Next batch of compounds sent for biological testing June 2018

edwintse commented 6 years ago

The third batch for the year has just been sent out to Dundee for screening against P. falciparum. This is the largest set we've sent this year and it contains a number of key compounds.

UPDATE 6/7/18: Results are here.

5-/8-sub'd Thioethers: Set of 4 compounds isolated in the resynthesis of the thioethers with different substitutions on the pyrazine (#49)
SSP Compounds: 2018 SSP compounds that were resynthesised due to difficulties in isolation and characterisation of the undergrad samples (#53)
The OHOH Compounds: The compound identified from the Pfizer biofunctionalisation experiments, resynthesised by @david1597 along with the difluoro and dimethylamine derivatives and the diol protected compounds (#36)
Suzuki/Indole Compounds: Derivatives made through Suzuki coupling by @maratsydney based on the original potent RHS indole hit (#31)
Miscellaneous Compounds: (L to R) the m-carborane, ± ether carbon chain length compounds (#27), benzyl protected versions of derivatives from the initial Pfizer phenol (#23), acetyl compound originally intended for faster access to OHOH derivatives but found to be 8-sub'd (#44), 8-sub'd amines made while trying to synthesise the 5-sub'd products (#47)

MMV Number	SMILES	InChI	InChI Key
MMV1581330	FC1=CC(CCOC2=CN=CC3=NN=C(N4C=CN=C4)N32)=CC=C1F	InChI=1S/C16H12F2N6O/c17-12-2-1-11(7-13(12)18)3-6-25-15-9-20-8-14-21-22-16(24(14)15)23-5-4-19-10-23/h1-2,4-5,7-10H,3,6H2	WQBHKNFYSCUMJC-UHFFFAOYSA-N
MMV1580437	FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC=CC(C(O)=O)=C4)N32)=CC=C1F	InChI=1S/C20H14F2N4O3/c21-15-5-4-12(8-16(15)22)6-7-29-18-11-23-10-17-24-25-19(26(17)18)13-2-1-3-14(9-13)20(27)28/h1-5,8-11H,6-7H2,(H,27,28)	GYFXXYGBOJTVGJ-UHFFFAOYSA-N
MMV1581331	FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC5=C(C=C4)C=CN5C)N32)=CC=C1F	InChI=1S/C22H17F2N5O/c1-28-8-6-15-3-4-16(11-19(15)28)22-27-26-20-12-25-13-21(29(20)22)30-9-7-14-2-5-17(23)18(24)10-14/h2-6,8,10-13H,7,9H2,1H3	YDNZCOWSOGIBPE-UHFFFAOYSA-N
MMV1581332	FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC5=C(C=C4)CC(N5)=O)N32)=CC=C1F	InChI=1S/C21H15F2N5O2/c22-15-4-1-12(7-16(15)23)5-6-30-20-11-24-10-18-26-27-21(28(18)20)14-3-2-13-9-19(29)25-17(13)8-14/h1-4,7-8,10-11H,5-6,9H2,(H,25,29)	PUDALCIATSASSD-UHFFFAOYSA-N
MMV1581333	FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC5=C(C=C4)CCN5)N32)=CC=C1F	InChI=1S/C21H17F2N5O/c22-16-4-1-13(9-17(16)23)6-8-29-20-12-24-11-19-26-27-21(28(19)20)15-3-2-14-5-7-25-18(14)10-15/h1-4,9-12,25H,5-8H2	FNBXJZBLBXZUFU-UHFFFAOYSA-N
MMV1581334	FC1=CC(CCOC2=CN=CC3=NN=C(C4=CC=C(F)C(N)=C4)N32)=CC=C1F	InChI=1S/C19H14F3N5O/c20-13-3-1-11(7-15(13)22)5-6-28-18-10-24-9-17-25-26-19(27(17)18)12-2-4-14(21)16(23)8-12/h1-4,7-10H,5-6,23H2	VZPHEOZUAXBEIA-UHFFFAOYSA-N
MMV1581306	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(NCCC4=CC=CC=C4)=NC=CN32	InChI=1S/C20H17F2N5O/c21-20(22)28-16-8-6-15(7-9-16)18-25-26-19-17(24-12-13-27(18)19)23-11-10-14-4-2-1-3-5-14/h1-9,12-13,20H,10-11H2,(H,23,24)	JFZKBRTVRMLMOX-UHFFFAOYSA-N
