My next set of compounds

[edwintse]

The next set of compounds that I'm working to synthesise are as follows:

• It was previously found that the mono-Me amine was inactive compared to the free amine and the di-Me amine. To further investigate any trends in this, the EtMe amine and the di-Et amine will be made.

• To see how the solubility compares with the related OH compounds the ketone and the hydroxylamine will be made.

• For investigation into hERG related issues the carboxylic acid and the boronic acid will be made.

• Replacement of the OCHF2 group with NO2 was suggested in issue #480 (this compound is lower on the to-do list at the moment)

Strings

EtMe amine FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(N(C)CC)C4=CC(F)=C(F)C=C4)N32 InChI=1S/C23H21F4N5O2/c1-3-31(2)19(15-6-9-17(24)18(25)10-15)13-33-21-12-28-11-20-29-30-22(32(20)21)14-4-7-16(8-5-14)34-23(26)27/h4-12,19,23H,3,13H2,1-2H3 XPBTWBXREHLVRP-UHFFFAOYSA-N di-Et amine FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(N(CC)CC)C4=CC(F)=C(F)C=C4)N32 InChI=1S/C24H23F4N5O2/c1-3-32(4-2)20(16-7-10-18(25)19(26)11-16)14-34-22-13-29-12-21-30-31-23(33(21)22)15-5-8-17(9-6-15)35-24(27)28/h5-13,20,24H,3-4,14H2,1-2H3 FFKUJTSUMDVIQH-UHFFFAOYSA-N ketone FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC(F)=C(F)C=C4)=O)N32 InChI=1S/C20H12F4N4O3/c21-14-6-3-12(7-15(14)22)16(29)10-30-18-9-25-8-17-26-27-19(28(17)18)11-1-4-13(5-2-11)31-20(23)24/h1-9,20H,10H2 OPCIMEMUOABUMK-UHFFFAOYSA-N hydroxylamine FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC/C(C4=CC(F)=C(F)C=C4)=N/O)N32 InChI=1S/C20H13F4N5O3/c21-14-6-3-12(7-15(14)22)16(28-30)10-31-18-9-25-8-17-26-27-19(29(17)18)11-1-4-13(5-2-11)32-20(23)24/h1-9,20,30H,10H2/b28-16- YQUNTGXTFALRIH-NTFVMDSBSA-N carboxylic acid FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C(O)=O)C4=CC(F)=C(F)C=C4)N32 InChI=1S/C21H14F4N4O4/c22-15-6-3-12(7-16(15)23)14(20(30)31)10-32-18-9-26-8-17-27-28-19(29(17)18)11-1-4-13(5-2-11)33-21(24)25/h1-9,14,21H,10H2,(H,30,31) VTEIUQIAQALMDK-UHFFFAOYSA-N boronic acid FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(B(O)O)C4=CC(F)=C(F)C=C4)N32 InChI=1S/C20H15BF4N4O4/c22-15-6-3-12(7-16(15)23)14(21(30)31)10-32-18-9-26-8-17-27-28-19(29(17)18)11-1-4-13(5-2-11)33-20(24)25/h1-9,14,20,30-31H,10H2 OFZNYZMZJNDDAG-UHFFFAOYSA-N nitro FC(C=C1)=C(F)C=C1CCOC2=CN=CC3=NN=C(C4=CC=C(N+=O)C=C4)N32 InChI=1S/C19H13F2N5O3/c20-15-6-1-12(9-16(15)21)7-8-29-18-11-22-10-17-23-24-19(25(17)18)13-2-4-14(5-3-13)26(27)28/h1-6,9-11H,7-8H2 ANXKNNLWLQBISN-UHFFFAOYSA-N

[MFernflower]

Great stuff. Wondering if sulfonic acid might be good to add to acid series? @edwintse

[edwintse]

@MFernflower I was just thinking about that yesterday :) It appears that there are some drugs out there that contain this group but our worry is that it'll be much too acidic so we'll hold off on this one.

[MFernflower]

Tetrazole perhaps? @edwintse

Edit: That seems like a horrible idea now that I think of it

[MedChemProf]

@edwintse @mattodd I may have not not searched hard enough, but does the OSM have a site that will text new compounds for antimalarial activity for us? My contact at the Broad Institute is not contacting me back, so I do not have a location to has our new compounds tested. We have finally had some luck with some of our back-logged compounds. Update soon to follow. Thanks.

[MFernflower]

@edwintse regarding the nitro idea - it might be better to couple P-Fluorophenethyl alcohol instead of the di-f alcohol

[mattodd]

Hi @MedChemProf - sure we can ask MMV to include them in OSM's testing at Dundee. Hopefully OK. How many compounds are you thinking, and are you OK to Fedex them there?

[mattodd]

I've a general question about this issue of acidity. Perhaps the fear of the sulfonic acid being "too acidic" is misplaced, given that under any normal biologically-relevant conditions a drug containing such a group would be encountered as the neutral salt or a zwitterion. Is there another reason why we don't often see sulfonic acids (i.e. as anions/salts) in pharmaceuticals? Is it because of a tendency to form toxic byproducts either during synthesis or in vivo? Same question for boronic acids (e.g. forming unwanted byproducts) though there is more precedence there (Bortezomib).

[MedChemProf]

Thank you @mattodd We will have two (2) compounds to be tested by the end of the week. They are the reversed amides that we have been struggling to make. We are planning two additional compounds for the sole purpose of being able to do a matched pair analysis with compounds already tested by the OSM. We will have the additional two in about a month. I have been swamped, but I plan on providing a detailed update to the group within the next week. I will also update the OSM compound tracker at the same time. I will continue to try and get through to the Broad in the interim. Finally, sending the compounds via FEDEX is not a problem. I will just need to figure out which customs forms are required for research samples.

[MFernflower]

@mattodd @edwintse perhaps the sodium salt of the sulfonic acid could be made? I'm scared boronic will give PAINS

Edit: I second the idea of the sulfonic acid... It should not be too bad when buffered in solution

[MFernflower]

@edwintse https://www.alfa.com/en/catalog/H35736/ Another possible replacement for OCF2?

[mattodd]

Yes @edwintse we should consider SF5, I think, as @MFernflower suggests. Someone will have a better memory than me on this but I saw this motif in a drug/drug candidate recently, and have seen it in many screening campaigns recently.

[MFernflower]

@mattodd @edwintse I've also seen it in quite a few papers - SF5 is said to be a good drop in for CF3/OCHF2 but only way to find out is to bite the bullet and try it - just like we did with the cubanes - I'd also be curious about TMS as a replacement for the 4-OCHF2 - LogP gets a bit heavy with some of these however!!!

[MFernflower]

@edwintse @mattodd Did some price checking : 4-(Trimethylsilyl)benzaldehyde can be got for about 44 USD a gram and 4-SF5 benzaldehyde for less than 80 USD

[MFernflower]

@mattodd @edwintse I'm also curious about compounds that have been conformationally locked:

Predicted EC50 (using Vito's program) = 0.69 micromolar Datawarrior Predicted LogP = 4.16 (Could remove some F atoms to reduce this) SMILES = FC(F)OC1=CC=C(C=C1)C1=NN=C2C=NC=C(OCC3(CCCC3)C3=CC(F)=C(F)C=C3)N12

[MFernflower]

@edwintse I wonder if you can deprotect and oxidize EGT 197 in the same step... H2O2 and HCL in DCM perhaps?