Biological Evaluation of Compounds

A further set of Series 4 Triazolopyrazine compounds were sent to have their efficacy evaluated against Plasmodium falciparum in-vitro at Syngene.

Some compounds were synthesised by the SSP group at The University Sydney and then purified in the research lab.

The following results were optained:

 

 Brief Analysis:

Compounds substituted with pyridyl ether are inactive.

3,5-difluorophenyl compounds are inactive.

Moving 'Cl-substitution' from para to meta to ortho results in progressive (and quite dramatic) erosion of activity.

Napthyl compound MMV689973 and even benzodioxole compound MMV689972 suggest that further exploration of disubstitution of the aromatic ring could be explored - perhaps with groups that allow for lower CLog P values.

 

General assay principle:

"This protocol assesses compound efficacy against Plasmodium falciparum in-vitro. This assay is using [3H]-hypoxanthine incorporation or DNA labeling by SYBR Green as a markers of parasite growth. 
This procedure is designed for use with culture adapted P. falciparum strains or clones only. On one 96-well plate typically 03 drugs are tested in duplicate. Standard strains: Plasmodium falciparum, NF54 (sensitive to all known drugs), Plasmodium falciparum, K1 (chloroquine and pyrimethamine resistant). The assay can be performed in dose response mode (12 concentrations in duplicate, 24 data points) which allows determining IC50, or in single concentration mode (one concentration in triplicate, 3 data points) which allows determining the percentage of growth inhibition.
For more information, see Desjardins et al. (Antimicrob. Agents Chemother., 16(6), 710, 1979)."

(Post originally authored by Alice Williamson)

Strings:

OSM-S-291 MMV689968

ClC(C=CC=C1)=C1C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3

InChI=1S/C19H15ClN4O/c20-16-9-5-4-8-15(16)19-23-22-17-12-21-13-18(24(17)19)25-11-10-14-6-2-1-3-7-14/h1-9,12-13H,10-11H2

OSM-S-292 MMV689969 

ClC1=CC=CC(C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3)=C1

InChI=1S/C19H15ClN4O/c20-16-8-4-7-15(11-16)19-23-22-17-12-21-13-18(24(17)19)25-10-9-14-5-2-1-3-6-14/h1-8,11-13H,9-10H2

OSM-S-293 MMV663915 

ClC(C=C1)=CC=C1C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3

InChI=1S/C19H15ClN4O/c20-16-8-6-15(7-9-16)19-23-22-17-12-21-13-18(24(17)19)25-11-10-14-4-2-1-3-5-14/h1-9,12-13H,10-11H2

OSM-S-294 MMV689970 

C12=NN=C(C3=CC=CC=C3)N1C(OCCC4=CC=CC=C4)=CN=C2

InChI=1S/C19H16N4O/c1-3-7-15(8-4-1)11-12-24-18-14-20-13-17-21-22-19(23(17)18)16-9-5-2-6-10-16/h1-10,13-14H,11-12H2"

OSM-S-295 MMV689971 

FC1=CC(C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3)=CC(F)=C1

InChI=1S/C19H14F2N4O/c20-15-8-14(9-16(21)10-15)19-24-23-17-11-22-12-18(25(17)19)26-7-6-13-4-2-1-3-5-13/h1-5,8-12H,6-7H2

OSM-S-296 MMV689972

C12=NN=C(C3=CC(OCO4)=C4C=C3)N1C(OCCC5=CC=CC=C5)=CN=C2

InChI=1S/C20H16N4O3/c1-2-4-14(5-3-1)8-9-25-19-12-21-11-18-22-23-20(24(18)19)15-6-7-16-17(10-15)27-13-26-16/h1-7,10-12H,8-9,13H2

OSM-S-297 MMV689973

C12=NN=C(C3=CC(C=CC=C4)=C4C=C3)N1C(OCCC5=CC=CC=C5)=CN=C2

InChI=1S/C23H18N4O/c1-2-6-17(7-3-1)12-13-28-22-16-24-15-21-25-26-23(27(21)22)20-11-10-18-8-4-5-9-19(18)14-20/h1-11,14-16H,12-13H2

