Next batch of samples sent for biological evaulation

[edwintse]

The next batch of compounds from this years work so far (shown below) have now been shipped to Dundee for screening against P. falciparum.

THE RELEVANT POTENCY DATA HAS BEEN RECEIVED AND IS POSTED HERE

• My new compounds: Things that I've been working on so far (My next set of compounds #481, Benzylic amine compounds update #504, Caged Isosteres of Benzene #510)
• Resolved compounds: Key racemic frontrunner compound that was resolved into its two enaniomers by Mark Butler and his team at the University of Queensland (Resolution of a Series 4 Frontrunner #470)
• SSP 2017 compounds: Compounds synthesised in the 1st year undergraduate Special Studies Program at the University of Sydney (Caged Isosteres of Benzene #510, Special Studies Program (SSP) 2017 #514)
• Late stage functionalisation compounds: Key precursor compounds to be used for late stage functionalisation as part of @ConorGraham's honours project at the University of Sydney
• Resynthesised Series 3 compound: Key Series 3 compound resynthesised as part of @mbhebhe's PhD project at the University of Sydney (Potency data for Series 3  #501)

MMV Number	SMILES	InChI	InChI Key
MMV1557931	IC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC(F)=C(F)C=C4)N32	InChI=1S/C19H13F2IN4O/c20-15-6-1-12(9-16(15)21)7-8-27-18-11-23-10-17-24-25-19(26(17)18)13-2-4-14(22)5-3-13/h1-6,9-11H,7-8H2	SYOXDOQMLHMQGB-UHFFFAOYSA-N
MMV1557932	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
MMV1557933	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(OC)(OC)C4=CC(F)=C(F)C=C4)N32	InChI=1S/C22H18F4N4O4/c1-31-22(32-2,14-5-8-16(23)17(24)9-14)12-33-19-11-27-10-18-28-29-20(30(18)19)13-3-6-15(7-4-13)34-21(25)26/h3-11,21H,12H2,1-2H3	HFRRKTROCJVLKP-UHFFFAOYSA-N
MMV1557934	FS(F)(F)(F)(F)C(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32	InChI=1S/C19H15F5N4OS/c20-30(21,22,23,24)16-8-6-15(7-9-16)19-27-26-17-12-25-13-18(28(17)19)29-11-10-14-4-2-1-3-5-14/h1-9,12-13H,10-11H2	PEMORNCGKKXBCP-UHFFFAOYSA-N
MMV1557935	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4(CC5C6)CC6CC@@HC4)N32	InChI=1S/C24H26F2N4O2/c25-23(26)32-19-3-1-18(2-4-19)22-29-28-20-13-27-14-21(30(20)22)31-6-5-24-10-15-7-16(11-24)9-17(8-15)12-24/h1-4,13-17,23H,5-12H2/t15-,16?,17?,24?	BSXLJNOXQMXUOB-CRFYJIHUSA-N
