Follow up for the cluster 6 fragment hits for MurE Ligase

[drc007]

This cluster contains two similar fragments, and they bind at a point very close to the substrate binding site.

Details of the fragment screen results

[drc007]

You can now view these fragments using NGLviewer

I've also recorded a very quick intro movie here

[fidiris]

I've been thinking about potential analogues I can make of fragments 198 and 114.

I'm hoping to use a nucleophilic substitution approach employing a number of commercially available amines and amides with benzyl bromides/chlorides (Route 1). The aim will be to make various analogues with different amine and aromatic tethers, to establish the importance of these motifs. This will likely give us an idea of whether structural changes to the thiomorpholine core is tolerated. I've listed a few examples of heterocyclic motifs that I can incorporate into the structures. This is not an extensive list and I will continuously look for building blocks I can either buy or make fairly easily. I would also like to start to investigate different linkers (Route 2). I hope to make the corresponding sulfone, sulfoxide, amine and amide containing compounds. If we find that amines other than the thiomorpholine 1,1-dioxide are well tolerated, I can make several other analogues such as sulfoximines. In terms of growing the fragments, we can think about incorporating analogues that contain functional groups that can allow for coupling reactions in subsequent steps (i.e. aryl halides).

[drc007]

Reaction with thiomorpholine would also allow you to make the sulphoxide via oxidation of the sulphur.
How about piperidin‐4‐ol, could oxidise to carbonyl also, then react to form oximes etc.

[fidiris]

Yes, I’m hoping to make the sulfoxide by oxidising thiomorpholine with 1 equivalent of m-CPBA initially. I should have included that in the scheme!

I can definitely incorporate piperidin-4-ol into the scaffolds too. We have the amine in the lab. You’re correct, it would allow me to quickly diversify the carbonyl.

[fidiris]

Below is a summary of the compounds included in the 2/12/2019 shipment (#12). The key structural modifications are highlighted. Looking forward to getting some data back on these!

[danaklug]

Closing - a link has been installed on the relevant wiki page