MMV1581297	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4(COC(C)(C)O4)C5=CC=C(F)C(F)=C5)N32	InChI=1S/C24H20F4N4O4/c1-23(2)34-13-24(36-23,15-5-8-17(25)18(26)9-15)12-33-20-11-29-10-19-30-31-21(32(19)20)14-3-6-16(7-4-14)35-22(27)28/h3-11,22H,12-13H2,1-2H3	AUPGROSOGHDOGI-UHFFFAOYSA-N
MMV1581300	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4(COC(C)(C)O4)C5=CC=CC=C5)N32	InChI=1S/C24H22F2N4O4/c1-23(2)32-15-24(34-23,17-6-4-3-5-7-17)14-31-20-13-27-12-19-28-29-21(30(19)20)16-8-10-18(11-9-16)33-22(25)26/h3-13,22H,14-15H2,1-2H3	VBOKZAGPDKNJEQ-UHFFFAOYSA-N
MMV1581296	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4(COC(C)(C)O4)C5=CC=C(N(C)C)C=C5)N32	InChI=1S/C26H27F2N5O4/c1-25(2)35-16-26(37-25,18-7-9-19(10-8-18)32(3)4)15-34-22-14-29-13-21-30-31-23(33(21)22)17-5-11-20(12-6-17)36-24(27)28/h5-14,24H,15-16H2,1-4H3	QNYUKWXXUMWURS-UHFFFAOYSA-N
MMV1581301	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(NCC4=CC=CC=C4)=NC=CN32	InChI=1S/C19H15F2N5O/c20-19(21)27-15-8-6-14(7-9-15)17-24-25-18-16(22-10-11-26(17)18)23-12-13-4-2-1-3-5-13/h1-11,19H,12H2,(H,22,23)	YQPNVUSTPHQUIF-UHFFFAOYSA-N
MMV1581302	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=CC=CC=C4OCC5=CC=CC=C5)N32	InChI=1S/C28H24F2N4O4/c29-28(30)38-22-12-10-20(11-13-22)27-33-32-25-14-31-15-26(34(25)27)37-18-21(16-35)23-8-4-5-9-24(23)36-17-19-6-2-1-3-7-19/h1-15,21,28,35H,16-18H2	NGZQBMVQKLXCFS-UHFFFAOYSA-N
MMV1581303	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=C(OCC5=CC=CC=C5)C=C4)N32	InChI=1S/C27H22F2N4O3/c28-27(29)36-23-12-8-21(9-13-23)26-32-31-24-16-30-17-25(33(24)26)34-15-14-19-6-10-22(11-7-19)35-18-20-4-2-1-3-5-20/h1-13,16-17,27H,14-15,18H2	XFBPGJAKOMHHKZ-UHFFFAOYSA-N
MMV1581295	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)(O)C4=CC=CC=C4)N32	InChI=1S/C21H18F2N4O4/c22-20(23)31-16-8-6-14(7-9-16)19-26-25-17-10-24-11-18(27(17)19)30-13-21(29,12-28)15-4-2-1-3-5-15/h1-11,20,28-29H,12-13H2	LVBNVRWXODMMAV-UHFFFAOYSA-N
MMV1581305	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)(O)C4=CC=C(N(C)C)C=C4)N32	InChI=1S/C23H23F2N5O4/c1-29(2)17-7-5-16(6-8-17)23(32,13-31)14-33-20-12-26-11-19-27-28-21(30(19)20)15-3-9-18(10-4-15)34-22(24)25/h3-12,22,31-32H,13-14H2,1-2H3	XLVBTEMBQJMBDA-UHFFFAOYSA-N
MMV1581299	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(OCC(C)=O)=NC=CN32	InChI=1S/C15H12F2N4O3/c1-9(22)8-23-14-13-20-19-12(21(13)7-6-18-14)10-2-4-11(5-3-10)24-15(16)17/h2-7,15H,8H2,1H3	MXHWALUHBSFDFZ-UHFFFAOYSA-N
MMV1581298	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)(O)C4=CC=C(F)C(F)=C4)N32	InChI=1S/C21H16F4N4O4/c22-15-6-3-13(7-16(15)23)21(31,10-30)11-32-18-9-26-8-17-27-28-19(29(17)18)12-1-4-14(5-2-12)33-20(24)25/h1-9,20,30-31H,10-11H2	GXKONCOXFIUYEL-UHFFFAOYSA-N
MMV1581304	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=CC(OCC5=CC=CC=C5)=C4)N32	InChI=1S/C27H22F2N4O3/c28-27(29)36-22-11-9-21(10-12-22)26-32-31-24-16-30-17-25(33(24)26)34-14-13-19-7-4-8-23(15-19)35-18-20-5-2-1-3-6-20/h1-12,15-17,27H,13-14,18H2	CGZBFPBJKVQMJF-UHFFFAOYSA-N
MMV1581335	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(SCC4=CC=CC=C4)=NC=CN32	InChI=1S/C19H14F2N4OS/c20-19(21)26-15-8-6-14(7-9-15)16-23-24-17-18(22-10-11-25(16)17)27-12-13-4-2-1-3-5-13/h1-11,19H,12H2	JDPMDXDHQOZVJL-UHFFFAOYSA-N
