OpenSourceTB:OSTB Series 1

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Background to the Spiro Series

In XXXX 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 because of their XXX.

The two lead members of this series were

Preliminary Work on the Series Outside GSK

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

Focus of First Two Open Spiros Projects

Project 1

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

Compounds Synthesized in the First Round, and their Potencies

One compound (OSTBS4, TCMDC-142379, GSK2200150A) had been tested previously by GSK (CHEMBL2098175), and one has been made previously for a non-TB project.

A paper describing this project is in press in PLoS ONE.

Project 2

Exploration of the heterocycle was performed by Javier González Osende at The University of Sydney. Preliminary biological evaluation was performed by 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

Strings

(Makes molecules on this page machine-discoverable)

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 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 CHEMBL2064198

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) 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 CHEMBL2098175 TCMDC-142379 GSK2200150A

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

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