UCL-UNC CNP4 Meetings Jan 2022 Notes

[mattodd]

1) First list of suggested compounds from @kipUNC :

• [x] @TomkUCL will post. Not possible to triage the molecules further since they all met the design criteria. We could of course alter the deign criteria, iteratively.

2) To triage by similarity, you have to decide what you mean by similarity. Tanimoto? It's something we definitely want to do in order to identify any key structural motifs that we want to pursue. We'd like to arrange the suggestions in a similarity map and check for any dominating substructures that we should prioritise.

• [ ] @edwintse to try out Datawarrior and post

3) Initial Joseph Newman data

• [x] @edwintse to post

Mat will chat to Joe Thurs to establish:

• How he does the solubilisation?

• What do we deduce from these results?

• Shall we include the original frags in screens? i.e. are they a meaningful control?

• [ ] @TomkUCL to check whether we have more of the synthesised compounds for Masoud's ATPase assay?

Do we Include original frags in the shipment to Masoud also?

John Diffley at the Crick has an alternative FRET-based helicase assay. Mat has mailed him to assess interest in screening. Will be sending ca 300 Enamine compounds to Masoud, 100 for each site. Could also ship to Diffley.

4) Merged cyclic compound? Design not looking too fantastic. We need the new synthetic ideas docked in, and we can discuss next week. More at #12 @jemimahaque are you able to send over the nicest 5-10 SMILES?

[TomkUCL]

@mattodd Here are the updated slides on progress so far from last week's update meeting. Current work is focused on developing a short sequence / high yield and generalized method for making 2,5-dialkyl pyrrole amides. This would hopefully allow us to generate a small library of novel small molecules that resemble the 3rd fragment derived from Heba's initial pharmacophore (See slides).

The oxalyl chloride acylation (slide 15, R = H), Fenton reaction (slide 17, R = H), and Pd-catalysed alkylation (slide 18, R = H) have all been attempted this week. The first reaction looks to have given us 390 mg (18%) of the ketoacid, with scope to optimise the yield through the workup. I'm currently interpreting data for the second and third reactions to determine if they have worked.

Update 19.01.2022.pptx

[mattodd]

• [ ] @mattodd to reach out to Masoud to check whether a parallel biophysical assay is being developed for binding (e.g. SPR) though one would expect to need micromolar binding to see anything
• [ ] What are the fragments that are most similar to the original hits that can be bought? We could buy and try. Someone want to pick each hit and see what we can buy, where the Tanimoto is >90% and the molecular weight is between 20 and 60 heavier than the original hits? @H-agha @jemimahaque @TomkUCL @edwintse ?

[mattodd]

@TomkUCL Good job posting the presentation. Slide 17. Functionalise one side (R group) then functionalise the other side with alpha-halo ester/acid. Then direct amidation in the ball mill. Actually slide 18. Got to be a winner?

[TomkUCL]

@mattodd It's missing that extra CH2 we wanted between the pyrrole and carbonyl. I believe I've made the alkyl pyrrole ester (minus CH2), just waiting on MS and to rerun 13C NMR - https://uk-mynotebook.labarchives.com/share/Thomas%2520Knight/MjQuN3wxMDQ0MS8xOS9UcmVlTm9kZS8xOTUxMDg0Mjk1fDYyLjY5OTk5OTk5OTk5OTk5Ng==

Also managed to get the oxoacid in decent yield, again awaiting HRMS on this. https://uk-mynotebook.labarchives.com/share/Thomas%2520Knight/MjMuNDAwMDAwMDAwMDAwMDAyfDEwNDQxLzE4L1RyZWVOb2RlLzEyMTYwNDQyMzF8NTkuNA==

Based on those prelim experiments, I think the best option might be the route on slide 15... but that's a 6-step synthesis for a novel product, so it depends if we want to dedicate that much time to just get the extra CH2 at this stage? Otherwise, we can probably get to the amide in 2 (if ball milling works) or 3 steps without the CH2 there as shown on slide 18.

I think the best plan is to go for the shorter route first, then spend time on the longer synthesis if the other side of the molecule shows good binding in soaking. What do you think?