Biological Evaluation of Compounds

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:

Here are the combined results.

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

MMV689019 OSM-S-37 CC1=C(/C=C2S/C(NC\2=O)=N\C3=CC=CC=C3)C=C(C)N1C4=CC=C(C)C=C4 InChI=1S/C23H21N3OS/c1-15-9-11-20(12-10-15)26-16(2)13-18(17(26)3)14-21-22(27)25-23(28-21)24-19-7-5-4-6-8-19/h4-14H,1-3H3,(H,24,25,27)/b21-14- XCTPMKNSBDOHRB-STZFKDTASA-N

MMV689020 OSM-S-39 CC1=C(/C=C2S/C(NC\2=O)=N\C3=CC=CC=C3)C=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

MMV689021 OSM-S-51 CC1=C(/C=C2S/C(NC\2=O)=N\C3=CC=CC=C3)C=C(C)N1C4=NC=CC=C4 InChI=1S/C21H18N4OS/c1-14-12-16(15(2)25(14)19-10-6-7-11-22-19)13-18-20(26)24-21(27-18)23-17-8-4-3-5-9-17/h3-13H,1-2H3,(H,23,24,26)/b18-13- WFGBKPBKZGJAHY-AQTBWJFISA-N