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12th July 2015 @ 16:12

SGS 7-1 and 7-2 were washed in with ethyl acetate and solvents were removed. Both samples were analysed with 1H NMR (300 MHz, CDCl3). The 7-1 sample was purified by column chromatography using ethyl acetate and petroleum eluent as some impurities were detected by TLC. The resulting fractions were combined to form 5 fractions.

Based on previous NMR results of this particular compound (AEW 94, DS 3, DS 8) it is likely that the product is present in fraction 1 and 2 only.

Data:

SGS 7-1 CDCl3

SGS 7-1 CDCl3 300 MHz AEW and PK.pdf
SGS 7-1 CDCl3 AEW and PK.zip

SGS 7-2 CDCl3

SGS 7-2 CDCl3 300 MHz AEW and PK.pdf
SGS 7-2 CDCl3 AEW and PK.zip

Column Fractions:

SGS 7-1 frac 1.pdf
SGS 7-1 frac 2.pdf
SGS 7-1 frac 3.pdf
SGS 7-1 frac 4.pdf
SGS 7-1 frac 5.pdf

Strings:

SMILES: ClC1=CN=CC2=NN=C(C3=CC=C(C#N)C=C3)N21

InChi: InChI=1S/C12H6ClN5/c13-10-6-15-7-11-16-17-12(18(10)11)9-3-1-8(5-14)2-4-9/h1-4,6-7H

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12th July 2015 @ 15:54

The product provided contained solvent which was washed and then removed with ethyl acetate (~100 mL). However, this brown product also contained a greasy contaminant that did not evaporate under vacuum (20 mPa, 40oC, ~6 h). Nevertheless, the product was analysed with 1H NMR (200 MHz, DMSO). As the product was found to have impurities, it was purified by column chromatography with ethyl acetate and hexane. The columned product was analysed with NMR (200 MHz, CDCl3).

Data:

Pre-column:

SGS 9-1 DMSO AEW and PK.pdf
SGS 9-1 DMSO AEW and PK.zip

Post-column:

SGS 9-1 column.pdf
SGS 9-1 column.zip

Strings:

SMILES: ClC1=CN=CC2=NN=C(C3=CC=NC=C3)N21

InChI=1S/C10H6ClN5/c11-8-5-13-6-9-14-15-10(16(8)9)7-1-3-12-4-2-7/h1-6H

Attached Files
12th July 2015 @ 15:29

The solvents were removed by washing with ethyl acetate (~100 mL), and the SGS 8-1 left under high vacuum. The remaining dark brown solid was contaminated with an unknown, greasy compound and could not be completely dried in 20 mPa, 40oC or under high vacuum, 25oC.

Nevertheless, the sample was analysed by 1H NMR (300 MHz) in CDCl3.

The product was purified with column chromatography in ethyl acetate and hexane then analysed with NMR (200 MHz, CDCl3).

Note: Files are shown as 8-2 but are in fact, 8-1 due to an error in labelling.

Data:

SGS 8-1 CDCl3 300 MHz AEW and PK.pdf
SGS 8-1 CDCl3 AEW and PK.zip

SGS 8-2 Paul Columned.pdf
SGS 8-2 Paul Columned.zip

Strings:

SMILES: ClC1=CN=CC2=NN=C(C3=CC=CN=C3)N21

InChI=1S/C10H6ClN5/c11-8-5-13-6-9-14-15-10(16(8)9)7-2-1-3-12-4-7/h1-6H

Attached Files
12th July 2015 @ 13:59

SGS 6-2 was fully dissolved by adding ethyl acetate (~300 mL), dichloromethane (~10 mL), methanol (~10 mL), and washed with water (~30 mL) then brine (~70 mL). The organic layer was collected and dried with sodium sulfate and the solvent was removed. 

The crude product was dissolved in dichloromethane (~100 mL), ethyl acetate (~50 mL), and methanol (~1 mL). Silica was added and the solvent was removed under vacuum and the SGS 6-2 product was separated by column chromatography. Fractions were combined based on TLC character into 8 larger fractions. Based on NMR data, it was concluded that the most likely fraction containing the desired product was fraction 3.

Data:

SGS 6-2 Frac One.pdf
SGS 6-2 Frac Two.pdf
SGS 6-2 Frac 3.pdf
SGS 6-2 Frac 5.pdf
SGS 6-2 Frac 6.pdf
SGS 6-2 Frac 7.pdf
SGS 6-2 Frac 8.pdf
SGS 6-2 Frac 1-8.zip

Strings:

SMILES: ClC1=CN=CC2=NN=C(C3=NC=CC=C3)N21

InChI=1S/C10H6ClN5/c11-8-5-12-6-9-14-15-10(16(8)9)7-3-1-2-4-13-7/h1-6H

Attached Files
1st February 2014 @ 00:41

This paper from Novartis/Scripps/MMV describes a compound (KAI407) effective against a model of P. vivax. There are obvious similarities (gut-feeling, not quantified or substantiated) between this compound and OSM's Series 4:

OSM Series 4 vs KAI407

The known SAR is shown in more detail on the Series 4 wiki, in particular what is known of transposing ring nitrogens and the pendant chain on the pyrazine ring.

Action item was raised on Github here to evaluate whether to run some Series 4 compounds in the same assay.

 

(Note the Novartis compound is KAI (the letter i) not KA1 (the number 1) - important for search purposes)

Update/Answer - From Paul Willis by email March 5th:

These Novartis compounds that bear some similarity to OSM's Series 4 do not appear to hit PfATP4 (the suspected target of Series 4) – i.e. it has been evaluated for this. Data in the Novartis Nature paper [10.1038/nature12782] shows the MOA of the compounds is PI4K. There is also data in the paper (Extended Data Figure 5A) which tests a PfATP4 inhibitor against PI4K mutants, showing no cross resistance, suggesting a different MOA. From the paper, imidazopyrazines KDU691 and KDU751 are active against Py liver schizonts.  We now have data [spreadsheet attached to this post:

U Sydney liver data.xlsx
] showing the OSM compounds MMV669844 and MMV670944 are v weakly active against Pb liver schizonts (and a big difference from blood potency). Novartis will be unaware which OSM Series 4 compounds have been tested as MMV coordinates the screening of non-Novartis compounds in these screens.

To date, there appears good evidence that the OSM series does not share the same mechanism as the Novartis compounds highlighted: The Novartis imidazopyrazines are reported active against all liver stages in several Plasmodium species, including hypnozoites. For completeness this month, the two OSM compounds will be progressed into the Pc hypnozoite assay mentioned in the Novartis paper.

 

 

Strings:

KAI407

O=C(N(C1=CC=C(C#N)C=C1)C)C(N=C2)=CN3C2=NC=C3C4=CC=C(C(F)(F)F)C=C4

InChI=1S/C22H14F3N5O/c1-29(17-8-2-14(10-26)3-9-17)21(31)18-13-30-19(11-28-20(30)12-27-18)15-4-6-16(7-5-15)22(23,24)25/h2-9,11-13H,1H3

XAZOWMVYGFASLH-UHFFFAOYSA-N

MMV669542

O=C(NC1=CC=CC(Cl)=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32

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)

AJGOFYWOTIIYLR-UHFFFAOYSA-N

MMV669846

ClC(C=C1)=CC=C1C2=CN=C3C=NC=C(OCCC4=CC=C(F)C(F)=C4)N32

InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)18-10-25-19-11-24-12-20(26(18)19)27-8-7-13-1-6-16(22)17(23)9-13/h1-6,9-12H,7-8H2

MQHQNFQVEXYAMO-UHFFFAOYSA-N

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