Open Source Antibiotics Series 2, 15 Oct 2021

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From YouTube: Open Source Antibiotics Science Update Oct 15th 2021

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/96
On the call: Professor Matthew Todd, Dr Dana Klug, Dr Edwin Tse (UCL), Dr Daniel Gedder (University of Sao Paulo), Dr Lori Ferrins, Dr Quillon Simpson, Thomas Kresina (NEU), Anthony Sama (Citizen Scientist), Dr Chris Swain (Cambridge Medchem Consulting).

A

Okay, welcome everyone. It is um 15th of october and we, um if I go behind the window, it's the usual thing. Hang on man. um Let me get the right thing here. Sorry, I've got the wrong thing being shared, so uh open source, nbx series, 2 um and the video is posted. There was. I was just looking again at the video, the last meeting um and there was one person on the video and I didn't know their name um had a mask on.

A

I think it's maybe northeastern person had a mask on blonde hair, say again, thomas. Is it.

B

It was a guy with blonde hair.

A

B

Yeah, thomas and how.

A

Do you spell it uh I'll pop it in the chat.

A

Okay, um just want to make sure I've met everybody, and so uh we have um some actions that I put up last night, um which we can go through, which may take into account everything. So, as I understand it, dana you've made that high profile high priority total combat already.

C

Yeah, it's all done.

A

Awesome, so that is ready to go, which is really good, um so that can go into the next round which, which you know we've kind of vaguely planned for the end of the month, and I will reach out to paul to check whether he can do that.

A

Just on that before we talk about other compounds. um I raised this issue about the activity ceiling and I guess you know making sure that we were using an assay that was able to detect where the active compounds, if indeed we had really active compounds because we're really hitting that ceiling.

A

And so I just I guess when I talk to paul about his assay, um I need to raise the idea of him using a highly active control, compound positive control, compound which I'm not sure he's currently doing um from what I can tell from the data so something which definitely would be expected to be more active than two micrograms per mil.

A

um I don't know what that should be.

C

Yeah, I'm pretty sure alex has been using vancomycin um as a control in her experiments yeah. I think so. We can confirm with her next week, but I I think she has been using in that um to sort of benchmark her stuff.

C

A

Okay, I mean that would be fine right. I guess I just need to raise that with him, and um I was wondering if anyone remember what the controls were that were used by coad without digging through. I can't remember what they were. We could try and match that, but.

C

That might also be vancomycin, but I'm not 100 sure. I'm.

D

Actually going to look on cohen's site right now, maybe they'll, I think they detail their testing protocol right.

A

C

Yeah, actually, that that would be probably on the um series 2 repository as well, because we had the protocols from them: okay, yeah. We can find that information.

A

Right so justin before we talk about sar halls the if we are going to try and aim for you know another evaluation compounds by the end of the month, then the the aim was really to see if we could secure any incoming compounds from daniel and from quillin and laurie from by the end of the month kind of thing that was kind of like just a target so that we can try and arrange ourselves.

A

um So daniel.

E

A

With with research stuff before, like you know, report writing before, but we were talking about maybe being able to get some of the homologous compounds by the end of the month. Is that still realistic?.

F

uh I'm planning to send to you next month next month next week, uh maybe seven compounds uh I finished one more this week uh the reactions are working out uh and I I guess next week I could ship like seven compounds, uh because I I I could make more compounds, but we should evaluate first if this scaffold is going to work and then, if that works, uh the step that I need to work is just making the inoculation first and then diminish reactions that works.

E

F

I I did I did it this week and worked well. uh I bought few more uh iodine uh compounds, but then you should you should test the the the compounds and then which I could work better there. They are, but I guess next week I would be able to shift at least uh six or seven compounds.

A

Fantastic, I.

F

Can I can show you the scaffolds? Actually I have the scaffolds here. Oh what now yeah can I share them.

D

Yeah, I think that would be useful because I haven't seen what they look like.

F

Okay, just one second.

F

uh It's seven compounds if we count the intermediates, because I don't know if you should test the intermediates or not, uh can you see my screen yep uh here I have like, for example, I start to test the reactions without the pyridine in the imidazole portion. So I have those three compounds without the nitrogen here.

G

F

We have the cf3 group here then I have with the pyridine and we have the inoculated uh manish product here and now I'm working to have uh intermediate with two meteor propane, but I'm trying to calculate the the cf aniline have in the cf3 uh just to have more uh variations in the main scaffolds.

G

F

Would be the next compound having a cf3 in this uh in this? I don't know if you can see, because I'm pointing here with yeah.

