OpenSourceMalaria:GSK Arylpyrrole Series

From OpenWetWare

Revision as of 19:41, 4 April 2012 by Paul M. Ylioja (Talk | contribs)
Jump to: navigation, search

Malaria Home        OSM So Far        Compound Series        Links        Open Source Research Home        Tech Ops        FAQ       


Contents

The Arylpyrrole Series

These compounds are currently under study by the Todd lab at the University of Sydney and the Medicines for Malaria Venture, Geneva. As an open source project, anyone may participate:
Coordination/Discussion site
Electronic Lab Notebooks
Undergraduate Project Report

The initial two subseries of leads have the general structure:

  • TCMDC Aryl pyrrole core InChi Key: LNROIXNEIZSESG-UHFFFAOYSA-N
  • Near-Neighbour core InChi Key: JZQOEGKHCXONAV-ZROIWOOFSA-N
GSK Tres Cantos Arylpyrrole Generic Structure
Near Neighbour Generic Structure

A number of these compounds and intermediates are available for biological testing from Todd group by request. If you would like to contribute new analogues, please check the list of desired compounds.

The two known TCMDC series starting points

Compounds are commercially-available
Series was listed as one of the most promising leads from TCAMS set (though lacking aryl F)

TCMDC 123812

TCMDC123812

InChI=1/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)
SMILES: O=C(N)COC(=O)c2c(n(c1ccc(F)cc1)c(c2)C)C
CAS Registry Number: 733026-12-5
Chemspider page
ChEMBL Page
Resynthesis:

TCMDC 123794

TCMDC123794

InChI=1/C26H25FN4O4/c1-16-14-22(17(2)30(16)20-12-10-19(27)11-13-20)26(34)35-15-23(32)28-24-18(3)29(4)31(25(24)33)21-8-6-5-7-9-21/h5-14H,15H2,1-4H3,(H,28,32)
SMILES: Fc1ccc(cc1)n2c(cc(c2C)C(=O)OCC(=O)NC=4C(=O)N(c3ccccc3)N(C=4C)C)C
Chemspider page
ChEMBL Page
Resynthesis:

The proposed resynthesis strategy for these two compounds:

Proposed Synthesis Strategy

The Near-Neighbour Sub-series

Known "Near Neighbours" contained in the Tres Cantos set

The original idea for investigation of the near-neighbour set came from Paul Willis and was posted on the synaptic leap.

Known GSK Arylpyrrole Near Neighbours

Data/links for these compounds:

TCMDC-123563, CHEMBL546966, CHEMBL page: 637010 Cc1ccc(cc1)n2c(cc(c2C)C(=O)CN3C(=O)C(NC3=O)Cc4ccccc4)C

TCMDC-125698, CHEMBL587989, CHEMBL: 627784 Cc1cc(c(n1c2ccc(cc2)Cl)C)C=C3C(=O)N(C(=Nc4ccccc4)S3)C5CCCC5

TCMDC-125697, CHEMBL581336, CHEMBL: 640978 CCOC(=O)c1ccc(cc1)n2c(cc(c2C)C=C3C(=O)N(C(=Nc4ccccc4)S3)C5CCCC5)C

TCMDC-125659, CHEMBL528140, CHEMBL: 626220 Cc1ccnc(c1)n2c(cc(c2C)C=C3C(=O)N(C(=Nc4ccccc4)S3)Cc5ccco5)C

TCMDC-124103, CHEMBL588465, CHEMBL: 643107 Cc1cc(cc(c1)n2c(cc(c2C)C=C3C(=O)NC(=Nc4ccc(cc4)Cl)S3)C)C

TCMDC-124456, CHEMBL548395, CHEMBL: 640006 CCn1c(cc(c1C)C=C2C(=O)NC(=Nc3ccccc3)S2)C

Initial synthesis strategy toward near-neighbours

Initial synthesis of near neighbours

Experimental information available from PMY 13-1, PMY 14-1 and PMY 16-1, PMY 14-3.

Current synthesis strategy toward near-neighbours

Current synthesis of near neighbours

Synthesis method taken from this paper.


Alternative side-chains

Some alternative heterocyclic side-chain ideas have been proposed here at the Synaptic Leap.

Oxazoles

The [1] side chain would target ester isosteres (see TCMDC-123812) but with greater biological stability.

Other known incidences of these molecules/this series

Related compounds are known to inhibit the proteasome, according to this Nature paper.

According to this paper, similar compounds are agonists of the sphingosine-1-phosphate receptor subtypes 1-5, which have a role in immune system function.

A new class of antimalarial was recently published by Novartis, Imidazolopiperazines.

