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Next batch of samples sent for biological evaulation #517

Closed edwintse closed 6 years ago

edwintse commented 7 years ago

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

dundee compounds 140717

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 commented 7 years ago

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

spadavec commented 7 years ago

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 commented 7 years ago

Nice @spadavec . We shall see!

edwintse commented 7 years ago

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

MFernflower commented 7 years ago

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 structure @mattodd

mattodd commented 7 years ago

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 commented 7 years ago

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 commented 7 years ago

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 commented 7 years ago

This isomer aspect was mentioned already in https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/533#issuecomment-321202699 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 commented 7 years ago

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 commented 7 years ago

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.