C

F

Okay, uh that would be the next compound having a cf3 in the the three position and io and uh meteor propane in the nitrogen, and then I could ship those compounds to you and you could see if that's gonna work or.

A

Not okay, that sounds great yeah. I think the the the compound where your cursor currently is is the is the key one that I guess everyone here would expect to be. The most active and all the others would be leading up to that. So so still worth it absolutely.

H

Okay, can I just check that the the methyl and the benzo ring is in a different place in the diff in the pyridal and the female? Is that correct.

F

Yeah yeah, the nature group is different place. Yeah yeah.

D

Have we tested compounds with those um with methylations on the core?

D

Sorry, I didn't understand, remember.

C

I I think we have a few one-offs from uh northeastern yeah. I think yeah, I don't. uh I don't think they were active, but I think they had. um Maybe they didn't have the two-parental or something they had something I don't know. I would expect that it would be its sign.

F

My concern uh my concern this compound. It would be this michelin group linker here if you have any problem with this activity, maybe this methylene methylene linker doesn't work. Let's see which kind of results you're gonna have.

A

Yeah but I mean that's what we're testing that's exactly.

F

A

A

All right, fantastic uh yeah, those would be really great. So yes, if, if those could be shipped next week, that would um coincide with our essay, which would be really really useful.

F

I will talk to you maybe monday, to get some information, how I can ship which address and if I need to fill up some documents.

A

Yep sure sure, great okay and then um I guess, last time we were talking about um the compounds that you guys had at northeastern, which might be relevant to what you want to do. um That could be shipped because you already have some um and I dumped um some of those and I took sneaky screenshots of your slides quillin. That's all right.

E

No I'm sorry, I.

A

E

I forgot to send those um to github so I'll make sure that's done today.

A

So these are, um I guess, you know, compounds that we were discussing. You were talking about the synthesis progress towards this guy and then compounds like this that were ready for shipment. I mean these would be obviously really great to have a look at if you, uh if you had samples to spare, um did you have any other updates? You wanted to mention about these compounds. You know we were looking at the ced vault last time and you were. We were looking at the the dmap compound where we had the n-dimethyl.

E

Yeah, so I had a look through our stocks um this morning and I've got a little slide prepared for that. um These. These three compounds here are already good to go um and on the slide, two slides above that there was one of the cyclopropyls.

E

That's in the seven position was synthesis synthesized yesterday and purified yesterday, but we don't have any qc on it yet um so the the biotag looks like a good purification, so it should be fine, um so that we'll be able to add that to that those three um that we could send whenever larry thinks it's a good time to send okay, that one's up to larry. um Did you say you had a slide yeah.

A

E

Did um so you know one sec.

B

Sorry matt, when you were talking about before getting compounds tested at the end of the month, are you like? When are you targeting, because it's probably going to take with customs it could take about a week for the compounds to get there? So, oh.

A

Sure I mean end of the month. I was thinking.

B

So if we ship them out like next week.

A

A

So these have a lot. These are all nhs, not alkylated.

E

Yeah, so these are yeah, as you just said, they're all all the nhs is unalkalated, um but there's plenty of stock so that all of these are able to be alkylated if there was any interest in them. um The only exception, obviously, is this acetyl compound, which is good to send. Now, if you're interested in having that sort of a mid component in the molecule as well- um and I guess this one is a match pair- perhaps um so- that you could match that back uh to the compounds daniel's making.

A

E

um But yeah so this whole this whole suite. We have like somewhere between 50, to 100 milligrams of each of these compounds, so there's more.

F

E

Enough to our plate.

E

That's awesome all right and- and I had my hands on them, so there are real amounts in each of these. Okay.

A

um Let's think I mean well, I mean all very useful and interesting um and I I can't really say that any of them I.

D

Have a question about the um one: that's not substituted on the bottom. Could you do a uh like uh eschweiler clark on that and dimethylate it that would knock out one of the compounds in the sar hole table.

D

The unsubstituted amine.

B

E

Yeah, you think you could dimethylate that could just do a reductive emanation with an aldehyde with a ketone.

G

I put some yeah put two output groups on there, because that was one of those star holes. What not with nothing in that position.

D

No, I didn't have two alkyl groups. It was one of those star holes.

C

um Yeah, I think I know what you're talking about. So we have the arrow substituent, then they're, then alkylated, but we don't have anything. That's got a like an alka-pill outcome.

C

So what kind of quality I'm sorry um I mean the closest would be well. I don't know.

E

If you make it symmetrical, it's like pretty straightforward to make.

C

Yeah, it might be interesting to look at, but we also obviously have never tested just the unsubstituted amine.

