OpenSourceMalaria:GSK Arylpyrrole Series

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Contents

The Arylpyrrole Series

The initial two leads have the general structure:

GSK Tres Cantos Arylpyrrole Generic Structure
GSK Tres Cantos Arylpyrrole Generic Structure

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

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

A number of these compounds and intermediates are available for biological testing from Todd group by request.

The two known series examples

TCMDC 123812

TCMDC123812
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
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
Proposed Synthesis Strategy

Known "Near Neighbours" contained in the Tres Cantos set

Known GSK Arylpyrrole Near Neighbours
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
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
Current synthesis of near neighbours

Synthesis method taken from this paper.

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
CXCR4 active compound

US 2011251184 (A1)

HDAC6 inhibitor
HDAC6 inhibitor

Obesity/diabetes GIP receptor inhibitor JP 2011184298 (A)

GIP inhibitor
GIP inhibitor

Proteasome WO 2011094545 (A2)

Proteasome agonist
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

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