OSM-S-298 MMV689974

FC1=CC(C2=NN=C3N2C(OCC4=NC=CC=C4)=CN=C3)=CC(F)=C1

InChI=1S/C17H11F2N5O/c18-12-5-11(6-13(19)7-12)17-23-22-15-8-20-9-16(24(15)17)25-10-14-3-1-2-4-21-14/h1-9H,10H2"

OSM-S-299 MMV689975

C12=NN=C(C3=CC(OCO4)=C4C=C3)N1C(OCC5=NC=CC=C5)=CN=C2

InChI=1S/C18H13N5O3/c1-2-6-20-13(3-1)10-24-17-9-19-8-16-21-22-18(23(16)17)12-4-5-14-15(7-12)26-11-25-14/h1-9H,10-11H2

OSM-S-300 MMV689976

C12=NN=C(C3=CC(C=CC=C4)=C4C=C3)N1C(OCC5=NC=CC=C5)=CN=C2

InChI=1S/C21H15N5O/c1-2-6-16-11-17(9-8-15(16)5-1)21-25-24-19-12-22-13-20(26(19)21)27-14-18-7-3-4-10-23-18/h1-13H,14H2

OSM-S-301 MMV689977

FC(OC(C=C1)=CC=C1C2=NN=C3N2C(OCC4=NC=CC=C4)=CN=C3)F

InChI=1S/C18H13F2N5O2/c19-18(20)27-14-6-4-12(5-7-14)17-24-23-15-9-21-10-16(25(15)17)26-11-13-3-1-2-8-22-13/h1-10,18H,11H2

A further set of Series 4 Triazolopyrazine compounds have been sent to have their efficacy evaluated against Plasmodium falciparum in-vitro at Syngene.

Some compounds were synthesised by the SSP group at The University Sydney and then purified in the research lab.

Structures are as follows and data will be published in due course:

General assay principle:

"This protocol assesses compound efficacy against Plasmodium falciparum in-vitro. This assay is using [3H]-hypoxanthine incorporation or DNA labeling by SYBR Green as a markers of parasite growth. 
This procedure is designed for use with culture adapted P. falciparum strains or clones only. On one 96-well plate typically 03 drugs are tested in duplicate. Standard strains: Plasmodium falciparum, NF54 (sensitive to all known drugs), Plasmodium falciparum, K1 (chloroquine and pyrimethamine resistant). The assay can be performed in dose response mode (12 concentrations in duplicate, 24 data points) which allows determining IC50, or in single concentration mode (one concentration in triplicate, 3 data points) which allows determining the percentage of growth inhibition.
For more information, see Desjardins et al. (Antimicrob. Agents Chemother., 16(6), 710, 1979)."

(Post originally authored by Alice Williamson)

Strings:

OSM-S-291 MMV689968

ClC(C=CC=C1)=C1C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3

InChI=1S/C19H15ClN4O/c20-16-9-5-4-8-15(16)19-23-22-17-12-21-13-18(24(17)19)25-11-10-14-6-2-1-3-7-14/h1-9,12-13H,10-11H2

OSM-S-292 MMV689969

ClC1=CC=CC(C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3)=C1

InChI=1S/C19H15ClN4O/c20-16-8-4-7-15(11-16)19-23-22-17-12-21-13-18(24(17)19)25-10-9-14-5-2-1-3-6-14/h1-8,11-13H,9-10H2

OSM-S-293 MMV663915

ClC(C=C1)=CC=C1C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3

InChI=1S/C19H15ClN4O/c20-16-8-6-15(7-9-16)19-23-22-17-12-21-13-18(24(17)19)25-11-10-14-4-2-1-3-5-14/h1-9,12-13H,10-11H2

OSM-S-294 MMV689970

C12=NN=C(C3=CC=CC=C3)N1C(OCCC4=CC=CC=C4)=CN=C2

InChI=1S/C19H16N4O/c1-3-7-15(8-4-1)11-12-24-18-14-20-13-17-21-22-19(23(17)18)16-9-5-2-6-10-16/h1-10,13-14H,11-12H2"