MMV1557936	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC(C)CC4=CC=CC=C4)N32	InChI=1S/C21H18F2N4O2/c1-14(11-15-5-3-2-4-6-15)28-19-13-24-12-18-25-26-20(27(18)19)16-7-9-17(10-8-16)29-21(22)23/h2-10,12-14,21H,11H2,1H3	HJOHTEUEFDSADX-UHFFFAOYSA-N
MMV1557937	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC45CC@@HC[C@@h]6C4)N32	InChI=1S/C23H24F2N4O2/c24-22(25)31-18-3-1-17(2-4-18)21-28-27-19-11-26-12-20(29(19)21)30-13-23-8-14-5-15(9-23)7-16(6-14)10-23/h1-4,11-12,14-16,22H,5-10,13H2/t14-,15+,16-,23?	PIOOGPDPQVQAFQ-QUXYOMGYSA-N
MMV1557938	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4C[C@H]5C=C[C@@h]4C5)N32	InChI=1S/C20H18F2N4O2/c21-20(22)28-16-5-3-13(4-6-16)19-25-24-17-9-23-10-18(26(17)19)27-11-15-8-12-1-2-14(15)7-12/h1-6,9-10,12,14-15,20H,7-8,11H2/t12-,14+,15?/m0/s1	OMOCZBKUEFTIAC-DJIKBVBFSA-N
MMV1557939	CC1(C)[C@@h]2C[C@H]1C(CCOC3=CN=CC4=NN=C(C5=CC=C(OC(F)F)C=C5)N43)=CC2	InChI=1S/C23H24F2N4O2/c1-23(2)16-6-3-14(18(23)11-16)9-10-30-20-13-26-12-19-27-28-21(29(19)20)15-4-7-17(8-5-15)31-22(24)25/h3-5,7-8,12-13,16,18,22H,6,9-11H2,1-2H3/t16-,18-/m0/s1	PQILDBPUDLGKJU-WMZOPIPTSA-N
MMV1557940	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC=CC=C4)=O)N32	InChI=1S/C20H14F2N4O3/c21-20(22)29-15-8-6-14(7-9-15)19-25-24-17-10-23-11-18(26(17)19)28-12-16(27)13-4-2-1-3-5-13/h1-11,20H,12H2	MQSMCJANEPVRGE-UHFFFAOYSA-N
MMV1557941	ClC(C=C1)=CC(Cl)=C1C2=NN=C3C=NC=C(OCC45CC@@HC[C@@h]6C4)N32	InChI=1S/C22H22Cl2N4O/c23-16-1-2-17(18(24)6-16)21-27-26-19-10-25-11-20(28(19)21)29-12-22-7-13-3-14(8-22)5-15(4-13)9-22/h1-2,6,10-11,13-15H,3-5,7-9,12H2/t13-,14+,15-,22?	XRHQAPBKYTXPOW-HBJUSLLUSA-N
MMV1557942	ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC45CC@@HC[C@@h]6C4)N32	InChI=1S/C22H23ClN4O/c23-18-3-1-17(2-4-18)21-26-25-19-11-24-12-20(27(19)21)28-13-22-8-14-5-15(9-22)7-16(6-14)10-22/h1-4,11-12,14-16H,5-10,13H2/t14-,15+,16-,22?	MFXXXMMQULKXIX-GGTBJBEQSA-N
MMV1557943	CC1(C)[C@@h]2C[C@H]1C(CCOC3=CN=CC4=NN=C(C5=C(Cl)C=C(Cl)C=C5)N43)=CC2	InChI=1S/C22H22Cl2N4O/c1-22(2)14-4-3-13(17(22)9-14)7-8-29-20-12-25-11-19-26-27-21(28(19)20)16-6-5-15(23)10-18(16)24/h3,5-6,10-12,14,17H,4,7-9H2,1-2H3/t14-,17-/m0/s1	OYFPJLPMJIFAIS-YOEHRIQHSA-N
MMV1557944	CC1(C)[C@@h]2C[C@H]1C(CCOC3=CN=CC4=NN=C(C5=CC=C(Cl)C=C5)N43)=CC2	InChI=1S/C22H23ClN4O/c1-22(2)16-6-3-14(18(22)11-16)9-10-28-20-13-24-12-19-25-26-21(27(19)20)15-4-7-17(23)8-5-15/h3-5,7-8,12-13,16,18H,6,9-11H2,1-2H3/t16-,18-/m0/s1	BDWPPKIAXRRNII-WMZOPIPTSA-N