E

Well that that one I have the most of out of everything, it's.

A

E

It's I I didn't, have a gram amount for you this morning, but it's it's half of an eight mil vial.

D

That would be interesting.

B

I think I think it might be better to keep with the like methyl propane substituent, um but I was just going to ask: were you specifically looking for aromatic head groups, because the other thing is, we do have some aliphatic and we could potentially have a look and see if we put any of those in sufficient quantity to actually alkylate.

E

Yeah, so this is just a set that I went through of my own personal compounds that I had on hand. um I was under the impression that you guys had previously gone through um antonio and hertes compounds where we have those alcohols up. The top.

B

Like we've got things like the the t-butyl, the cyclo pental.

F

B

Yeah, we probably have a whole sweet. um We can certainly have a look and see if there's anything there as well.

E

um Keeping in mind, though, that when you have the like bulky, alkyl groups up the top, they tend to just eliminate out.

E

C

E

That's how you make this compound here is doing the the one pot with the tert-butyl um isocyanide, and then you just treat it with a little bit of acid and that just goes away and you're left with with the hbr salt.

D

Okay, the other possibility is, if dana has the bromide she. She has a brominated intermediate buckwalt heart wave using xanthos and the name by substituted amy like diethylamine, and then.

C

Yes, I thought about that, so I think we requested um the morphaline, so we could make a few more that that one wasn't active um but yeah. That's another.

I

Sort possibility with the methylamine and hardly go.

E

Xanthelas catalyst, so so in my hands I was never able to get the book world to go when you have a bromine in the core. um The reason I synthesized this compound was actually so that I could have the amine on the core and do a book one to make this compound here. um This went in about an hour 95 conversion with the amine on the core, the bromine on the core, doing the same reaction with the opposite partners. Never went I'd, get like a 5 conversion overnight.

E

What catalyst did you use? I mean all of them.

A

Yeah, that's interesting, okay um into I mean yeah. That would be so all these suggestions are very good and it depends on the capacity you've got for doing some of this. These reactions, the um alkylation reaction.

A

I mean, as I was thinking back to something chris said in a previous meeting where, when the methoxy is on the pyridine ring, we increase the basicity of the nitrogen and make the compound potentially more soluble, so some of the ones in the middle layer I mean the one on the right, for example, has the methoxy in the right place to do that nicely, um and so I guess, if we were thinking about alkylating any then it would be something like that where we have a um a strong likelihood of having decent solubility.

A

That would be the if that was going to be a prioritization for me, that would be it so.

E

This this compound here has about an order of magnitude better solubility than all of the others. In fact, both both of these ortho-substituted compounds here, um the the issue is that I've never been able to get the alkylation to go smoothly with these compounds right.

C

I was also going to say those are interesting because that's basically the only modification we've seen to that to peridol. That gives us uh any sort of potency.

E

uh These compounds here with the ortho substitution.

C

That's just substituting off of it.

E

D

Yeah, the substitution of the main core kills potency, but substitution of the periodic functionality is allowed.

A

And so of these querm, which which do you think, would be more straightforward for the alkylation reaction.

E

um I mean, as a general rule, not these auto-substituted compounds as a secondary rule when you start to load both the core and the periodic component up with electron donating functionalities. As you said, the basicity goes up, which means you tend to get a lot more of the byproduct of the pure dial in alkylation.

E

In theory, that should be reversible. So if we left it long enough and gave it enough heat, it should sort of act like dmap we're sort of making a more reactive, alkylating, reagent yeah, but in practice I I haven't been able to get clean conversion for any compound that has a like too much electron donating. So these compounds down here are a bit of a nightmare right, um but it's saying that it's they're all possible. With exception of these two.

D

The methoxy on the core has uh been shown to kill potency, so it would be interesting. uh The past will be um the parameters of the paradigm. That's interesting, because you've only had ortho substituted paradise.

C

No okay, so the um let me just go back to the sar stuff. So I think the issue with the methoxy on the core is a tox issue, not a potency issue um and the substitution on the two pyrital we've had.

C

All right, let me I'm just trying to find it. uh We've had a the paramethoxy, not we haven't looked at the ortho or the meta. Yet this is relative to that ring. Nitrogen.

I

Which I'm reversed in my head? I guess.

B

Yeah, um the meta is actually one of the ones on the whole list, yeah, so that second row, third one in from the left, would be one that we should think about alkylating and actually it does say, h4 methyl. So I mean I don't know if you actually do want to test the h.

C

I think that, well for the sake of completing the sar table, we it doesn't have to be outdated. Now, for the question of whether it's going to be potent against merced, I think we've shown.

