound choices?

[holeung]

Lowest energy conformation of OSM-S-412 and analogs were calculated and then energy minimized by PM7 semi-empirical method.

Zipped pymol session file containing 3D structures: OSM-S-412_overlay.pse.zip

[MFernflower]

@david1597 how difficult would it be to make a glucoside of the Pfizer phenol

[drc007]

@holeung Looking at the low energy structures it seems like the methine proton next to the hydroxymethyl sits over the phenyl ring. Is there any evidence for this in the NMR? Could be experimental evidence to support modelling studies?

[holeung]

Good question. I did a more thorough conformational analysis with OSM-S-412. I allowed the torsion angles to rotate and energy minimized the best conformers. The lowest energy conformation was then geometry/energy optimized with the PM7 semi-empirical method with COSMO water solvation model. This conformation is similar to the one I previously posted here. The conformation was further geometry/energy optimized with DFT (density functional theory) with the B3LYP-D hybrid functional with 6-31++G** basis set with the conductor-like polarizable continuum model (CPCM) for water solvation with the ORCA software package (https://orcaforum.cec.mpg.de). There are some significant shifts from my previously posted structure. The figure below shows distances from the two nearby hydrogen atoms to nearest carbon atoms in the RHS phenol.

I am happy to take a closer look at molecule conformations, but these DFT calculations take a very long time.

DFT optimized .mol2 coordinates

[MFernflower]

If I'm not mistaken cant a NMR of OSM-S-412 in heavy water be done to once and for all confirm the structure when solvated in water? @holeung @mattodd

[david1597]

Looking at the low energy structures it seems like the methine proton next to the hydroxymethyl sits over the phenyl ring. Is there any evidence for this in the NMR? Could be experimental evidence to support modelling studies?

@drc007 What should we be looking for in the NMR specturm? Below is a spectrum for a related compound taken in MeOD.

[david1597]

If I'm not mistaken cant a NMR of OSM-S-412 in heavy water be done to once and for all confirm the structure when solvated in water

@MFernflower Unfortunately this compound will not be sufficiently soluble in water to get any NMR data in this solvent.

[MFernflower]

@david1597 cd3cn is a pretty good hwater mimic - or is this compound that non polar that it will not dissolve? I'm a bit new to this whole NMR thing !

[david1597]

Poll results (as of 21st Dec)

Many thanks to all of you who gave an opinion. There have been 13 responses to the poll so far. Data and results as of 21st Dec are here. Clear trends are evident, and we will use this data to guide our synthetic targets in the new year. The poll will remain open until Jan 8th when we return from our Christmas shutdown here in Sydney.

Priority Compounds

Number of times voted for as a high priority target. Top three on the hitlist are H, C, and P. To me, these look highly sensible as priorities.

Good Ideas

Combined total votes for high priority and good ideas, excluding the three already designated priority compounds. D, U, S and V are the top four in this category. We will also make compound R, the bromo analogue of S, for further coupling reactions.

Least Popular

Those that received most votes in the 'don't bother with' category. N, Q and M gaining this honour. Cost of Q likely factored into this, relative to perceived benefits. And the issues with N and M are mentioned above too.

Full Voting Data

Compound	High Priority	Good Ideas	Don't bother with
A	4	1	1
B	1	3	1
C	7	2	1
D	6	2	1
E	0	1	4
F	1	1	4
G	1	0	4
H	8	0	2
I	4	1	1
J	1	3	1
K	1	3	1
L	2	1	3
M	0	2	5
N	0	0	7
O	3	1	3
P	7	0	0
Q	2	1	6
R	2	2	2
S	4	3	3
T	3	3	0
U	5	3	1
V	2	5	3

Additional responses: "And an acetate ester of the original compound."

"I'd also suggest 2-aminopyridines - either 4- or 5-linked, as they've worked for me as phenol replacements that had far less PhII metabolism than the phenol and similar potency. The indazole was also good for me, and oxindoles worked well too."

[drc007]

@david1597 I'd expect that if the methine is over the aromatic ring then the proton would be shielded and the signal moved upfield in the NMR. Would be interesting to compare with the NMR of the precursor side-chain before coupling to the core.

[mcoster]

This ^^^^^^^^^

[MFernflower]

@mcoster I cannot find any 1H NMR spectra for 2-Phenyl-1,3-propanediol but I have found spectra for a related compound where one of the hydroxy's has been replaced with a methyl: https://spectrabase.com/compound/C4d9tBsdUNP#B5WuM3Y6Usn

Update: it seems to be a pay per view service - Don't think it's worth it - Would be wiser to just purchase some diol and do your own NMR in heavy water!