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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
11th December 2013 @ 07:31

Professor Sue Charman's team (Monash University) have conducted physiochemical evaluation and metabolism studies for the following eight compounds:

Physiochemical Evaluation

Study Objective: To evaluate the physicochemical properties of the selected compounds.

CDCO_MMV_OSDD_13_004_Chem.pdf

Metabolism in Human and Mouse Liver Microsomes

Study Objective: To determine the in vitro metabolic stability of the selected compounds using human and mouse liver microsomes as a preliminary indication of the likely in vivo metabolic clearance.

CDCO_MMV_OSDD_13_005_Met.pdf

Analysis:

Paul Willis made the following conclusions from the studies:

'Solubility is low and improvement should be one of the goals for LO. The metabolic stability is not a mouse specific event and needs to be improved to deliver a candidate – the met ID data will follow and may help in the design of new, analogues with improved stability (but we could also look at correlations with Log D etc. to drive new target design)'

Data:

Strings:

MMV668957

InChI=1S/C22H19F2N5O/c23-22(24)30-18-8-6-16(7-9-18)21-27-26-19-12-25-13-20(29(19)21)28-11-10-17(14-28)15-4-2-1-3-5-15/h1-9,12-13,17,22H,10-11,14H2

MMV668958

InChI=1S/C20H14ClF2N5O2/c21-14-3-1-2-12(8-14)9-25-19(29)16-10-24-11-17-26-27-18(28(16)17)13-4-6-15(7-5-13)30-20(22)23/h1-8,10-11,20H,9H2,(H,25,29)

MMV669304

InChI=1S/C21H18F2N4O/c22-21(23)28-18-11-9-16(10-12-18)20-26-25-19-14-24-13-17(27(19)20)8-4-7-15-5-2-1-3-6-15/h1-3,5-6,9-14,21H,4,7-8H2

MMV670438

InChI=1S/C22H16F4N4O3/c23-16-6-3-14(7-17(16)24)22(10-31-11-22)12-32-19-9-27-8-18-28-29-20(30(18)19)13-1-4-15(5-2-13)33-21(25)26/h1-9,21H,10-12H2

MMV670944

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)

MMV671651

InChI=1S/C20H15F4N5O2/c21-14-6-3-12(7-15(14)22)16(25)10-30-18-9-26-8-17-27-28-19(29(17)18)11-1-4-13(5-2-11)31-20(23)24/h1-9,16,20H,10,25H2/t16-/m0/s1

MMV672723

InChI=1S/C21H16F4N4O3/c1-21(30,13-4-7-15(22)16(23)8-13)11-31-18-10-26-9-17-27-28-19(29(17)18)12-2-5-14(6-3-12)32-20(24)25/h2-10,20,30H,11H2,1H3

MMV672727

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






Linked Posts
Attached Files
28th November 2013 @ 02:06

Sandra Duffy from Vicky Avery's group at Griffith University has carried out a late stage gametocyte assay on two compounds, OSM-S-106 and OSM-S-111.

Uni Sydney14-06-13-Late stage GAM-SD OSM.xlsx
LSGA.cdxml

 

Comments on data from Sandra Duffy

"In the gametocyte late stage (IV-V) imaging assay, viable gametocytes have an elongated solid GFP fluorescent morphology and a MTR fluorescent staining pattern of a small intense spot within the GFP body of the gametocyte image. The MTR object is classified based on its relative fluorescent intensity, radius and contrast to background.  Gametocytes when treated with 5uM Puromycin loose the elongated morphology becoming a small disorganized object with no classified MTR objects. Essentially the gametocytes are destroyed in structure and have no centralized or recognizable MTR signal.

 
Gametocytes treated with OSM-S-111 demonstrate a different phenotype to puromycin treated gametocytes. The parasite morphology is still intact as demonstrated by the GFP fluorescence but the MTR signal has no concentrated spot of intensity. There is a small low fluorescent MTR staining pattern distributed throughout the parasite structure but there is no singular intense localized MTR signal to identify as an active mitochondria. Compounds with this phenotype may be determined as not active if geimsa staining and light microscopy were performed to determine compound action.

This phenotype is seen for small numbers of other compounds tested within this assay. At present we are unable to give a definitive reason for this different phenotype, but have hypothesized that it could be related to a slow acting mechanism where by the parasite slowly dies due to a direct effect on mitochondrial metabolism but not exclusively so. As the compound action is slow, the parasite structure is still intact within the assay time frame of a total of 96hours. We have not as yet tested compounds with this activity phenotype for longer treatment times as the total of 96 hours is already a significant activity time frame.'
 

Related publication here: http://www.malariajournal.com/content/12/1/408

Linked Entries
Attached Files
12th November 2013 @ 04:41

Professor Kiaran Kirk's laboratory at the Australian National University have kindly agreed to test some OSM compounds in a their 'parasite ion regulation assay'.

The compounds below have been sent for evaluation:

InChi (in order OSM-S-4, 5, 35, 51, 111, 106)

InChI=1S/C13H12FNO2/c1-8-7-12(13(16)17)9(2)15(8)11-5-3-10(14)4-6-11/h3-7H,1-2H3,(H,16,17)

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)

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-

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-

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-

InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-2-1-3-8(4-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18)

Excel File:

Kiaran Kirk Cmpnds.xlsx

ChemDraw:

Parasite Ion Regulation Assays.cdxml
Linked Posts
Attached Files
11th November 2013 @ 23:59

Posted on behalf of Joie Garfunkle:

"Here is a list of compounds submitted for both MetID (3 compounds) and microsomal stability/LogD/solubility studies (8 compounds). When we receive the data we will post the results to the OSDD community. In the meantime, if there is another institution willing to assist in DMPK work for free, we are more than willing to help supply solid samples if available."

 

 
Requests for DMPK November 1 2013.xlsx
Attached Files