MMV693161	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(SCC4=CC=CC=C4)N32	InChI=1S/C19H14F2N4OS/c20-19(21)26-15-8-6-14(7-9-15)18-24-23-16-10-22-11-17(25(16)18)27-12-13-4-2-1-3-5-13/h1-11,19H,12H2	KEZIWQVAJDNGBM-UHFFFAOYSA-N
MMV693164	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(SCCC4=CC=CC=C4)=NC=CN32	InChI=1S/C20H16F2N4OS/c21-20(22)27-16-8-6-15(7-9-16)17-24-25-18-19(23-11-12-26(17)18)28-13-10-14-4-2-1-3-5-14/h1-9,11-12,20H,10,13H2	KBHHUJAAUNEUJP-UHFFFAOYSA-N
MMV1581336	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(SCCC4=CC=CC=C4)N32	InChI=1S/C20H16F2N4OS/c21-20(22)27-16-8-6-15(7-9-16)19-25-24-17-12-23-13-18(26(17)19)28-11-10-14-4-2-1-3-5-14/h1-9,12-13,20H,10-11H2	GFJJCWGNCVLFNL-UHFFFAOYSA-N
MMV1581343	FC(OC1=CC=C(C2=NN=C3C=NC=C(N32)OCC[C]4BB[CH]BBBBBBBB4)C=C1)F	InChI=1S/C16H22B10F2N4O2/c27-16(28)34-11-3-1-10(2-4-11)15-31-30-13-7-29-8-14(32(13)15)33-6-5-12-19-17-9-18-21-23-25-26-24-22-20-12/h1-4,7-9,16-26H,5-6H2	BYDBKGSAFBHXHO-UHFFFAOYSA-N
MMV1581337	CC(OC(N(CC1)CCC1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32)=O)(C)C	InChI=1S/C23H29N5O3/c1-23(2,3)31-22(29)27-12-9-18(10-13-27)21-26-25-19-15-24-16-20(28(19)21)30-14-11-17-7-5-4-6-8-17/h4-8,15-16,18H,9-14H2,1-3H3	QGAWBQPLDGJFLD-UHFFFAOYSA-N
MMV1581338	C12=NN=C(C3CCOCC3)N1C(OCCC4=CC=CC=C4)=CN=C2	InChI=1S/C18H20N4O2/c1-2-4-14(5-3-1)6-11-24-17-13-19-12-16-20-21-18(22(16)17)15-7-9-23-10-8-15/h1-5,12-13,15H,6-11H2	YFBDXIIKLFDPQE-UHFFFAOYSA-N
MMV1581339	CC(OC(N(CC1)CC1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32)=O)(C)C	InChI=1S/C22H27N5O3/c1-22(2,3)30-21(28)26-11-9-17(15-26)20-25-24-18-13-23-14-19(27(18)20)29-12-10-16-7-5-4-6-8-16/h4-8,13-14,17H,9-12,15H2,1-3H3	HGLXYGXXFKFILC-UHFFFAOYSA-N
MMV1581340	C12=NN=C(C3COCC3)N1C(OCCC4=CC=CC=C4)=CN=C2	InChI=1S/C17H18N4O2/c1-2-4-13(5-3-1)6-9-23-16-11-18-10-15-19-20-17(21(15)16)14-7-8-22-12-14/h1-5,10-11,14H,6-9,12H2	SBUYDARTZYGJBS-UHFFFAOYSA-N
MMV1581341	C12=NN=C(C3CCNCC3)N1C(OCCC4=CC=CC=C4)=CN=C2	InChI=1S/C18H21N5O/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/h1-5,12-13,15,19H,6-11H2	QWXIVICLDFUZFI-UHFFFAOYSA-N
MMV1581342	C12=NN=C(C3CNCC3)N1C(OCCC4=CC=CC=C4)=CN=C2	InChI=1S/C17H19N5O/c1-2-4-13(5-3-1)7-9-23-16-12-19-11-15-20-21-17(22(15)16)14-6-8-18-10-14/h1-5,11-12,14,18H,6-10H2	XMFSPYQJWNPEAS-UHFFFAOYSA-N
MMV1581344	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCCC4=CC=CC=C4)N32	InChI=1S/C21H18F2N4O2/c22-21(23)29-17-10-8-16(9-11-17)20-26-25-18-13-24-14-19(27(18)20)28-12-4-7-15-5-2-1-3-6-15/h1-3,5-6,8-11,13-14,21H,4,7,12H2	JNQZAPNWBVAOJV-UHFFFAOYSA-N
MMV1581345	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC4=CC=CC=C4)N32	InChI=1S/C18H12F2N4O2/c19-18(20)26-14-8-6-12(7-9-14)17-23-22-15-10-21-11-16(24(15)17)25-13-4-2-1-3-5-13/h1-11,18H	UTIUAZFJLHTVFG-UHFFFAOYSA-N
MMV1581346	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCOC4=CC=CC=C4)N32	InChI=1S/C20H16F2N4O3/c21-20(22)29-16-8-6-14(7-9-16)19-25-24-17-12-23-13-18(26(17)19)28-11-10-27-15-4-2-1-3-5-15/h1-9,12-13,20H,10-11H2	LIQWNTBRXAAMDF-UHFFFAOYSA-N

