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4th May 2016 @ 13:21

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

Attached Files
8th November 2015 @ 23:13

Four OSM Series 1 compounds were evaluated in a P. falciparum dual gamete formation assay, with data in the attached report. Literature on this assay is in this paper. The assay was performed by the original Imperial team

All compounds were found to be inactive (low activity) against both male and female gametocytes, though the levels of activity for some compounds were higher vs. female than any antimalarials originally tested in the above-linked paper (where the maximum % inhibition at this concentration was 27%).

These data are a little surprising given that several of these compounds had previously displayed very high levels of activity in a late stage gametocyte assay:

Late stage gametocyte testing of a sample set of GSK-Arylpyrrole Series

Late Stage Gametocyte Assay (OSM-S-111)

it might have been expected that there would have been more activity vs (the more susceptible) males.

 DGFA Compounds Assayed from OSM Series 1

Compounds tested:

OSM-S-5

CC(N1C2=CC=C(F)C=C2)=C(C(OCC(N)=O)=O)C=C1C InChI=1S/C15H15FN2O3/c1-9-7-13(15(20)21-8-14(17)19)10(2)18(9)12-5-3-11(16)4-6-12/h3-7H,8H2,1-2H3,(H2,17,19) YSUCFIZUNLQZDX-UHFFFAOYSA-N

OSM-S-38

CC1=CC(/C=C(C(N/2)=O)\SC2=N/C3=CC=CC=C3)=C(C)N1C(C=C4)=CC=C4C(F)(F)F InChI=1S/C23H18F3N3OS/c1-14-12-16(15(2)29(14)19-10-8-17(9-11-19)23(24,25)26)13-20-21(30)28-22(31-20)27-18-6-4-3-5-7-18/h3-13H,1-2H3,(H,27,28,30)/b20-13- YBBWTVGRVHTTDD-MOSHPQCFSA-N

OSM-S-39

CC1=CC(/C=C(C(N/2)=O)\SC2=N/C3=CC=CC=C3)=C(C)N1C4=CC(C(F)(F)F)=CC(C(F)(F)F)=C4 InChI=1S/C24H17F6N3OS/c1-13-8-15(9-20-21(34)32-22(35-20)31-18-6-4-3-5-7-18)14(2)33(13)19-11-16(23(25,26)27)10-17(12-19)24(28,29)30/h3-12H,1-2H3,(H,31,32,34)/b20-9- GVGNOLWIUGQIHW-UKWGHVSLSA-N

OSM-S-111

CC1=CC(/C=C(C(N/2)=O)\SC2=N/C3=CC=CC=C3)=C(C)N1C4=CC=C(OC)C=C4 InChI=1S/C23H21N3O2S/c1-15-13-17(16(2)26(15)19-9-11-20(28-3)12-10-19)14-21-22(27)25-23(29-21)24-18-7-5-4-6-8-18/h4-14H,1-3H3,(H,24,25,27)/b21-14- KXIVXNPEYYNDHE-STZFKDTASA-N

 

This post originally authored by Mat Todd

Attached Files
6th September 2015 @ 18:13

Recent analysis was undertaken by Corey Nislow (see GHI20) on predicting the mechanism of action of Series 1 compounds. In discussions that took place by email (sorry) which are being incorporated into the final draft of the paper about to be submitted on Series 1, a suggestion was made by Corey that the different compounds in Series 1 may have different MoAs. To verify whether this might be true, one arylpyrrole and several Near Neighbours were sent for evaluation in a Parasite Reduction Ratio (PRR) (colloquially, Rate of Killing) assay at GSK Tres Cantos. Thank you to Benigno Crespo and Laura Sanz for doing this, and to Javier Gamo for signing off on the report, which is attached.

The PRR assay can reveal possible MoA based on a comparison of the killing profile of the compounds. If the pattern of parasite ratio, followed over several days, matches the profile found using an existing compound, it's possible they may share a MoA.

Here are the compounds analysed:

GSK PRR Assay Compounds

Here are the combined results.

 Combined GSK PRR Data

Conclusions

Within the noise of this experiment it would seem as though the compounds share a common MoA. A suggestion was made by Corey that, based on the HipHop results, one compound (OSM-S-39) may share commonalities with artemisinin. Though artemisinin was not evaluated in the present assay run, it is known to possess a very rapid rate of killing that would not match the profiles obtained  for the present compounds.

Compounds examined:

Aryl Pyrrole:

MMV019247 OSM-S-5

Near Neighbours:
MMV689017 OSM-S-10
MMV689018 OSM-S-35
MMV689019 OSM-S-37
MMV689020 OSM-S-39
MMV689021 OSM-S-51

 

Compound Strings:

MMV019247 OSM-S-5 FC1=CC=C(N2C(C)=CC(C(OCC(N)=O)=O)=C2C)C=C1 InChI=1S/C15H15FN2O3/c1-9-7-13(15(20)21-8-14(17)19)10(2)18(9)12-5-3-11(16)4-6-12/h3-7H,8H2,1-2H3,(H2,17,19) YSUCFIZUNLQZDX-UHFFFAOYSA-N

MMV689017 OSM-S-10 FC1=CC=C(N2C(C)=CC(/C=C3S/C(NC\3=O)=N\C4=CC=CC=C4)=C2C)C=C1 InChI=1S/C22H18FN3OS/c1-14-12-16(15(2)26(14)19-10-8-17(23)9-11-19)13-20-21(27)25-22(28-20)24-18-6-4-3-5-7-18/h3-13H,1-2H3,(H,24,25,27)/b20-13- IMCPBTMVWRMBHR-MOSHPQCFSA-N

MMV689018 OSM-S-35 CC1=C(/C=C2S/C(NC\2=O)=N\C3=CC=CC=C3)C=C(C)N1C4=CC=CC=C4 InChI=1S/C22H19N3OS/c1-15-13-17(16(2)25(15)19-11-7-4-8-12-19)14-20-21(26)24-22(27-20)23-18-9-5-3-6-10-18/h3-14H,1-2H3,(H,23,24,26)/b20-14- QTDBAHFMTAMGMZ-ZHZULCJRSA-N

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Attached Files