Misc papers to digest/assimilate regarding antimycobacterial/tuberculosis activity: Antimycobacterial 1,5-diphenyl pyrroles, 10.1016/j.ejmech.2009.06.005, 10.1016/j.bmc.2010.09.006, 10.1002/cmdc.201000526

Scifinder Search: 2,4,5-alkyl-1-aryl-pyrrole: 77552 hits, 905 biological studies:

WO 2011127333 (A2)

CXCR4 active compound

US 2011251184 (A1)

HDAC6 inhibitor

Obesity/diabetes GIP receptor inhibitor JP 2011184298 (A)

GIP inhibitor

Proteasome WO 2011094545 (A2)

Proteasome agonist

WO2006076202 Steroid nuclear receptor ligands

WO 2011075684 (A1) Inhibitors of Plasma Kallikrein/Protease

WO 2009137133 (A2) 5-Substituted-2-Imino-Thiazolidinone Compounds And Their Use As Inhibitors Of Bacterial Infection

Bacterial inhibitor
Personal tools
{"cc_re__cc_re__cc_by_sa_2_5": ["a href=\"/wiki/OpenWetWare:How_to_join\">\n\t\t\t<img style=\"margin:2px;\" \n\t\t\t\tsrc=\"http://openwetware.org/images/0/03/88x31_JoinOWW.png\" border=0 /></a>\n                </div>\n        </div>\n\t\t\t\t\t\t\t</div>\n\n\t\t\t</div><!-- end of the left column -->\n\t\t\n\t\t\n\t\t\t<div class=\"visualClear\"></div>\n\t\t\t<div id=\"footer\">\n\t\t\t\t<div id=\"f-poweredbyico\"><a href=\"http://www.mediawiki.org/\"><img src=\"/skins/common/images/poweredby_mediawiki_88x31.png\" alt=\"Powered by MediaWiki\" /></a></div>\n\t\t\t\t<div id=\"f-copyrightico\"><a href=\"http://creativecommons.org/licenses/by-sa/2.5/\"><img src=\"/somerights20.png\" alt='GNU FDL or Creative Commons BY-SA' /></a></div>\n\t\t\t<ul id=\"f-list\">\n\t\t\t\t<li id=\"copyright\">Content is available under <a href=\"/wiki/Copyright\" title=\"Copyright\">GNU FDL or Creative Commons BY-SA</a>.</li>\n\t\t\t\t<li id=\"privacy\"><a href=\"/wiki/OpenWetWare:Privacy_policy\" title=\"OpenWetWare:Privacy policy\">Privacy policy</a></li>\n\t\t\t\t<li id=\"about\"><a href=\"/wiki/OpenWetWare:About\" title=\"OpenWetWare:About\">About OpenWetWare</a></li>\n\t\t\t\t<li id=\"disclaimer\"><a href"], "copyright__copyright__copyright": ["", "", "552 hits, 905 biological studies:\n\nWO 2011127333 (A2)\n\nCXCR4 active compound\n\nUS 2011251184 (A1)\n\nHDAC6 inhibitor\n\nObesity/diabetes GIP receptor inhibitor JP 2011184298 (A)\n\nGIP inhibitor\n\nProteasome WO 2011094545 (A2)\n\nProteasome agonist\n\nWO2006076202 Steroid nuclear receptor ligands\n\nWO 2011075684 (A1) Inhibitors of Plasma Kallikrein/Protease\n\nWO 2009137133 (A2) 5-Substituted-2-Imino-Thiazolidinone Compounds And Their Use As Inhibitors Of Bacterial Infection\n\nBacterial inhibitor\nPersonal tools", "552 hits, 905 biological studies:\n\nWO 2011127333 (A2)\n\nCXCR4 active compound\n\nUS 2011251184 (A1)\n\nHDAC6 inhibitor\n\nObesity/diabetes GIP receptor inhibitor JP 2011184298 (A)\n\nGIP inhibitor\n\nProteasome WO 2011094545 (A2)\n\nProteasome agonist\n\nWO2006076202 Steroid nuclear receptor ligands\n\nWO 2011075684 (A1) Inhibitors of Plasma Kallikrein/Protease\n\nWO 2009137133 (A2) 5-Substituted-2-Imino-Thiazolidinone Compounds And Their Use As Inhibitors Of Bacterial Infection\n\nBacterial inhibitor\nPersonal tools", "552 hits, 905 biological studies:\n\nWO 2011127333 (A2)\n\nCXCR4 active compound\n\nUS 2011251184 (A1)\n\nHDAC6 inhibitor\n\nObesity/diabetes GIP receptor inhibitor JP 2011184298 (A)\n\nGIP inhibitor\n\nProteasome WO 2011094545 (A2)\n\nProteasome agonist\n\nWO2006076202 Steroid nuclear receptor ligands\n\nWO 2011075684 (A1) Inhibitors of Plasma Kallikrein/Protease\n\nWO 2009137133 (A2) 5-Substituted-2-Imino-Thiazolidinone Compounds And Their Use As Inhibitors Of Bacterial Infection\n\nBacterial inhibitor\nPersonal tools", "552 hits, 905 biological studies:\n\nWO 2011127333 (A2)\n\nCXCR4 active compound\n\nUS 2011251184 (A1)\n\nHDAC6 inhibitor\n\nObesity/diabetes GIP receptor inhibitor JP 2011184298 (A)\n\nGIP inhibitor\n\nProteasome WO 2011094545 (A2)\n\nProteasome agonist\n\nWO2006076202 Steroid nuclear receptor ligands\n\nWO 2011075684 (A1) Inhibitors of Plasma Kallikrein/Protease\n\nWO 2009137133 (A2) 5-Substituted-2-Imino-Thiazolidinone Compounds And Their Use As Inhibitors Of Bacterial Infection\n\nBacterial inhibitor\nPersonal tools"]}