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22nd January 2015 @ 23:47

Melanie Ridgeway in Kiaran Kirk’s laboratory completed some cross-resistance studies, looking at growth-inhibition by several of the OSM Series 4 compounds of several Kirk ATP4 mutant strains (generated by long-term exposure to increasing concentrations of three Malaria Box hits, as documented in their recent paper).

The data are attached to this post. Each graph is averaged from three independent experiments. Upshot: Data are supportive of Series 4 targeting ATP4.

Series 4 growth assays[1].pdf

Each of the six panels shows the response of four strains (the Dd2 parent and three different PfATP4 mutants) to a different compound.  Panels A-C show growth inhibition by three different Series 4 compounds. Panel D shows growth inhibition by NITD/KAE 609. Panels E and F show growth inhibition by chloroquine and artemisinin.

The three mutant PfATP4 strains show resistance to all three of the Series 4 compounds (Panels A-C) and to NITD609 (Panel D), providing further evidence of a common mechanism of action.

(Note: For two of the three mutant strains there is no significant shift of the chloroquine or artemisinin dose-response curves. But for one of the three mutants there is what appears to be small shifts in the artemisinin and chloroquine dose-response curves, with the artemisinin and chloroquine curves shifted in opposite directions.  The meaning of this is currently unclear.)

Attribution for these data: Kiaran Kirk, Adele Lehane, Melanie Ridgeway. Received by email to Mat Todd, 20th October 2014.

Compound Structures:

Compounds used to generate ATP4 mutants

Compound Strings:

NITD609 KAE609 C[C@@H](C1)N[C@@]2(C(NC3=C2C=C(Cl)C=C3)=O)C4=C1C5=CC(F)=C(Cl)C=C5N4 InChI=1S/C19H14Cl2FN3O/c1-8-4-11-10-6-14(22)13(21)7-16(10)23-17(11)19(25-8)12-5-9(20)2-3-15(12)24-18(19)26/h2-3,5-8,23,25H,4H2,1H3,(H,24,26)/t8-,19+/m0/s1 CKLPLPZSUQEDRT-WPCRTTGESA-N

MMV011567 O=C(C1=CC(Cl)=C(OC)C=C1)NC2=NON=C2C3=CC=C(OC)C(OC)=C3 InChI=1S/C18H16ClN3O5/c1-24-13-6-5-11(8-12(13)19)18(23)20-17-16(21-27-22-17)10-4-7-14(25-2)15(9-10)26-3/h4-9H,1-3H3,(H,20,22,23) RUPCNQRICRCGRU-UHFFFAOYSA-N

MMV007275 ClC(C=C1C(NC2=C(C)C=CC(F)=C2)=O)=CC=C1NC3=CC=CC=C3 InChI=1S/C20H16ClFN2O/c1-13-7-9-15(22)12-19(13)24-20(25)17-11-14(21)8-10-18(17)23-16-5-3-2-4-6-16/h2-12,23H,1H3,(H,24,25) YDYIMBIBJGKUCE-UHFFFAOYSA-N

MMV670944 O=C(NC1=CC=NC(C(F)(F)F)=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C19H11F5N6O2/c20-18(21)32-12-3-1-10(2-4-12)16-29-28-15-9-25-8-13(30(15)16)17(31)27-11-5-6-26-14(7-11)19(22,23)24/h1-9,18H,(H,26,27,31) UEOZBGRWGZEYED-UHFFFAOYSA-N

MMV670767 O=C(NC1=CC=C(F)C(Cl)=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C19H11ClF3N5O2/c20-13-7-11(3-6-14(13)21)25-18(29)15-8-24-9-16-26-27-17(28(15)16)10-1-4-12(5-2-10)30-19(22)23/h1-9,19H,(H,25,29) WFJPUMPZNOYIKX-UHFFFAOYSA-N

MMV671677 O=C(NCC1=C(Cl)C(C(F)(F)F)=CC=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C21H13ClF5N5O2/c22-17-12(2-1-3-14(17)21(25,26)27)8-29-19(33)15-9-28-10-16-30-31-18(32(15)16)11-4-6-13(7-5-11)34-20(23)24/h1-7,9-10,20H,8H2,(H,29,33) YLYCMIJACQNNRW-UHFFFAOYSA-N

Attached Files
10th December 2014 @ 14:10

Biological activities of OSM-S-106 and PT-22-C1 performed at the Dundee Drug Discovery Unit by Irene Hallyburton.