Dundee Compounds 150618.zip

mattodd commented 6 years ago

Fantastic work guys, this is a lovely set of compounds.

david1597 commented 6 years ago

The results are in.

(For those that weren't online for the public meeting yesterday, these results came through during the meeting! Right on cue after I had concluded my section by saying we were awaiting the OHOH compound results that had arrived in Dundee, and just as Ed started summarizing our other recent potency results. Cue much excitement from the four of us huddled around our computers and scrambling to login and sift through the data. It wasn't quite as we hoped (see below), so for those that were present I hope it made sense as we tried to explain - it really was as live as possible on this occasion!)

Anyway, both runs of data are in (the second was uploaded an hour or so later) and the values below are the average of the two runs. Raw data is posted on my ELN, and data is linked on the wiki.

dundee results 150618

Some brief comments:

Thioethers

The 2-carbon 5-substituted compound was weakly active, this makes sense as it is comparable to the 2-carbon 5-substituted oxygen compounds that are are main focus on that LHS. Overrides that we previously thought they were inactive due to mis-assignment.
For the 1-carbon linked compounds, the 8-position actually shows greater activity than the 5-position.

2018 SSP Compounds

inactive (OSM-S-572 very weakly active)

The OHOH Compounds

the compound that was arguably of most interest, OSM-S-556, needs to be re-run as the data looks like this:
the protected versions are more potent than the OHOH compounds
the difluoro compounds are more active than the parent phenyl
the potency is not as low as we were expecting
caution against drawing too many conclusions at this stage, we still don't have good data on the OSM-S-556, and this was the lead we were following

Suzuki/Indole Compounds

the trend of an NH meta and something para still holds
an in depth look collating all the compounds made in this series would be wise, we should start a fresh issue for this

Misc compounds

another potent carborane
changing the chain length on the LHS adversely effects potency. 3C lowers potency, zero carbon linkers are inactive.
on the LHS, having an OR group in the meta position has again given a potent compound.

MFernflower commented 6 years ago

@david1597 Seeing the potency of the meta-obz got me thinking - has this molecule ever been screened?