OSM-S-295 MMV689971

FC1=CC(C2=NN=C3N2C(OCCC4=CC=CC=C4)=CN=C3)=CC(F)=C1

InChI=1S/C19H14F2N4O/c20-15-8-14(9-16(21)10-15)19-24-23-17-11-22-12-18(25(17)19)26-7-6-13-4-2-1-3-5-13/h1-5,8-12H,6-7H2

OSM-S-296 MMV689972

C12=NN=C(C3=CC(OCO4)=C4C=C3)N1C(OCCC5=CC=CC=C5)=CN=C2

InChI=1S/C20H16N4O3/c1-2-4-14(5-3-1)8-9-25-19-12-21-11-18-22-23-20(24(18)19)15-6-7-16-17(10-15)27-13-26-16/h1-7,10-12H,8-9,13H2

OSM-S-297 MMV689973

C12=NN=C(C3=CC(C=CC=C4)=C4C=C3)N1C(OCCC5=CC=CC=C5)=CN=C2

InChI=1S/C23H18N4O/c1-2-6-17(7-3-1)12-13-28-22-16-24-15-21-25-26-23(27(21)22)20-11-10-18-8-4-5-9-19(18)14-20/h1-11,14-16H,12-13H2

OSM-S-298 MMV689974

FC1=CC(C2=NN=C3N2C(OCC4=NC=CC=C4)=CN=C3)=CC(F)=C1

InChI=1S/C17H11F2N5O/c18-12-5-11(6-13(19)7-12)17-23-22-15-8-20-9-16(24(15)17)25-10-14-3-1-2-4-21-14/h1-9H,10H2"

OSM-S-299 MMV689975

C12=NN=C(C3=CC(OCO4)=C4C=C3)N1C(OCC5=NC=CC=C5)=CN=C2

InChI=1S/C18H13N5O3/c1-2-6-20-13(3-1)10-24-17-9-19-8-16-21-22-18(23(16)17)12-4-5-14-15(7-12)26-11-25-14/h1-9H,10-11H2

OSM-S-300 MMV689976

C12=NN=C(C3=CC(C=CC=C4)=C4C=C3)N1C(OCC5=NC=CC=C5)=CN=C2

InChI=1S/C21H15N5O/c1-2-6-16-11-17(9-8-15(16)5-1)21-25-24-19-12-22-13-20(26(19)21)27-14-18-7-3-4-10-23-18/h1-13H,14H2

OSM-S-301 MMV689977

FC(OC(C=C1)=CC=C1C2=NN=C3N2C(OCC4=NC=CC=C4)=CN=C3)F

InChI=1S/C18H13F2N5O2/c19-18(20)27-14-6-4-12(5-7-14)17-24-23-15-9-21-10-16(25(15)17)26-11-13-3-1-2-8-22-13/h1-10,18H,11H2

Attached sheet lists all compounds inherited by OSM from MMV at the start of the Series 4 campaign with remaining stock - SMILEs only, no structures - along with potencies. This is an update version of the sheet originally listed in MMV triazolopyrazine data

New data from July 2014:

 

Now also included is a PDF sheet containing the compound structures, generated by members of the community from the Excel file. 

 

Older data from March 2014:

 

(these files uploaded by Mat)

 

The PDF report attached to this post contains PK and efficacy information on Series 4 - the triazolopyrazines. The data will be incorporated into the relevant wiki, but is posted here for completeness. Document released to OSM by Paul Willis from MMV.

 

Compound of most interest in this report is MMV639565:

 Related:

Announcing OSM Series 4 - the Triazolopyrazines

Strings for MMV639565

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

InChI InChI=1S/C19H13ClF2N4O/c20-14-4-2-13(3-5-14)19-25-24-17-10-23-11-18(26(17)19)27-8-7-12-1-6-15(21)16(22)9-12/h1-6,9-11H,7-8H2