OpenSourceTB:OSTB Series 1: Difference between revisions

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{{OpenSourceTB}}
{{OpenSourceTB}}


==Current Activity==
Note - this page is now out of date. The active page is on Github [https://github.com/OpenSourceTB/OSTB_Series_1/wiki here].
 
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 [https://twitter.com/opensourcetb 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 [http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200428/abstract 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 [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060933 reported] that the mechanism of action was ''via'' the mycolic acid transporter Mmpl3, the target of multiple recently-identified chemotypes (e.g. [https://www.nature.com/articles/ncomms3907 indoleamides]) ([http://www.nature.com/nrd/journal/v13/n2/full/nrd4250.html Review]). A [http://aac.asm.org/content/58/11/6413 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 [https://www.ncbi.nlm.nih.gov/pubmed/24119636 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.
 
[[Image:Spirocycle projects.png|thumb|center|300px| '''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.
 
[[Image:First Round GSK.png|thumb|center|700px| '''Compounds Synthesized in the First Round, and their Potencies''']]
 
One compound (OSTBS4, TCMDC-142379) had been tested [http://www.ncbi.nlm.nih.gov/pubmed/23307663 previously by GSK] ([https://www.ebi.ac.uk/chembl/compound/inspect/CHEMBL2098175 CHEMBL2098175]), and one has been made previously for a [http://pubs.acs.org/doi/abs/10.1021/jm300302p non-TB project].
 
A paper describing this part of the project has been [http://dx.doi.org/10.1371/journal.pone.0111782 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.
 
[[Image:Second Round GSK.png|thumb|center|700px| '''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 [http://openwetware.org/wiki/OpenSourceMalaria:GSK_Arylpyrrole_Series OSM Series 1]) was explored by Jessica Baiget working at GSK Tres Cantos. The following compounds were made and evaluated.
 
[[Image:Third Round Jessica.png|thumb|center|700px| '''Compounds Synthesized in the Third Round, and their Potencies''']]
 
 
==Other Sources of These, or Similar, Compounds==
 
===Commercial===
 
===Literature===
 
==Data for this Page==
[http://bit.ly/1J2cqw7 Master List of OSTB Compounds] - this page details Series 1
 
[https://github.com/OpenSourceTB/Wiki-Files Files for this wiki page] and [https://github.com/OpenSourceTB/OSTB-Compounds/tree/master/Series%201 chemdraw/png files for all molecules].
 
[http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0111782 Published paper] on part of this series, including [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0111782#s5 SI], [http://ses.library.usyd.edu.au/handle/2123/10506 raw data files] and a [http://ses.library.usyd.edu.au/handle/2123/10461 browsable snapshot of the relevant lab notebook].
 
[https://au-mynotebook.labarchives.com/share/Jessica%2520Baiget%2520Gonzalez/MTI2LjF8NjU1Lzk3L1RyZWVOb2RlLzQyNjE1NzcyMDR8MzIwLjE= 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

Latest revision as of 18:02, 17 June 2018

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