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14th June 2016 @ 07:33

Update: Please see Wiki for updated SAR information

A further set of 12  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 Comments

Esters MMV69348-50 showed moderate activity.

3,4-halogentated SSP Compounds MMV69349 & -50 showed moderate activity whereas 4-fluoro (MMV69352) and 2,4-dichloro (MMV69353) showed promising activity and some insight into the importance of substituent position on the RH aromatic group.

Thioethers, sulfoxide and and sulfones were all inactive.

Triazole MMV693165 was also inactive.

Homologous alcohol MMV69355 showed promising activity, in common with the 3,4-difluoro anologue (MMV670947, 24 nM) and supports exploration of analogous amine and carboxylic acid.

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

 

MMV693148 OSM-S-346 AEW 284-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC(C)C4=CC=C(Cl)C(Cl)=C4)N32 InChI=1S/C20H14Cl2F2N4O2/c1-11(13-4-7-15(21)16(22)8-13)29-18-10-25-9-17-26-27-19(28(17)18)12-2-5-14(6-3-12)30-20(23)24/h2-11,20H,1H3 ILDZQTSEZGQWFR-UHFFFAOYSA-N

MMV693149 OSM-S-347 AEW 285-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4=CC=C(Cl)C(Cl)=C4)N32 InChI=1S/C19H12Cl2F2N4O2/c20-14-6-1-11(7-15(14)21)10-28-17-9-24-8-16-25-26-18(27(16)17)12-2-4-13(5-3-12)29-19(22)23/h1-9,19H,10H2 CSHOSFVEVPHTHZ-UHFFFAOYSA-N

MMV693150 OSM-S-348 AEW 286-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4=CC=C(Cl)C=C4)N32 InChI=1S/C19H13ClF2N4O2/c20-14-5-1-12(2-6-14)11-27-17-10-23-9-16-24-25-18(26(16)17)13-3-7-15(8-4-13)28-19(21)22/h1-10,19H,11H2 ROAUWAVERUYYHI-UHFFFAOYSA-N

MMV693151 OSM-S-349 AEW 290-1 FC(C=C1)=C(F)C=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H14F2N4O/c20-15-7-6-14(10-16(15)21)19-24-23-17-11-22-12-18(25(17)19)26-9-8-13-4-2-1-3-5-13/h1-7,10-12H,8-9H2 DNQWZOZQWWSJTR-UHFFFAOYSA-N

MMV693152 OSM-S-350 AEW 291-1 ClC(C=C1)=C(Cl)C=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H14Cl2N4O/c20-15-7-6-14(10-16(15)21)19-24-23-17-11-22-12-18(25(17)19)26-9-8-13-4-2-1-3-5-13/h1-7,10-12H,8-9H2 DJLRRTBQGVDDPH-UHFFFAOYSA-N

MMV693153 OSM-S-351 AEW 292-1 ClC(C=C(Cl)C=C1)=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H14Cl2N4O/c20-14-6-7-15(16(21)10-14)19-24-23-17-11-22-12-18(25(17)19)26-9-8-13-4-2-1-3-5-13/h1-7,10-12H,8-9H2 VJQTVLCLRZKBED-UHFFFAOYSA-N

MMV693154 OSM-S-352 AEW 293-1 FC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H15FN4O/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 QCWQNZCCYWUBQM-UHFFFAOYSA-N

MMV693155 OSM-S-353 AEW 294-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC=CC=C4)CO)N32 InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2 MGANJQKOPZQELF-UHFFFAOYSA-N

MMV693161 OSM-S-359 EGT 48-1 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

MMV693162 OSM-S-360 EGT 45-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(S(CC4=CC=CC=C4)=O)N32 InChI=1S/C19H14F2N4O2S/c20-19(21)27-15-8-6-14(7-9-15)18-24-23-16-10-22-11-17(25(16)18)28(26)12-13-4-2-1-3-5-13/h1-11,19H,12H2 HSYPMILIAZBMAQ-UHFFFAOYSA-N

MMV693163 OSM-S-361 EGT 39-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(S(CC4=CC=CC=C4)(=O)=O)N32 InChI=1S/C19H14F2N4O3S/c20-19(21)28-15-8-6-14(7-9-15)18-24-23-16-10-22-11-17(25(16)18)29(26,27)12-13-4-2-1-3-5-13/h1-11,19H,12H2 OCXPXTXAACVDON-UHFFFAOYSA-N

MMV693165 OSM-S-362 EGT 51-4 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N4N=NC(C5=CC=CC=C5)=C4)N32 InChI=1S/C20H13F2N7O/c21-20(22)30-15-8-6-14(7-9-15)19-26-25-17-10-23-11-18(29(17)19)28-12-16(24-27-28)13-4-2-1-3-5-13/h1-12,20H WUWMNWSXMOOYGG-UHFFFAOYSA-N

Attached Files
4th May 2016 @ 12:21

The following compounds were shipped to Syngene yesterday. These may be discussed over at Github Issue 384

 

 OSM Syngene Shipment May 2016

 

Strings

 