MMV1557945	ClC(C=C1)=CC(Cl)=C1C2=NN=C3C=NC=C(OCC4C[C@H]5C=C[C@@h]4C5)N32	InChI=1S/C19H16Cl2N4O/c20-14-3-4-15(16(21)7-14)19-24-23-17-8-22-9-18(25(17)19)26-10-13-6-11-1-2-12(13)5-11/h1-4,7-9,11-13H,5-6,10H2/t11-,12+,13?/m0/s1	OLAUIVKJLBCHFE-LAGVYOHYSA-N
MMV1557946	ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4C[C@H]5C=C[C@@h]4C5)N32	InChI=1S/C19H17ClN4O/c20-16-5-3-13(4-6-16)19-23-22-17-9-21-10-18(24(17)19)25-11-15-8-12-1-2-14(15)7-12/h1-6,9-10,12,14-15H,7-8,11H2/t12-,14+,15?/m0/s1	OWTVMOKESSEJOP-DJIKBVBFSA-N
MMV1557948	O=C(NC1=CC=NC=C1)C2=CN=CC3=NN=C(C4=CC=CC=C4)N32	InChI=1S/C17H12N6O/c24-17(20-13-6-8-18-9-7-13)14-10-19-11-15-21-22-16(23(14)15)12-4-2-1-3-5-12/h1-11H,(H,18,20,24)	JWMBXLLOVDKXRE-UHFFFAOYSA-N
MMV1557947	C12=NN=C(C3=CC=NC=C3)N1C(OCCC4=CC=CC=C4)=CN=C2	InChI=1S/C18H15N5O/c1-2-4-14(5-3-1)8-11-24-17-13-20-12-16-21-22-18(23(16)17)15-6-9-19-10-7-15/h1-7,9-10,12-13H,8,11H2	BSTOZULDVQMNLS-UHFFFAOYSA-N
MMV1557950	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC/C(C4=CC=CC=C4)=N/O)N32	InChI=1S/C20H15F2N5O3/c21-20(22)30-15-8-6-14(7-9-15)19-25-24-17-10-23-11-18(27(17)19)29-12-16(26-28)13-4-2-1-3-5-13/h1-11,20,28H,12H2/b26-16-	VJSBQKQNONLQQJ-QQXSKIMKSA-N
MMV1557949	FC(C=C1)=C(F)C=C1CCOC2=CN=CC3=NN=C(C4=CC=CC=C4)N32	InChI=1S/C19H14F2N4O/c20-15-7-6-13(10-16(15)21)8-9-26-18-12-22-11-17-23-24-19(25(17)18)14-4-2-1-3-5-14/h1-7,10-12H,8-9H2	RGEIFMMWUNGFHD-UHFFFAOYSA-N
MMV025100	NS(C1=CC(C2=CC3=NC=NC(N)=C3S2)=CC=C1)(=O)=O	InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-2-1-3-8(4-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18)	MQMXDJVOZKMSNT-UHFFFAOYSA-N
MMV897709	FC(C=C1)=C(F)C=C1C(OC)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32	InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3	PERKBMZWWUEZNJ-UHFFFAOYSA-N
MMV1557952	FC(C=C1)=C(F)C=C1C@@HCOC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32	InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3/t18-/m0/s1	PERKBMZWWUEZNJ-SFHVURJKSA-N
MMV1557951	FC(C=C1)=C(F)C=C1C@HCOC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32	InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3/t18-/m1/s1	PERKBMZWWUEZNJ-GOSISDBHSA-N
MMV1557953	FC(C=C1)=C(F)C=C1C(OC)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32	InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3	PERKBMZWWUEZNJ-UHFFFAOYSA-N
MMV1557962	C12=NN=C(N3CCCCC3)N1C(OCCC4=CC=CC=C4)=CN=C2	InChI=1S/C18H21N5O/c1-3-7-15(8-4-1)9-12-24-17-14-19-13-16-20-21-18(23(16)17)22-10-5-2-6-11-22/h1,3-4,7-8,13-14H,2,5-6,9-12H2	QFNWKXKUHMYRFI-UHFFFAOYSA-N

