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9th July 2014 @ 05:36

Compounds in OSM Series 4 and Series 3, as well as some compounds synthesised at the start of an open source TB project, were submitted to GSK for potency evaluation: Compounds Submitted for Testing at GSK Tres Cantos for anti-malarial and anti-TB activity

Single shot data was received from GSK (Laura Maria Sanz-Alonso) on June 27th 2014 and can be found here: Single Shot Potencies for Compounds Submitted to GSKCompounds found to have percentage of inhibition  50% (along with some controls) were progressed to IC50 determination assays.

Initial Comments:

Full data is here:

20140631_whole cell_IC50 determinatio_IC50 values.xlsx

Phenethyl ether compounds OSM-S-187 and OSM-S-189 look promising and have ClogP <5.

Striking difference in potency of amides OSM-S-201 and OSM-S-202 that differ only in the presence of an ortho-methyl group. Perhaps more notable was the low inhibition of OSM-S-204, bearing an ortho-fluoro group. OSM-S-204 wasn't subject to the IC50 assay but showed only 24% inhibition in the single shot assay, this might suggest that the nature of the ortho substituent, rather than steric bulk influences activity.

OSM-S-206 has a promising IC50 but ClogP is too high.

MMV669844, (OSM-S-218) an enantioenriched compound was inherited at the start of the series and was found to have an EC50 of 0.040 uM in an erythrocyte assay (NF54 with 3H-Hypoxanthine at 72hr time point). OSM-S-208 is the racemic form of this compound and was also found to have a high potency in the IC50 assay described.

Strings

OSM-S-106 Preparation of OSM-S-106 O=S(C1=CC=CC(C2=CC3=NC=NC(N)=C3S2)=C1)(N)=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)

OSM-S-142 Preparation of OSM-S-142 NC1=C2C(C=C(C3=CC(C(N4CCN(C)CC4)=O)=CC=C3)S2)=NC=N1 InChI=1S/C18H19N5OS/c1-22-5-7-23(8-6-22)18(24)13-4-2-3-12(9-13)15-10-14-16(25-15)17(19)21-11-20-14/h2-4,9-11H,5-8H2,1H3,(H2,19,20,21)

OSM-S-187 Preparation of OSM-S-187 N#CC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C20H15N5O/c21-12-16-6-8-17(9-7-16)20-24-23-18-13-22-14-19(25(18)20)26-11-10-15-4-2-1-3-5-15/h1-9,13-14H,10-11H2

OSM-S-189 Preparation of OSM-S-189 ClC1=CC=CC=C1CCOC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C20H14ClN5O/c21-17-4-2-1-3-15(17)9-10-27-19-13-23-12-18-24-25-20(26(18)19)16-7-5-14(11-22)6-8-16/h1-8,12-13H,9-10H2

OSM-S-194 Preparation of OSM-S-194 C12=CC=CC=C1C3=C(C4(CCN(CC5=CC=CC=C5)CC4)OCC3)N2 InChI=1S/C22H24N2O/c1-2-6-17(7-3-1)16-24-13-11-22(12-14-24)21-19(10-15-25-22)18-8-4-5-9-20(18)23-21/h1-9,23H,10-16H2

OSM-S-201 Preparation of OSM-S-201 O=C(NC1=CC=CC(Cl)=C1C)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)F)C=C4 InChI=1S/C20H14ClF2N5O2/c1-11-14(21)3-2-4-15(11)25-19(29)16-9-24-10-17-26-27-18(28(16)17)12-5-7-13(8-6-12)30-20(22)23/h2-10,20H,1H3,(H,25,29)

OSM-S-202 OSM-S-202 O=C(NC1=CC=CC(Cl)=C1)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)F)C=C4 InChI=1S/C19H12ClF2N5O2/c20-12-2-1-3-13(8-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-4-6-14(7-5-11)29-19(21)22/h1-10,19H,(H,24,28)

OSM-S-204 OSM-S-204 O=C(NC1=CC=CC(Cl)=C1F)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)F)C=C4 InChI=1S/C19H11ClF3N5O2/c20-12-2-1-3-13(16(12)21)25-18(29)14-8-24-9-15-26-27-17(28(14)15)10-4-6-11(7-5-10)30-19(22)23/h1-9,19H,(H,25,29)

OSM-S-206 Preparation of OSM-S-206 O=C(NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C21H11F8N5O2/c22-19(23)36-14-3-1-10(2-4-14)17-33-32-16-9-30-8-15(34(16)17)18(35)31-13-6-11(20(24,25)26)5-12(7-13)21(27,28)29/h1-9,19H,(H,31,35)

OSM-S-208 OSM-S-208 FC1=C(F)C=CC(C(OC)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32)=C1 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

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Attached Files
20140631_whole cell_IC50 determinatio_IC50 values.xlsx
GSK Data July IC50.cdxml
GSK Data July IC50.png