MMV693148 OSM-S-346 AEW 284-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC(C)C4=CC=C(Cl)C(Cl)=C4)N32 InChI=1S/C20H14Cl2F2N4O2/c1-11(13-4-7-15(21)16(22)8-13)29-18-10-25-9-17-26-27-19(28(17)18)12-2-5-14(6-3-12)30-20(23)24/h2-11,20H,1H3 ILDZQTSEZGQWFR-UHFFFAOYSA-N

MMV693149 OSM-S-347 AEW 285-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4=CC=C(Cl)C(Cl)=C4)N32 InChI=1S/C19H12Cl2F2N4O2/c20-14-6-1-11(7-15(14)21)10-28-17-9-24-8-16-25-26-18(27(16)17)12-2-4-13(5-3-12)29-19(22)23/h1-9,19H,10H2 CSHOSFVEVPHTHZ-UHFFFAOYSA-N

MMV693150 OSM-S-348 AEW 286-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC4=CC=C(Cl)C=C4)N32 InChI=1S/C19H13ClF2N4O2/c20-14-5-1-12(2-6-14)11-27-17-10-23-9-16-24-25-18(26(16)17)13-3-7-15(8-4-13)28-19(21)22/h1-10,19H,11H2 ROAUWAVERUYYHI-UHFFFAOYSA-N

MMV693151 OSM-S-349 AEW 290-1 FC(C=C1)=C(F)C=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H14F2N4O/c20-15-7-6-14(10-16(15)21)19-24-23-17-11-22-12-18(25(17)19)26-9-8-13-4-2-1-3-5-13/h1-7,10-12H,8-9H2 DNQWZOZQWWSJTR-UHFFFAOYSA-N

MMV693152 OSM-S-350 AEW 291-1 ClC(C=C1)=C(Cl)C=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H14Cl2N4O/c20-15-7-6-14(10-16(15)21)19-24-23-17-11-22-12-18(25(17)19)26-9-8-13-4-2-1-3-5-13/h1-7,10-12H,8-9H2 DJLRRTBQGVDDPH-UHFFFAOYSA-N

MMV693153 OSM-S-351 AEW 292-1 ClC(C=C(Cl)C=C1)=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H14Cl2N4O/c20-14-6-7-15(16(21)10-14)19-24-23-17-11-22-12-18(25(17)19)26-9-8-13-4-2-1-3-5-13/h1-7,10-12H,8-9H2 VJQTVLCLRZKBED-UHFFFAOYSA-N

MMV693154 OSM-S-352 AEW 293-1 FC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32 InChI=1S/C19H15FN4O/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 QCWQNZCCYWUBQM-UHFFFAOYSA-N

MMV693155 OSM-S-353 AEW 294-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC=CC=C4)CO)N32 InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2 MGANJQKOPZQELF-UHFFFAOYSA-N

MMV693161 OSM-S-359 EGT 48-1 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

MMV693162 OSM-S-360 EGT 45-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(S(CC4=CC=CC=C4)=O)N32 InChI=1S/C19H14F2N4O2S/c20-19(21)27-15-8-6-14(7-9-15)18-24-23-16-10-22-11-17(25(16)18)28(26)12-13-4-2-1-3-5-13/h1-11,19H,12H2 HSYPMILIAZBMAQ-UHFFFAOYSA-N

MMV693163 OSM-S-361 EGT 39-1 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(S(CC4=CC=CC=C4)(=O)=O)N32 InChI=1S/C19H14F2N4O3S/c20-19(21)28-15-8-6-14(7-9-15)18-24-23-16-10-22-11-17(25(16)18)29(26,27)12-13-4-2-1-3-5-13/h1-11,19H,12H2 OCXPXTXAACVDON-UHFFFAOYSA-N

MMV693164 OSM-S-362 EGT 51-4 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N4N=NC(C5=CC=CC=C5)=C4)N32 InChI=1S/C20H13F2N7O/c21-20(22)30-15-8-6-14(7-9-15)19-26-25-17-10-23-11-18(29(17)19)28-12-16(24-27-28)13-4-2-1-3-5-13/h1-12,20H WUWMNWSXMOOYGG-UHFFFAOYSA-N

Attached Files
9th December 2015 @ 23:47

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

Attached Files
11th November 2015 @ 01:28

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

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14th June 2015 @ 21:26

Compounds 1, 2, 3, 5, 8, 9 and 10 from the top ten compounds were sent to have their efficacy evaluated against Plasmodium falciparum in-vitro at Syngene.

All values in nanoMolar.

They were repeated twice owing to poor quality statistics in the first assay:

 The results didn't reveal any 'killer' compounds but provided the team with some important SAR information.

  • Aliphatic groups in top right of the molecule kill activity.
  • Unsubstituted aromatic group in top right of the molecule kill activity.
  • Substituted pyridines more potent than unsubstituted.
  • Replacing alcohol side chain with methanol kills activity.
  • Polar group in benzylic position of side chain improves activity but mono-methylation of benzylic amine kills activity.

 

The team are currently digesting the latest data and a new set of target molecules will be proposed later today and discussed in an online meeting to be arranged next week. 

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)

Attached Files