OpenSourceTB:OSTB Series 1

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Current Activity

The data on this page are now (March 2016) being combined with closed data at GSK Tres Cantos and being written up for publication. Updates will go on Twitter, or email opensourcetb@gmail.com.

Background to the Spiro Series

In 2012 GSK performed a phenotypic screen against M. bovis BCG as a surrogate of the virulent strain of Mycobacterium tuberculosis (H37Rv), ultimately discovering 177 small molecules displaying <10 micro molar inhibitory concentration against H37Rv which also possessed favorable good membrane permeability, alignment with the Rule of 5.

One such series, the Spiros, were viewed as one of seven particularly promising sets of compounds.

Mechanism of Action

It was reported that the mechanism of action was via the mycolic acid transporter Mmpl3, the target of multiple recently-identified chemotypes (e.g. indoleamides) (Review). A more recent paper suggests that Mmpl3 is not the target of these chemotypes, but rather that these compounds act to dissipate transmembrane proton gradients. This brings into question whether Mmpl3 is the target of the Spiros series. There is also the question of why so many compounds are discovered that appear to hit membrane targets, with the likely fault being high logP.

Preliminary Work on the Series Outside GSK

Three open research projects have been completed on analog synthesis and evaluation.

Focus of First Open Spiros Projects

Project 1

Exploration of the N-substituent was performed by Katrina Badiola at The University of Sydney, with the potency data being obtained by A/Prof Jamie Triccas at the same university.

Compounds Synthesized in the First Round, and their Potencies

One compound (OSTBS4, TCMDC-142379) had been tested previously by GSK (CHEMBL2098175), and one has been made previously for a non-TB project.

A paper describing this part of the project has been published.

Project 2

Exploration of the heterocycle was performed by Javier González Osende at The University of Sydney. Preliminary biological evaluation was performed by A/Prof Jamie Triccas at The University of Sydney, and full evaluation was performed by GSK Tres Cantos. The data obtained are summarised below.

Compounds Synthesized in the Second Round, and their Potencies

Project 3

Variation in the promising "hybrid compound" consisting of the spirocycle core appended with the aryl pyrrole (used widely in OSM Series 1) was explored by Jessica Baiget working at GSK Tres Cantos. The following compounds were made and evaluated.

Compounds Synthesized in the Third Round, and their Potencies


Other Sources of These, or Similar, Compounds

Commercial

Literature

Data for this Page

Master List of OSTB Compounds - this page details Series 1

Files for this wiki page and chemdraw/png files for all molecules.

Published paper on part of this series, including SI, raw data files and a browsable snapshot of the relevant lab notebook.

Jessica Baiget's Lab notebook

OSTBS1 [H]N(CC1)CCC21C3=C(SC=C3)CCO2 InChI=1S/C11H15NOS/c1-7-13-11(3-5-12-6-4-11)9-2-8-14-10(1)9/h2,8,12H,1,3-7H2 KARGZLCFESUWBW-UHFFFAOYSA-N

OSTBS2 (CHEMBL2064198) C12=C(SC=C2)CCOC13CCN(CC4=CC=CC=C4)CC3 InChI=1S/C18H21NOS/c1-2-4-15(5-3-1)14-19-10-8-18(9-11-19)16-7-13-21-17(16)6-12-20-18/h1-5,7,13H,6,8-12,14H2 WRPOPKKINJVHKF-UHFFFAOYSA-N

OSTBS3 O=C(OCCCl)N(CC1)CCC21C3=C(SC=C3)CCO2 InChI=1S/C14H18ClNO3S/c15-5-9-18-13(17)16-6-3-14(4-7-16)11-2-10-20-12(11)1-8-19-14/h2,10H,1,3-9H2 RXXGDCXYAFFODV-UHFFFAOYSA-N

OSTBS4 (OSM-S-210 CHEMBL2098175 TCMDC-142379) C12=C(SC=C2)CCOC13CCN(CC4=CC(OCCO5)=C5C=C4)CC3 InChI=1S/C20H23NO3S/c1-2-17-18(23-11-10-22-17)13-15(1)14-21-7-5-20(6-8-21)16-4-12-25-19(16)3-9-24-20/h1-2,4,12-13H,3,5-11,14H2 NCRPMBWORFWNGT-UHFFFAOYSA-N

OSTBS5 C12=C(SC=C2)CCOC13CCN(CC4=CC(OCO5)=C5C=C4)CC3 InChI=1S/C19H21NO3S/c1-2-16-17(22-13-21-16)11-14(1)12-20-7-5-19(6-8-20)15-4-10-24-18(15)3-9-23-19/h1-2,4,10-11H,3,5-9,12-13H2 ACOYQJHGMQYDJB-UHFFFAOYSA-N

