Project Update

27 Nov
Published by Alice Williamson
Where is the project up to?

We've been busy working on the synthesis of the ten 'final' aryl pyrrole compounds chosen after the consultation in July. 

This post is a brief summary of the current project status to let people know what has been achieved and which compounds still need to be conquered.


So here we go:

SA: Matin has synthesised this compound (OSM-S-68), which was found to be inactive.

SB: Paul was pretty sure that he had made this compound but didn't manage to get a clean spectra owing to its incredibly low solubility. Murray has also taken on the synthesis and now has 11 mg of what should be this compound. We have doubts about gaining biological data for this compound as it even crashes out of DMSO and water.

SC: A structurally similar tetiary amide (OSM-S-59), where R = H, was found to be inactive. Therefore, this compound was placed on hold. Matin is attempting to synthesise a related ester at the moment, and we are optimistic that he will have made this compound by the end of the week as well as some bonus intermediate compounds for testing.

SD: This ether is still proving evasive. I have tried a number of alkylations in addition to Paul's attempts but with no joy. I have since been trying out some reductions using an indium tribromide/triethylsilane system. The crude 1H NMR looks like the ester has formed (albeit in <5% yield) and an LCMS trace supports this conclusion. Flash chromatography has not enabled isolation of this compound, so next I am going to try prep. HPLC. If anyone wants to have a go at this compound, that would be splendid.

SE: Matin has been trying to make this compound. He found a nifty method for the synthesis of the sulfonate using sulfur trioxide pyridine. However, the chlorination step required for the synthesis of SE is proving to be problematic. He also tried to use chlorosulfonic acid to make the intermediate required for synthesis of the desired sulfonamide. These methods aren't working so well, so please feel free to lend some suggestions.

SF: I am currently targeting two oxadiazoles and experiencing some unexpected difficulties along the way. The cyclisation methods attempted for the 1,3,4-oxadiazole have not been successful and the 1,2,4-oxadiazole is also not playing ball. I will write a separate post on these compounds when I have tried a few more attempts.

SG: Matthew managed to get to the ester of this compound and then passed the baton to Murray who completed the synthesis of OSM-S-105. This compound has been submitted for biological testing.

SH: I have synthesised a few of these compounds now and submitted two for biological testing. OSM-S-95 showed moderate to good activity and so we are intrigued to find out how some of the other molecules synthesised will perform. The problem with these compounds is that they are very polar and so purification is tricky once more than one nitrogen is introduced into the appended ring. Prep HPLC may be necessary for these compounds.

SI: Sanjay Batra posted a route to this compound, which he and his group are ready to tackle. The team have also been thinking about some other fused ring structures that could be interesting.

SJ: Paul made this pyrazole (OSM-S-92), which was found to be inactive.

The molecules are nearly there but the team are having particular problems with SD, SE and SF. If you are a chemist who is willing to tackle one or more of these molecules please contact OSDDMalaria, come and join the team.


MatTodd's picture

There are some definite things that people can quickly help with here. It should be stated that we can send people starting materials if that speeds things up. Also, for compound SI, we were toying with the idea of a different heterocycle, right? What about that triazole idea? Could be quick for someone. i.e. FC1=CC=C(N2C=C(COCC(N)=O)N=N2)C=C1

m.robertson's picture

I think the basic pyrole would be useful too but I've just had a quick look and I think it might involve a few more steps to get there.  I'm basing this on the fact that all the pyrazole were inactive.  The methyl groups could be helping the activity or maybe the pyrazole ring just isn't tollerated. 
R = H - InChI=1S/C13H12N2O3/c14-12(16)9-18-13(17)10-6-7-15(8-10)11-4-2-1-3-5-11/h1-8H,9H2,(H2,14,16)
R = F - InChI=1S/C13H11FN2O3/c14-10-1-3-11(4-2-10)16-6-5-9(7-16)13(18)19-8-12(15)17/h1-7H,8H2,(H2,15,17)
R = CF3 - InChI=1S/C14H11F3N2O3/c15-14(16,17)10-1-3-11(4-2-10)19-6-5-9(7-19)13(21)22-8-12(18)20/h1-7H,8H2,(H2,18,20)

Are these analogues of interest ?  They are coming in at Tanimoto ~ 0.85 and have vendors

MatTodd's picture simple are they? We could make them, but if they are $80 for 5 mg, then we'd have to be able to make them in, what, 1.5 hours to make it economical? Murray, Alice - what do you think? Purchase, if one of you makes the triazole to go with them?

This may be in  past discussions and results somewhere but how far was the SAR space  "walked" round the the most potent lead, OSM-3-39  =  ZHY7 =  CID 57515664   (not OSM-38 as in first post) ?

Did anyone try isosteres for those trifluoromethyls on the phenyl  (e.g. Cl or Br)  and still stay low nM ?
There is a substancial cluster of 67 analogues in the pre-computed similar compounds (90% tanimoto) but none have those TFs
A few of these were ordered I seem to remember - did they get tested ?
While doing some clustering of the GSK hits in PubChem  I came across what I think is the only other TF substructure among the actives as CID 5081913 = TCMDC-125465
Interestingly,  this is a human kinase inhibitor that has suppliers.  As ever,  this could be a red herring  but maybe worth checking some time.  

Alice Williamson's picture

Yes, we should order these, thanks Christopher, will try and find out prices.

Alice Williamson's picture

We can order the two compounds for 234 (US$), they are from separate suppliers and so the postage costs as much as the compounds. Should we have a think about other molecules we might want to order alongside?

I could tinker with this, since it seems at the moment that my time/resources are very limited. If I'm reading the context right, it would be a low-priority punt on something interesting and it looks reasonably simple - azido-aromatic, propargyl alcohol and 2-hydroxyacetamide give or take some protecting groups? I'd also be able to cut my teeth on the blogging side of things etc.

MatTodd's picture

That's right - it's a "well, why not" shot. The S/Ms are simple and the chemistry should be fine. Would be great if you wanted to take a pop at it. See my comment below about the lab book though - important to share the data.

Note that anything you make in the UK can be screened for activity there/in Europe vs. controls - no need to mail to Aus...

JimCronshaw's picture

I think this has been discussed previously. For Matin's compound, is there a way to get a sulfur (II) on the pyrrole? I tried doing a SciFinder search before and couldn't find much. If there was a method though, and you managed to get a substituent on that sulfur which forms a stable carbocation (eg benzyl), you could perform an oxidative chlorination and couple the product. The sulfonyl chloride product was - for me - easily isolated by vaccing off the residual water and acetic acid.

I've dropped Matin a comment as the sulfonamides look interesting: We're playing with chlorosulfonation here in Edinburgh. Given that I'm about 12,000 miles away I'll just make some of the fluoroaryl-pyrrole SM myself this weekend.

MatTodd's picture

That'd be great. Happy to use the online lab notebook to record your data? Even repeats of reactions are useful, but certainly when you get to new/trial things. You could use Matin's, or start your own. Any of the team can help with that. The chlorosulfation seems to be going, but since we don't isolate the intermediate, or at least characterise it properly, it's not clear what's going wrong.