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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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1st July 2014 @ 00:23

Adelaide Dennis, from Kiaran Kirk's lab at the ANU, sent data on June 9th by email:

"I have attached my raw data from experiments testing the effect of compounds OSM-S-4/5/35/51/106/111 at 150 µM and 1 µM on [Na+]i of saponin-isolated SBFI-loaded trophozoite stage 3D7 parasites.

Originally sent: Compounds sent for parasiste ion regulation assays at ANU

These compounds were tested at 150 µM and 1 µM. At 150 µM OSM-S-5 appeared to increase [Na+]i within the parasite. At 150 µM OSM-S-4 did not cause an increase in [Na+]i, and the remaining four compounds (35, 51, 106, 111) caused an 'optical effect'. In this assay, excitation wavelengths are 340 nm and 380 nm, while emission is measured at 520 nm. An 'optical effect' occurs when the addition of a compound causes a disturbance at one of these wavelengths.

At 1 µM OSM-S-4, OSM-S-5 and OSM-S-111 showed no effect on [Na+]i within the parasite, and OSM-S-35, OSM-S-51 and OSM-S-106 showed slight 'optical effects'.

Fluorescence intensity (FI) was calibrated to [Na+]i for the traces showing compounds tested at 150 µM. Fluorescence intensity was not calibrated for traces showing compounds tested at 1 µM."

This assay is used to suggest whether bioactives are targeting PfATP4. This screen was carried out to investigate whether OSM Series 1 or 3 might have such a mechanism of action, as Series 4 appears to. The data suggest they do not.

Compounds assayed:

Preparation of OSM-S-4

Preparation of OSM-S-5

Preparation of OSM-S-35

Preparation of OSM-S-51

Preparation of OSM-S-106

Preparation of OSM-S-111

Adelaide made her original lab book entry available - the team uses Labarchives:

https://mynotebook.labarchives.com/share/Adelaide%2520Dennis/MTIwLjl8MjYyODgvOTMvVHJlZU5vZGUvNTI1ODM5NDMwfDMwNi45

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