OSM-S-106 was resynthesised in Edinburgh (PT-23-C1) and found to have an activity of 150 nM, consistent with that reported as TCMDC 135294 but a little lower than the Avery results. Adding a methyl group to improve solubility by introducing an axial twist gave PT-22-C1, which was inactive.





OSM-S-106 and PT-22-C1.pdf
Attached Files
17th November 2014 @ 17:48

A set of 12 compounds were sent to Syngene for evaluation against blood stage asexual NF54 strain of Plasmodium falciparum.

Samples sent for in vitro efficacy evaluation against Plasmodium falciparum asexual blood stage

Data were received (via the ScienceCloud portal at MMV) on October 10th. Data for one compound was missing, and subsequently received on Oct 23rd. Data:

Syngene Data Oct 2014


1. CF3 tolerated as a replacement for CHF2 in northeast, which may make synthesis simpler. Impact of using Me looks to be to reduce potency.

Impact of CH3 vs CF3 vs CHF2

(Note - need analysis along similar lines for impact of Cl and CN)

2. High sensitivity to changes in northwest ring. Compare MMV675951 and MMV675950


3. Pyridyl is a bad substitution. Compare MMV675963 with MMV675961, MMV675962. Also compare MMV675949 with OSM-S-189.

4. Benzylic in northwest not bad, but deleterious compared to phenethyl (MMV639565, 38 nM).


This post originally authored by Mat Todd

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Attached Files
16th November 2014 @ 22:57

Context: 12 compounds were sent for evaluation for metabolic clearance by aldehyde oxidase (Discussion, Compounds sent:

Which Compounds to Send for Aldehyde Oxidase Assay?

Assay performed by: Christine Orozco, Scott Obach, Pfizer, Groton CT.


Aldehyde Oxidase Results OSM Series 4


The compounds were incubated in 1 mg/mL cytosol out to 3 hours. Controls: carbazeran, zoniporide and zaleplon were assayed in each incubation plate to represent high, moderate and low AO clearance respectively. The Open Source Malaria compounds were assayed along with the controls and compared using a relative yardstick approach.

The test compounds had a range of clearances. There was one high clearance compound similar to carbazeran, three moderate clearance compounds similar to zoniporide, two compounds with moderate to low clearance, and the remaining four compounds were stable/low clearance with no turnover within 3 hours.

Two compounds were not included for technical reasons. Compound MMV670250 was not detected under the analytical methods used so new LC/MS methods are being developed for this compound. For MMV672939, there was variability in the later time points of both replicates. These two compounds can be repeated in the future.

More detail on the data, protocol, assay notes and conditions is in the attached spreadsheet.

