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5) Design set of 5 amines for inclusion in first round of amide synthesis using the now-preferred pathway, with a view to increased predicted solubility. #123

Closed
alintheopen opened this Issue · 10 comments
@alintheopen
Owner

No description provided.

@PatrickThomson
Collaborator

I have nominally selected 2-trifluoromethyl-4-aminopyridine, but I can't remember why.

@mattodd mattodd was assigned
@mattodd
Owner

Well, that's a good choice - it's MMV670944, a potent compound.
I have digested the MMV amide spreadsheet (http://malaria.ourexperiment.org/uri/4ab) and made a figure in the relevant wiki page (http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Pyrazine_side-chain_modifications_-_amides). This makes it much easier to select some candidate amides. It would seem as though chlorines on that ring provide good levels of potency. Shall we see what is available, commercially, that might fit the bill, perhaps with CF3's on the ring and with n=0-2 carbons in the linker? We should be aiming to re-make only one, and propose 5 new compounds. Small (e.g. F/Cl substitutions) are fine, if you look at the sensitivity to substitutions already seen with this set of compounds.

@mattodd
Owner

Inga has now done an analysis of commercial amines related to those already evaluated: http://malaria.ourexperiment.org/osm_logos_and_templ/8578/post.html
Combined with the known set: http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Pyrazine_side-chain_modifications_-_amides
This should now yield a candidate list.
One remaining issue: we should include 1-2 secondary amines too - Inga's search focussed on primary. Perhaps another quick search on those needed. For possible examples, though using expensive amines, see http://malaria.ourexperiment.org/osdd_malaria_shared/8039/post.html

@mattodd
Owner

@IngaTopolnicki has completed an analysis of secondary amines: http://malaria.ourexperiment.org/the_osm_blog/8936
So: can we clarify between us - @alintheopen @tscmacdonald @IngaTopolnicki which amines (primary and secondary) we are:
a) Currently using in synthesis - Tom?
b) Have on order - Alice?
c) Think we need to buy to make up our current list of 5-6? - Everyone?

I'm not sure we have the acyclic secondary (N-Me) amine Inga found yet, is that right? Seems like an excellent one to try. Rather than focus on diversity at this stage we should be looking to explore possible theories of what's important based on what's known from the data so far as shown on the Series 4 wiki for the amide series.

@alintheopen
Owner

Here are the amines that are currently in use or on order:
amines series 4

@mattodd
Owner

Beauty, thanks Alice. An excellent set. These appear to keep the strengths of what is known of the series (Ar with EWG attached) but address whether cyclic/acyclic/N-Me amides are best. Final question for @IngaTopolnicki or @tscmacdonald - can one of you sketch up the final Series 4 compounds that would be made using these amines and check that the cLogP values are sensible? Once this is established, we can close this issue and open up individual issues for each target.

@IngaTopolnicki
Collaborator

I’ll check the cLogP values and upload a table hopefully by the end of today.

@IngaTopolnicki
Collaborator

Okay, here are the cLogP values for the amides to be synthesised. Are the values sensible? @mattodd @alintheopen @tscmacdonald
series four amides clogp values_2
series four amides clogp values

@mattodd
Owner

Nicely done Inga. 5 or below is usually fine. Alice's compound is pushing it, but is by no means outrageous. These are approximate values, so I'd only be looking to an accuracy of 1 d.p., but that's fine. You used Chemdraw to calculate?
Conclusion - looks like we're generally in the clear with this set, so closing the Issue now. For the two that are being made already we need "Being Synthesised Now" Issues set up if they are not already.

@mattodd mattodd closed this
@IngaTopolnicki
Collaborator

Yep, I used Chemdraw.

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