Project Launch. 1. Which Other Epichem Compounds to Screen?

[mattodd]

As described in the preprint of the paper at project launch, there exists a large library of relevant analogs at Epichem, in Perth (Western Australia). A subset (about 5%) of these compounds were evaluated for the paper. Based on the data available (in the paper, in the Master sheet and shown graphically below), the question is: Of the remaining compounds in the Epichem library (contained in a sheet in the Master List, which compounds (if any) should be evaluated next?

Ideal situation: we identify 20 compounds with promising characteristics (potentially active based on data obtained so far, good pharmacokinetic properties) and these are shipped to Wendy van de Sande's lab in Rotterdam. Notice that in the paper, it appears we need to keep the logD low, to promote in vivo efficacy. This should be a design criterion.

Chemdraw of Epichem compounds evaluated: Structures of all Fenarimols copy.zip

[MFernflower]

@mattodd @drc007 I'd be curious to see what happens if you try to stick an OAc in place of the central carbon alcohol

[mattodd]

Sure, but the interesting thing for me is that the central OH (a hydrogen bond donor) is not needed. Again, on the assumption that in situ the methyl ether is not converted to the parent alcohol because of the thermodynamic stability of the triply Ar-substituted carbocation. A central OAc would be more likely to undergo conversion to the OH either through that mechanism or through hydrolysis. Either way, this can be factored into the design.

[MFernflower]

@mattodd I was thinking about altering the electrical characteristics of the och3 group in the center of the molecule - ochf2 springs to mind but I'm pretty certain getting your hands on chf2br is going to be challenging

[bendndi]

Could be a prodrug for the alcohol, of course, depending on how good a leaving group that central OH or OMe is.

@mattodd I'd be quite suprised if that methoxy group came off under assay conditions, so yez this is quite interesting.

ochf2 springs to mind but I'm pretty certain getting your hands on chf2br is going to be challenging

@MFernflower I think this is a better idea that OAc, which may not fall off in the assay but would almost definitely fall off in vivo. The CF2 group is actually quite easy to put on to an alcohol - doesnt require CF2Br... a number of options. Perhaps we add a new section of design ideas around this into the OSN list...

[MFernflower]

Did a 3d render of the OCHF2 molecule:

It adopts an interesting conformation!

chf2_render_3d.zip

SMILES STRING: FC(F)OC(C1=CC=C(Cl)C=C1)(C1=CN=CC=C1)C1=CC=CC=C1Br

@bendndi @mattodd

Also might I have a link to the paper about green difluoromethyl transfer? IIRC it uses TMSCF2Br

[bendndi]

Hi @wwjvdsande I was wondering if we have any update on new data coming through?

I think some new compounds had been sent on from UCL, plus the idea of generating dose response for second batch of EPL-BS1025 and also the HPD20_1

[wwjvdsande]

Hi @bendndi, I updated the list with the compounds from UCL and I added additional MIC data on the last EPIchem batch. We did not do G. mellonella screenings yet due to capacity problems in the lab.

[MFernflower]

@wwjvdsande so of all the new compounds you screened it seems the piperidine one had the best IC50?

@dmitrij176 perhaps the azetidine version is in order?

[MFernflower]

@wwjvdsande I think it's good anyway to do plate assays first so that you can weed out the low potency compounds before wastefully committing them to an insect assay

[wwjvdsande]

@MFernflower currently we can only do plate assays against hyphae. Those were the assays we used for determining the IC50 and the MIC50. However to see if they are potent against grains, the structures present during infection it is currently not possible to do that in vitro unfortunately. That's where we need the larvae assay. The grains simply won't form in vitro. We are trying to develop such an assay but so far we did not succeed.

[wwjvdsande]

Any suggestions for further in vitro screenings are welcome.

[drc007]

Any suggestions for further in vitro screenings are welcome.

Do you mean samples or targets?

[wwjvdsande]

Both I guess. If you think there a other assays we could add that would be good, but other molecules are also fine. The new fenarimol analogues tested appear not to be toxic for our larvae.

[MFernflower]

I think I mentioned this once before but I'm very curious as to what Paclobutrazol will do to the fungus @wwjvdsande

It's sort of an open frame analogue of the molecules we are testing

[wwjvdsande]

Sorry, I m not a chemist can you explain what you mean with open frame analogue? And its relation to the fenarimols. I noted that the compound is available at sigma and not too expensive.

[MFernflower]

Open frame in this case means that the molecule looks a bit like the fenarimol parent molecule itself but minus one ring and having the pyridine swapped for triazole

@wwjvdsande

[wwjvdsande]

Would you than expect it to have the same target in case it inhibits?

[MFernflower]

@wwjvdsande I'd say with confidence that it will hit CYP51 but might bind at a slightly different site within the enzyme!