Open Source Antibiotics Series 2, 30 Oct 2020

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From YouTube: Open Source Antibiotics Science Update Oct 30 2020

Description

Weekly open project meeting for Open Source Antibiotics Series 2.
Full Project: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles
Relevant GitHub Issue: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/issues/37
On the call: Dr Dana Klug, Dr Edwin Tse (University College London), Dr Chris Swain (Cambridge MedChem Consulting), Anthony Sama, Lori Ferrins (Northeastern University).

A

Okay hi: this is open source antibiotics series, 2 meeting on october, 30th um I'll just go ahead and share my screen with the agenda on it. Can you guys see that.

B

A

Okay cool, um so I guess the first thing is just jump into the new data that we have, um which is posted in issue number 35.

A

I think I have pulled up somewhere.

A

Right so this included some of the dndi compounds, um as well as some of the ones that ed.

B

A

Made so I think it can um yeah, so I guess the question now is based on this. What should we targeting next um so.

A

Does anybody want to jump in or.

C

So we have um some compounds with so where you've got that endocyclic. Sorry exocyclic, nitrogen, the nh. We have some compounds. I have to check to see if they would be exact matches back to like with the coarse scaffold substitution pattern um yeah, we would have potentially some where we've actually alkylated that nitrogen or replaced it with an ether.

A

Cool yeah, I think those would be worth screening, especially since, given the eight three nine and eight five one are active, yeah.

C

um Yeah cool, so I can. I can double check what we have on campus.

C

I have the like the benzylic with the the extra ch2, but this.

D

C

Yeah we we've got a lot now with the sort of four fluorophenyl at the top. Okay.

E

F

Or fluorophenyl should probably be okay, uh you need something in the power position. On top, it seems.

C

Yeah yeah, so I I let me double check exactly what we have, because we've also um quillen who's been uh working. The project um has taken off um antonio's synthesis and so they've made a bit of a library now an alcohol type okay. So we can check for those.

A

um That would be really good.

F

I have a small powerpoint of a different couple compounds. I spit ball, just wouldn't be wouldn't mind, hearing everyone's opinions on them, cool.

D

F

Go for it! Let me just get that loaded. You use open office, so it's a little.

A

F

Compared to microsoft, powerpoint, that's.

D

F

You should see open office and press open up yeah there. It is.

F

So let me all right: you can see all this yeah yeah yeah, so obviously the first thing we were looking at was: we need something in the power position. It seems a little lipophilic is better. Now, that's not great for metabolism, of course, as we all know, because most likely to achieve you know it's going to probably get shredded first pass, but I was interested in particular in the one with the the dndi type core, with the paratolo substitution.

F

uh Another one was another out these and alkylated ones which use this. This other dnd provided core.

F

um Obviously you'd have to go through the bromide, because methylphenolyzocyanate is basically very volatile and uh you have to go through those cores, but I'm not sure if any of these peak anyone's interest. Obviously a couple of these are very easy substitutions.

F

You know basic style stuff that you'd see in every early drug design program.

A

Yeah, so I think um matt also was interested in that dndi core with the the tolerable substituent. So I can the.

F

A

Yeah should be easy to make. um I also have, or.

B

Well, is it worth checking that that um dnd I haven't got that compound.

A

Yeah we could um reach out to ben and see if they have made that.

F

Yeah, that's not a bad idea, um there's also these two, which are dndi derived again. I think the dndi core is quite interesting because uh it seems to be easier to synthesize if I'm not mistaken than the the one with the smaller ring.

C

uh It's a one part reaction that we do to make to make, but this.

F

One you can't, because the uh eisenhower trial was unstable.

C

uh So, oh, we can still make the isocyanides um yeah it. It stinks, can confirm not great, um but no we we can still. um We can still do them, um quillen, actually uh just distills off the isocyanide and so keeps it all in the fume hood and that actually.

F

Yeah because uh doing a literature search seemed to result in a lot of uh but yeah this should just be. I mean this shouldn't be too hard. You know.

A

Yeah I've ordered the starting material to see if we can make that core through our current youth roots, which.