E

B

C

Is going to be more potent if it's alkylated yeah.

B

I mean we could probably just take two meats out, though, and then alkylate yeah we could test. We could try both.

A

That would be really good, yeah um and the a might in the bottom in the middle. If, if that's available, I mean I guess it's just that you know an sar hole, we didn't realize we had.

E

It was completely dead for us for memory chomped immediately, um but it did have slightly better solubility.

A

Okay, um an of time could I just suggest that um dana, because you have this series in your head with great freshness, would you be able to correspond with krillin and decide and lori was like and decide on a list of compounds that you think is is best and reasonable. um Yeah.

C

A

Really tremendous yeah, because I think the all of these will be really nice and I just want to make sure we're picking. You know a small number that will cover a bunch of holes and you know we're choosing the compounds that we think are going to be either filling holes or most potent okay. Yes, I could do that fantastic, really, good. Okay! Thank you. That's fantastic!

A

uh We're only a few more minutes and I just wanted to um highlight one thing that you've been doing chris on the machine. The discoverability of the data.

E

A

So you forwarded something to me which I'll share, um which is this guy all right. Do you want to explain what what some happened here.

H

Okay, so I took the uh or wrote a script which extracts all the data from the google uh sheet, that we have and then uses rd kit to create the images of the structures and then outputs that to an html page. So this is just a static page which hopefully, google will index.

H

The question is what information do you want on this page?

H

The question I guess is okay. This allows people to find that these structures exist, but as it stands, it doesn't really help them find out more information about them.

A

Yeah so I mean the the great thing is, of course is because the smiles are there and all the other strings are there, but it can be found on google. So you imagine you put the molecule and you say I wonder if anyone's made this and it takes you to this page and you go that's interesting. Where is it so? You need another link somewhere.

I

A

More information now, of course, with some of these things, we do have that right. We've got the wiki link and that presumably comes from our original spreadsheet yeah. So if we do our original spreadsheet better, then those links will appear there correct.

A

So that's the answer. Isn't it we've got to get our house in order and provide and provide a link such that the interested chemist knows what's going on here?

A

Is there a way of including something so that at the top of this page there is like a little nano readme I mean if we had a cell at the top of our osa sheet with that information with that information come through to here, no.

H

You can't do that because um the the first row has to be the column headers right.

A

Yeah yeah, okay and you can't have entry, zero being read me. uh I could experiment with that. I don't know okay, okay, because I mean that is neat, and that is so.

A

This is where the wizardry thing comes in, because I've actually no idea how you're doing any of this, but is this is something which um happens when you run something but but could be set to be running automatically.

H

That is the plan yeah, so the script is written and at the moment it has to be activated by hand and you're on your computer. It is yes, but I could set it up as described as a cron job, so it happens at regular intervals, say once a week or something like this would run and generate a new file.

A

And then that's posted here and that's obviously hosted on github.

H

Yes, it's actually in the uh ligase wiki or documents folder.

A

Right so that and that will just sit there yeah um if your computer blows up, then it will stop doing that, but it won't change the page.

H

That's correct, yes, I mean the script is relatively straightforward. The only thing is, it relies on rd kit um to to actually generate structures and things, but it works it. Could. The script could sit anywhere.

A

Right right I mean that is, that is a neat solution. um This is already on line right.

H

Yeah, so what I'm hoping and uh is that google also uh index the images, which is why I put them in there? So when people search for a particular string or something that is or identifier right, they may even find google images shows in the structure. Yeah.

A

That's neat, okay, um would you be happy in, I don't know day or something or a week to check whether google is seeing this.

H

Yes, I can do that yeah.

A

That is really a really neat solution. I think um we don't have time to talk about this now, but I guess one of the uh one of the questions we had last time was whether or not the the cdd vault stuff that you guys have at northeastern. If you've got any of that set to public, whether that's indexed by google.

A

uh I haven't had a chance to have a look. Sorry, no worries uh just it's a residual, interesting question for me. You know, I think I I guess the answer is going to be no but it'd be great to try it out.

A

You know so pick something in one of your cd volts that you know is unique to your cd vault and one which is public obviously and see whether or not it can be found.

A

Yeah we'll have a play around today, cool all right, great all right thanks just an interesting time. That's all! That's all I've got time for I'm afraid, but was there anything else anyone wanted to raise quickly, nope.

C

um The admin compounds- I guess we can probably discuss that next week-.

A

Yeah, okay, that's fine yeah! Let's dedicate some time to that next time. Okay, all right! Thanks! So much really great to see everybody take care.