[MFernflower]

It's like a chemical Christmas! @edwintse I came up with some really eccentric ideas over at #516 if you are curious

[spadavec]

A lot of the SMILES strings in the table didn't resolve for me, so I re-did them by hand; while I had them, I just ran them through my potency predictor and got the following results (link [here])--apologies for not putting the table in this post. The formatting kept chopping off half of the SMILES patterns for some reason.

[mattodd]

Nice @spadavec . We shall see!

[edwintse]

We have just received the 1st run potency data from Dundee (linked in the original post above).

[MFernflower]

Just got the notification! Looks like SF5 is a good functional group and it seems like the smaller the cage the more potent the drug is - Therefore I propose this monstrosity
@mattodd

[mattodd]

Nice data, Ed. Thoughts.

OSM-S-391: This was made to compare to the iodocubane. Looks like it was the cubane that was the problem there? Can you just remind us of the comparison compound?

OSM-S-394: So how does SF5 compare to OCHF2?

OSM-S-396: What effect does that Me have on potency? i.e. compare to non-Me (“des-Me”) compound.

OSM-S-415: reinforces idea we need a para-substituent in that position I think.

OSM-S-417: given the result for OSM-S-415 I’d say we look exclusively at Norcross compounds with something in the “para” position @maratsydney @mcoster

Caged compounds: not great activity, but remarkable that some are as active as they are: OSM-S-398 and OSM-S-406 for example.

OSM-S-393 and OSM-S-392 are interesting, in that I had thought they might, in vivo, be equivalent to some extent. Clearly not. Was a ketal ever made there? Don’t think so.

OSM-S-409: worth a shot. Again, changes here exert a huge effect.

The resolved compounds: This makes little sense, that the mixed fraction is most potent. Can we re-establish exactly what was in each fraction?

The Late Stage Functionalisation compounds OSM-S-407 and OSM-S-408. Well, @ConorGraham is going to react these. Things can only get better.

OSM-S-106: good ping @mbhebhe

[MFernflower]

I think while PhSF5 is about as potent as PhOCHF2 that there are some advantages with the SF5 but they will need to be confirmed experimentally

1. the SF5 compound will not cross the BBB and thus allow it to concentrate in blood and in liver tissue (the two main sites where the parasite lives but will render it useless in cases where it's gone neural)
2. The PhSF5 functionality will (most likely) not be attacked by any mammalian enzymes, thus greatly increasing the half life of the drug (we may get 12 hour half life)
3. While water solubility takes a hit, I believe this compound will be great in rat tests when given via I.M injection

Regarding the chiral methoxy compounds - I would like to see a steroselective synthesis of the "good" isomer and subsequent rescreen of said compound

@mattodd

[mattodd]

We need some clarity on the resolved compounds (#470). The HPLC traces were posted here. The potency data are confusing. Are we absolutely sure of the correspondence between the samples that were evaluated and the HPLC traces? Obviously under normal circumstances the scalemic compound would not be the most potent.

MMV897709 (OSM-S-218): “HPLC Trace”. Racemic. Retention times (Rt) 17.6 18.5. Potency 1.27 uM
MMV1557952 (OSM-S-413) “Isolated P1”. Enantiopure. Rt 17.9 Potency >10 uM
MMV1557951 (OSM-S-414) “Isolated P2”. Enantiopure. Rt 16.9 Potency 0.94 uM
MMV1557953 (OSM-S-416) “failed separation”. Scalemic P1+P2. Potency 0.45 uM

@edwintse and @alintheopen can you please double-check codes are right, and I'll ping Mark Butler on Twitter.

[cdsouthan]

This isomer aspect was mentioned already in #533 (comment) but I have split it out as a new point 9. We need to know the error bars for the results above before we can conclude anything. NOBA an obvious internal control is to make a "P1 added to P2" extra activity measurement that should ~ = racemate. NOBA I hope @edwintse can transfer these results across to the Master List sooner rather than later

[MFernflower]

I'm curious: How difficult would it be to do a stereoselective synthesis of the "good" isomer and subsequent rescreen of compound? This would greatly clear up confusion about the purified mixtures that were tested

@mattodd

[edwintse]

UPDATE:
The 2nd run potency data has been received. The values in the image on the ELN have been updated. For the most part, the activities are slightly lower, with a few exceptions. (The original image has been moved to the bottom of the page). An export of the data from ScienceCloud has also been uploaded to that page. These values will now be added to the master list.