G

A

So we'll see how that chemistry goes, I'm planning to give that a go.

C

Dana uh antonio, our former grad visiting grad student, actually did make the call it's following a similar prep to you, so I can actually show you.

A

Oh cool, he climbed instead of berminated.

C

But I would imagine.

A

Yeah yeah, I don't think.

F

Should be too, I mean this is very, very well hammered home chemistry in terms of uh another thing I had was this, which was to play around with the. If it was the way metal binding did you know, but it's still going to bind in between those two nitrogens, but it might be worth a shot if it is metal binding. I'm not sure, and this was an attempt to increase water solubility.

F

So this boronic acid is available and it's cheap.

A

F

uh So that was all I came up with.

B

The compounds with the the the benzo ring: um why have the methoxy there? Do you think it's essential?

B

F

A

um Yeah so there's a matched pair in the dndi compounds where you've got them with and without the methoxy on the core and the methoxy does add potency.

B

There's also, the methyl group seems to do similar yeah.

H

C

So one thing that I, I would say with the methoxy at that position, what we have found in terms of um so obviously we're looking at a completely different indication in terms of ntds, but looking at the host cell talks um when you're substituting that seven position, we do have more toxicity across some of the cell lines than we do.

C

If you have the substitution at the sixth position, so moving it, okay up one as drawn yeah, um so it might also be so we ten we have now kind of moved a little bit more away from that seven methoxy to the six. um But again I I can also have a look and see if we've got any of those. Although it's kind of introducing a second variable.

B

C

B

Did you ever make the compounds with the chloro there.

C

uh Off in place of the methoxy.

D

C

uh I would have to double check if we did anything, it probably would have been the fluoro um yeah.

F

Stable, I was, I was wondering- maybe cf3 in that position, but that's going to require a lot of finicking to get that assembled. Isn't it.

B

Yeah the problem is cf3 is quite lipophilic as well and we're quite a way up on yeah scale. Already yeah. I figured as much.

A

So I also bought the starting material to put a chloro in that position, so I'll give that.

B

A

And go and see how it how it, how it is.

C

um I was wondering, um have you tried substituting the imidazole or the parasol with anything other than a methyl.

A

C

Wait where the green part of the compounds that are on your side.

A

No, the bottom.

A

C

um So I guess one of the things that I'm also wondering is whether you could substitute with uh some sort of, and they might know where I'm going with this already um saturated cycle like a thp or pyridine, we.

F

Have a morphaline compound that was inactive, it was morphaline on the bottom. I don't know, we've not tried, we've not.

A

Tried we haven't done any substituted pyradils at the south west portion of the compound.

C

Not peridol, I'm thinking like off of the purisol or the imidazole nh. Instead of the methyl switch it out for like something a bit bigger, you could even do something small like the cyclopropyl initially or the um and then kind of work your way out, but it might give you the ability to bring in something like. If you did the pyridine, you would have the nh out there.

A

I think so yeah yeah so you're talking about the core, then yes, the green pot right. So we've only made bicyclic cores at this to up to now right yeah I've been trying to make the unsubstituted. The chemistry has not been amazing.

F

I wonder if there's any reports of a tricyclic core of that size.

C

You mean like a cabazole.

C

Is that what you mean by tricyclic.

F

I was all, maybe something I don't know we could try playing with the or putting another ring on the edge of the core.

C

Yeah, that's where I was going with that my comment, but okay.

A

C

And do a try like if you try and fuse those rings together, you're going to then be very flat. Yeah very insoluble would be my guess. That's.

B

Right yeah, I'm not sure, that's the direction you'd want to go. Actually I mean, I think, if you wanted to put another ring on, you could perhaps annulate it with something like, as you say, a piperadine or a morphaline, or something like this, but something that has a heteroatom in.

A

A

Cool, um yes, okay, uh I think so. I think what I've ordered some chemicals to make. Essentially some of the compounds that we've already discussed um some of the ones that are really more closely structurally related to ones that we've already made and then we'll just have to work out synthesis because to do some of these more modified cores, I think yeah, cool, okay.