OpenSource Malaria_Cytosol_Results_Protocol_CCO.xlsx

This post originally authored by Mat Todd

MMV668956 FC(F)OC(C=C1)=CC=C1C2=NN=C(N32)C=NC=C3OC4CN(C5=CC(F)=C(F)C=C5)C4 InChI=1S/C21H15F4N5O2/c22-16-6-3-13(7-17(16)23)29-10-15(11-29)31-19-9-26-8-18-27-28-20(30(18)19)12-1-4-14(5-2-12)32-21(24)25/h1-9,15,21H,10-11H2 FFDOLPKXJUAFAH-UHFFFAOYSA-N
MMV669784 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC4=CC=C(Cl)C=C4)N32 InChI=1S/C18H11ClF2N4O2/c19-12-3-7-13(8-4-12)26-16-10-22-9-15-23-24-17(25(15)16)11-1-5-14(6-2-11)27-18(20)21/h1-10,18H WXNPYOXFQUYIOI-UHFFFAOYSA-N
MMV669844 FC(C=C1)=C(F)C=C1[C@@H](OC)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3/t18-/m0/s1 PERKBMZWWUEZNJ-SFHVURJKSA-N
MMV669846 FC1=C(F)C=CC(CCOC2=CN=CC3=NC=C(C4=CC=C(Cl)C=C4)N32)=C1 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
MMV670947 FC(F)OC(C=C1)=CC=C1C2=NN=C(N32)C=NC=C3OCC(CO)C4=CC=C(F)C(F)=C4 InChI=1S/C21H16F4N4O3/c22-16-6-3-13(7-17(16)23)14(10-30)11-31-19-9-26-8-18-27-28-20(29(18)19)12-1-4-15(5-2-12)32-21(24)25/h1-9,14,21,30H,10-11H2 MKSKANAVVSFYNL-UHFFFAOYSA-N
MMV670246 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(C(NC4=CC=C(Cl)C=C4)=O)=CN=C3 InChI=1S/C19H12ClF2N5O2/c20-12-3-5-13(6-4-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-1-7-14(8-2-11)29-19(21)22/h1-10,19H,(H,24,28) CAFUHAVOTBMKAN-UHFFFAOYSA-N
MMV670250 FC1=C(F)C=CC(CCOC2=CN=CC3=CN=C(C4=CC=C(Cl)C=C4)N32)=C1 InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)20-25-11-16-10-24-12-19(26(16)20)27-8-7-13-1-6-17(22)18(23)9-13/h1-6,9-12H,7-8H2 JHORUMGXLQTHAD-UHFFFAOYSA-N
MMV670944 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(C(NC4=CC=NC(F)=C4)=O)=CN=C3 InChI=1S/C18H11F3N6O2/c19-14-7-11(5-6-23-14)24-17(28)13-8-22-9-15-25-26-16(27(13)15)10-1-3-12(4-2-10)29-18(20)21/h1-9,18H,(H,23,24,28) UEOZBGRWGZEYED-UHFFFAOYSA-N
MMV670946 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C=C(OCC4=CC=C(F)C(F)=C4)N=C3 InChI=1S/C19H12F4N4O2/c20-14-6-1-11(7-15(14)21)10-28-17-9-27-16(8-24-17)25-26-18(27)12-2-4-13(5-3-12)29-19(22)23/h1-9,19H,10H2 PPYIQNQWTQZDBZ-UHFFFAOYSA-N
MMV671927 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C=C(NCCC4=CC=C(F)C(F)=C4)N=C3 InChI=1S/C20H15F4N5O/c21-15-6-1-12(9-16(15)22)7-8-25-17-11-29-18(10-26-17)27-28-19(29)13-2-4-14(5-3-13)30-20(23)24/h1-6,9-11,20,25H,7-8H2 GVXYAEXVJYZTBB-UHFFFAOYSA-N
MMV672727 FC(F)OC(C=C1)=CC=C1C2=NN=C(N32)C=NC=C3OCC(F)(C)C4=CC=C(F)C(F)=C4 InChI=1S/C21H15F5N4O2/c1-21(26,13-4-7-15(22)16(23)8-13)11-31-18-10-27-9-17-28-29-19(30(17)18)12-2-5-14(6-3-12)32-20(24)25/h2-10,20H,11H2,1H3 MHMDPQOWBHVFHN-UHFFFAOYSA-N
MMV672939 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=CC(OCCC4=CC(F)=C(F)C=C4)=NN32 InChI=1S/C20H14F4N4O2/c21-15-6-1-12(11-16(15)22)9-10-29-18-8-7-17-25-26-19(28(17)27-18)13-2-4-14(5-3-13)30-20(23)24/h1-8,11,20H,9-10H2 POGWIRSWBGSGTG-UHFFFAOYSA-N

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25th September 2014 @ 10:00

Six "Near Neighbour" compounds in OSM Series 1 were synthesised by an undergraduate cohort at Lawrence University supervised by Stefan Debbert. The compounds have been evaluated for potency by Julie Clark in Kip Guy's lab. The results are summarised below and may be found in full in the attached spreadsheet. Julie said "I ran 2 independent experiments with a data analysis for each experiment, then I re-ran the data analysis for both runs together (combined analysis)." The data will be folded into the first OSM paper that is being written.

Debbert Guy Data

Two of the compounds (OSM-S-37 and OSM-S-111) have been evaluated for potency before. The new numbers matche very well in one case, and not so well in the other. One compound (OSM-A-2 note that the "A" stands for Appleton, where the compounds were made) appears to be unstable, given the difference in the values obtained between the two measurements. Two of the other compounds (OSM-A-1 and OSM-A-4) display low activity. One new compound of the six (OSM-A-3) displays good potency, in fact the best of the set.

At the time of writing, this series is parked, but can be pursued further by anyone. Compounds are potent and synthetically accessible.

(A note from the OSM team to the students who made these compounds - way to go, guys)


Julie Clark provided the attached Word file as a description of the protocol used in the assay.


(This entry authored by Mat)


OSM-S-111, SJ000849514-1, 

OSM-A-2, SJ000849515-1, 

OSM-A-1, SJ000849516-1, 

OSM-A-4, SJ000849517-1, 

OSM-S-37, SJ000849518-1, 

OSM-A-3, SJ000849519-1, 

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