OSTBS6 OC(C=C1)=C(OC)C=C1CN(CC2)CCC32C4=C(SC=C4)CCO3 InChI=1S/C19H23NO3S/c1-22-17-12-14(2-3-16(17)21)13-20-8-6-19(7-9-20)15-5-11-24-18(15)4-10-23-19/h2-3,5,11-12,21H,4,6-10,13H2,1H3 KBNYOKOGHUQGHP-UHFFFAOYSA-N

OSTBS7 ClC(C=C1)=CC=C1CN(CC2)CCC32C4=C(SC=C4)CCO3 InChI=1S/C18H20ClNOS/c19-15-3-1-14(2-4-15)13-20-9-7-18(8-10-20)16-6-12-22-17(16)5-11-21-18/h1-4,6,12H,5,7-11,13H2 IKDZLARXTXDYSV-UHFFFAOYSA-N

OSTBS8 (OSM-S-214) (HCl salt of OSTBS9) CC1=CC(CN(CC2)CCC32C4=C(SC=C4)CCO3)=C(C)N1C5=CC=C(F)C=C5.Cl InChI=1S/C24H27FN2OS.ClH/c1-17-15-19(18(2)27(17)21-5-3-20(25)4-6-21)16-26-11-9-24(10-12-26)22-8-14-29-23(22)7-13-28-24;/h3-6,8,14-15H,7,9-13,16H2,1-2H3;1H MHQORCJLAHARKG-UHFFFAOYSA-N

OSTBS9 (free amine on OSTBS8) CC1=CC(CN(CC2)CCC32C4=C(SC=C4)CCO3)=C(C)N1C5=CC=C(F)C=C5 InChI=1S/C24H27FN2OS/c1-17-15-19(18(2)27(17)21-5-3-20(25)4-6-21)16-26-11-9-24(10-12-26)22-8-14-29-23(22)7-13-28-24/h3-6,8,14-15H,7,9-13,16H2,1-2H3 JOUHIYBEDRSIMN-UHFFFAOYSA-N

OSTBS10 C12=C(SC=C2)CCOC13CCN(C4CCCCC4)CC3 InChI=1S/C17H25NOS/c1-2-4-14(5-3-1)18-10-8-17(9-11-18)15-7-13-20-16(15)6-12-19-17/h7,13-14H,1-6,8-12H2 XLYPXGDSQIIAGC-UHFFFAOYSA-N

OSTBS11 (OSM-S-216) O=C(C1=CC=CC=C1)N(CC2)CCC32C4=C(SC=C4)CCO3 InChI=1S/C18H19NO2S/c20-17(14-4-2-1-3-5-14)19-10-8-18(9-11-19)15-7-13-22-16(15)6-12-21-18/h1-5,7,13H,6,8-12H2 DJCDYAUIXOORLS-UHFFFAOYSA-N

OSTBS12 O=C(C1=CC=C(Br)C=C1)N(CC2)CCC32C4=C(SC=C4)CCO3 InChI=1S/C18H18BrNO2S/c19-14-3-1-13(2-4-14)17(21)20-9-7-18(8-10-20)15-6-12-23-16(15)5-11-22-18/h1-4,6,12H,5,7-11H2 NZVHUZGXLTUEBD-UHFFFAOYSA-N

OSTBS13 O=C(C1=C(Br)C=CC=C1)N(CC2)CCC32C4=C(SC=C4)CCO3 InChI=1S/C18H18BrNO2S/c19-15-4-2-1-3-13(15)17(21)20-9-7-18(8-10-20)14-6-12-23-16(14)5-11-22-18/h1-4,6,12H,5,7-11H2 LHLPZMBZHPYLMM-UHFFFAOYSA-N

OSTBS14 (OSM-S-198) C12=C(C=CS2)CCOC13CCN(CC4=CC=CC=C4)CC3 InChI=1S/C18H21NOS/c1-2-4-15(5-3-1)14-19-10-8-18(9-11-19)17-16(6-12-20-18)7-13-21-17/h1-5,7,13H,6,8-12,14H2 ZZQIGFUYNABBCP-UHFFFAOYSA-N

OSTBS15 (OSM-S-194) C12=C(C(C=CC=C3)=C3N2)CCOC14CCN(CC5=CC=CC=C5)CC4 InChI=1S/C22H24N2O/c1-2-6-17(7-3-1)16-24-13-11-22(12-14-24)21-19(10-15-25-22)18-8-4-5-9-20(18)23-21/h1-9,23H,10-16H2 ZZRXZXUKZZBHSK-UHFFFAOYSA-N

OSTBS16 (OSM-S-199) C12=C(C(C=CC=C3)=C3N2)CCOC14CCN(CC5=CC(OCCO6)=C6C=C5)CC4 InChI=1S/C24H26N2O3/c1-2-4-20-18(3-1)19-7-12-29-24(23(19)25-20)8-10-26(11-9-24)16-17-5-6-21-22(15-17)28-14-13-27-21/h1-6,15,25H,7-14,16H2 VOUYSWHZMJVQFH-UHFFFAOYSA-N