A

um I guess we will move on to the next stuff on the agenda and then obviously we can obviously keep this discussion going on that github issue um talks assays, they will be done um so alex. The postdoc is just checking on her cell line, but hopefully early next week, we'll be able to get the tax essays going. um We've picked eight compounds, that's github, issue number three!

A

um So if anybody has strong opinions about that, just go check us look and then you know: if we need to change it, we can change it, but I think the ones we have now are a good first step.

A

um Okay, ed, do you want to do the chemistry update.

A

G

um uh Yeah mine's just pretty quick, uh so I've gotten those three compounds on the bottom um that I was working on, uh so they should be good for the next round of assays.

A

Okay, mine's quick too, so the top two um I've been trying to purify this particularly 147. I've already done two columns on, but I do have enough material to try and purify it again. So hopefully I'll get some clean material out of that um 151. I've just done the bhakti protection with tsa and it does look to be cleaner that I haven't done any purification on yet so I just need to do that um and then this is the procedure that I've used, which I think there's a chance that it has worked.

A

um Sorry that should be a trial group, not a methyl group on the imidazole. um They don't ionize. Well, so I can't really tell by lcms, but by nmr it does look like. I got the boronic acid, so I did the suzuki and I just have to see if I can isolate the product.

A

So hopefully this will work.

A

uh And then that should give us, you know a bit more of an idea of the sar around the core again.

B

So you've got a tritone on the nitrogen.

A

B

Yeah you're, it's nearly all protecting group, then really isn't it. Yes,.

A

Yeah yeah, and just a hydrocarbon too so yeah.

B

Yeah that sounds hard hard work.

D

B

A

So fingers crossed for that. um Okay, I think most of the rest of the stuff on the agenda is on matte. So I'll just go back to this very quickly.

B

A

B

Assign him a few more things to do.

A

The units- I don't, I think we sort of resolved that last time right and he had more reading to do um ed- will make a video at some point uh newsletter. We have sent out- um and I don't know if matt's gotten any responses to that, but um hopefully there's some interest in that.

A

And yeah, oh mechanism of action, so we actually should check in on this um soon. I'll. Just do that! Put that on myself and I'll email lee, because I think it was around nowish that he said they would expect results and we're still waiting on haifa and gsk.

A

Cool okay: um if nobody has anything else, then I will.

B

The only other thing I was thinking was that you know these structures are quite simple and people may have them on their sample collections.

B

Should we try and do a sort of crowd sourcing to see if we can get anybody else to contribute.

A

B

And how would we do that if we did do it.

A

A

So I think for the mur ligase project we did try to put out a call basically via twitter um and didn't get too much of a response. So I don't know if that's the best way to do it.

A

Yeah um yeah, I guess unless.

F

We do the manual search and email campaign, but that's.

A

B

Right, I mean, I think it would be a a good topic to put in your next email.

A

B

But it would be nice if we had a landing page that you could just point to. If you came across anybody who was working in similar sort of compounds or might have them that we could just point them out.

A

A

Yeah, I think that that's a good idea.

A

um I mean, I guess we could kind of do that through github would probably be the easiest way to sort of fold it in.

A

Okay, um yep anybody have any other outstanding business.

A

Okay, I think we probably can leave it there, then um and lori. If you just want to be in touch with me um about whatever compounds you guys might have yeah, I'm also sending.

C

You now the um aromatic core that we that antonio made and.

A

Okay, I'll just upload that to github, so it's available.

F

Yeah, uh what was the original indication for dndi to explore these.

C

uh We're looking at it for shockers unleashed.

F

It was for shotguns, okay, was there ever animal way done on? Was there ever an moa study done on tripana somewhere.

C

Not that I'm aware of now, okay.

A

Okay, all right cool and then, if anybody has any other, you know lingering thoughts about what to make next. That, obviously can go on github, and then we can also talk about it. Next week's meeting.

F

Into a powerpoint.

A

Okay, cool thanks guys. I will see you next week.

B

All right thanks very much.

A

E