I'd also be curious about it's herg effects since the carboxylic acid is there but in a different spot @edwintse

3 u2010 2 u2010 3 u2010 4 u2010 difluoromethoxy phenyl u2010 1 2 4 triazolo 4 3 u2010a pyrazin u20105 u2010 yl oxy ethyl benzoic acid

o-methyl 3 u2010 2 u2010 3 u2010 4 u2010 difluoromethoxy phenyl u2010 1 2 4 triazolo 4 3 u2010a pyrazin u20105 u2010 yl oxy ethyl benzoic acid

Thoughts everyone?

david1597 commented 6 years ago

We have received extra repeats for that all important OHOH compound - OSM-S-556. The average potency is 660 nM with the four repeats being 425, 792, 817 and 601 nM. The curves for those four repeats are below. Ten data points are collected in each run but some data points appear to be missed off in some cases due to very low bottoms.

This value is not what we hoped or expected - it's a long way from the <10 nM that we got from the Pfizer biosynthesis. I'm unsure how to proceed with this. There's still a repeated biosynthesis sample we're awaiting the potency result for. And we will submit another sample of the DGS 81-1 batch to Dundee in the next shipment.

MFernflower commented 6 years ago

@David1597 @mcoster I wonder if the Pfizer 10 nm was a quinone? Could explain the efficacy - possibly killing cells via an oxidation mechanism along side atp4 blockade!

david1597 commented 6 years ago

Here are all the individual repeat values for this batch:

MMV number	OSM number	Internal number	Potency 1	Potency 2	Potency 3	Potency 4	Average
MMV1580437	OSM-S-552	MK070-2	>25.11	>25.11			>25
MMV1581295	OSM-S-556	DGS 81-1	0.425	0.792	0.817	0.601	0.659
MMV1581296	OSM-S-558	DGS 69-1	>25.11	>25.11			>25
MMV1581297	OSM-S-559	DGS 74-1	0.165	0.133			0.149
MMV1581298	OSM-S-560	DGS 77-1	0.295	0.239			0.267
MMV1581299	OSM-S-561	DGS 78-1	>25.11	>25.11			>25
MMV1581300	OSM-S-562	DGS 73-1	0.333	0.34			0.337
MMV1581301	OSM-S-563	DGS 84-1	18.32	20.88			19.600
MMV1581302	OSM-S-565	DGS 38-1	>25.11	>25.11			>25
MMV1581303	OSM-S-566	DGS 13-2	3.93	3.768			3.849
MMV1581304	OSM-S-567	DGS 26-1	0.142	0.151			0.147
MMV1581305	OSM-S-568	DGS 82-1	>25.11	>25.11			>25
MMV1581306	OSM-S-569	DGS 83-3	>25.11	>25.11			>25
MMV1581335	OSM-S-570	EGT 48-2 (f5-7)	6.57	4.674			5.622
MMV1581336	OSM-S-571	EGT 52-2 (f6-10)	1.099	0.997			1.048
MMV1581337	OSM-S-572	EGT 347-1	14.76	14.15			14.455
MMV1581338	OSM-S-573	EGT 348-1	>25.11	>25.11			>25
MMV1581339	OSM-S-574	EGT 349-1	>25.11	>25.11			>25
MMV1581340	OSM-S-575	EGT 350-1	>25.11	>25.11			>25
MMV1581341	OSM-S-576	EGT 351-1	>25.11	>25.11			>25
MMV1581342	OSM-S-577	EGT 352-1	>25.11	>25.11			>25
MMV1581344	OSM-S-578	EGT 353-1	1.36	1.288			1.324
MMV1581345	OSM-S-579	EGT 354-1	>25.11	>25.11			>25
MMV1581346	OSM-S-580	EGT 355-1	1.397	1.026			1.212
MMV1581330	OSM-S-581	MK057-3	>25.11	>25.11			>25
MMV1581331	OSM-S-582	MK079-1	0.393	0.357			0.375
MMV1581332	OSM-S-583	MK080-1	>25.11	>25.11			>25
MMV1581333	OSM-S-584	MK081-1	1.059	0.968			1.014
MMV1581334	OSM-S-585	MK082-1	0.898	0.728			0.813
MMV1581343	OSM-S-654	EGT 338-1	0.121	0.112			0.117

@MFernflower for your question above, a quinone would not be consistent with the NMR and MS they obtained. We're pretty confident on it's structure.

OpenSourceMalaria / Series4