OSTBS17 (OSM-S-197) C12=C(C(C=CC=C3)=C3N2)CCOC14CCNCC4 InChI=1S/C15H18N2O/c1-2-4-13-11(3-1)12-5-10-18-15(14(12)17-13)6-8-16-9-7-15/h1-4,16-17H,5-10H2 ADIFMQFOYVKYJG-UHFFFAOYSA-N

OSTBS18 (OSM-S-200) C12=C(C(C=CC=C3)=C3S2)CCOC14CCN(CC5=CC=CC=C5)CC4 InChI=1S/C22H23NOS/c1-2-6-17(7-3-1)16-23-13-11-22(12-14-23)21-19(10-15-24-22)18-8-4-5-9-20(18)25-21/h1-9H,10-16H2 BXTAXLWLFOLFKL-UHFFFAOYSA-N

OSTBS19 (OSM-S-195) ClC1=CC=CC2=C1CCOC23CCN(CC4=CC=CC=C4)CC3 InChI=1S/C20H22ClNO/c21-19-8-4-7-18-17(19)9-14-23-20(18)10-12-22(13-11-20)15-16-5-2-1-3-6-16/h1-8H,9-15H2 MMFIRWPCCHXYHI-UHFFFAOYSA-N

OSTBS20 (OSM-S-196) COC(C(OC)=C1)=CC2=C1C3(CCN(CC4=CC=CC=C4)CC3)OCC2 InChI=1S/C22H27NO3/c1-24-20-14-18-8-13-26-22(19(18)15-21(20)25-2)9-11-23(12-10-22)16-17-6-4-3-5-7-17/h3-7,14-15H,8-13,16H2,1-2H3 ADXUPDCQQACVPU-UHFFFAOYSA-N

OSTBS21 CC1=C(C=C(C)N1C2=CC=C(OC)C=C2)CN(CC3)CCC43C5=C(SC=C5)CCO4 InChI=1S/C25H30N2O2S/c1-18-16-20(19(2)27(18)21-4-6-22(28-3)7-5-21)17-26-12-10-25(11-13-26)23-9-15-30-24(23)8-14-29-25/h4-7,9,15-16H,8,10-14,17H2,1-3H3 SKYPEZIEIFQUKV-UHFFFAOYSA-N

OSTBS22 CC1=C(C=C(C)N1C2=CC=CC=N2)CN(CC3)CCC43C5=C(SC=C5)CCO4 InChI=1S/C23H27N3OS/c1-17-15-19(18(2)26(17)22-5-3-4-10-24-22)16-25-11-8-23(9-12-25)20-7-14-28-21(20)6-13-27-23/h3-5,7,10,14-15H,6,8-9,11-13,16H2,1-2H3 PRUZKNSDUCOGQL-UHFFFAOYSA-N

OSTBS23 CC1=C(C=C(C)N1C2=CC=CC=C2)CN(CC3)CCC43C5=C(SC=C5)CCO4 InChI=1S/C24H28N2OS/c1-18-16-20(19(2)26(18)21-6-4-3-5-7-21)17-25-12-10-24(11-13-25)22-9-15-28-23(22)8-14-27-24/h3-7,9,15-16H,8,10-14,17H2,1-2H3 MPUPSSIARGDOOI-UHFFFAOYSA-N

OSTBS24 CC1=C(C=C(C)N1C2=CC=CN=C2)CN(CC3)CCC43C5=C(SC=C5)CCO4 InChI=1S/C23H27N3OS/c1-17-14-19(18(2)26(17)20-4-3-9-24-15-20)16-25-10-7-23(8-11-25)21-6-13-28-22(21)5-12-27-23/h3-4,6,9,13-15H,5,7-8,10-12,16H2,1-2H3 QFOULAQETKMYPI-UHFFFAOYSA-N

OSTBS25 CC1=C(C=C(C)N1C2=CC=C(F)C=C2)C(N(CC3)CCC43C5=C(SC=C5)CCO4)=O InChI=1S/C24H25FN2O2S/c1-16-15-20(17(2)27(16)19-5-3-18(25)4-6-19)23(28)26-11-9-24(10-12-26)21-8-14-30-22(21)7-13-29-24/h3-6,8,14-15H,7,9-13H2,1-2H3 AGMHHROBLIOLOY-UHFFFAOYSA-N

OSTBS26 CC1=C(C=C(C)N1C2=CC=C(F)C=C2)CN(CC3)CCC43C5=C(C(C=CC=C6)=C6N5)CCO4 InChI=1S/C28H30FN3O/c1-19-17-21(20(2)32(19)23-9-7-22(29)8-10-23)18-31-14-12-28(13-15-31)27-25(11-16-33-28)24-5-3-4-6-26(24)30-27/h3-10,17,30H,11-16,18H2,1-2H3 FPOLKZMYVPDQIT-UHFFFAOYSA-N