OpenSourceMalaria:GSK Arylpyrrole Series

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{{OSDDMalaria}}
{{OSDDMalaria}}
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1) The initial two leads have the general structure:<br>
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== The Arylpyrrole Series ==
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[[Image:Arylpyrrole Generic.png|none|left|120px|GSK Tres Cantos Arylpyrrole Generic Structure]]<br>
+
This page contains a summary of all the data associated with this open source project. A more [[OSDDMalaria:GSK_Arylpyrrole_Series:Story_so_far|'''human-readable summary''']] is available.
-
<br>
+
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:<br>
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:<br>
[http://www.thesynapticleap.org/node/342 Coordination/Discussion site]<br>
[http://www.thesynapticleap.org/node/342 Coordination/Discussion site]<br>
-
[http://malaria.ourexperiment.org/tcmdc_ap Electronic Lab Notebooks]<br>
+
[http://malaria.ourexperiment.org/ Electronic Lab Notebooks]<br>
 +
[[Todd:Synthesis_of_Analogs_of_Arylpyrrole_Antimalarial_Drug_Leads|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
 +
 
 +
[[Image:Arylpyrrole Generic.png|thumb|right|120px|GSK Tres Cantos Arylpyrrole Generic Structure]]
 +
[[Image:Nearneighbour generic.png|thumb|right|120px|Near Neighbour Generic Structure]]
 +
 
 +
A number of these compounds and intermediates are [[OSDDMalaria:GSK_Arylpyrrole_Series:available_compounds|available]] for biological testing from Todd group by request. If you would like to contribute new analogues, please check the list of [[OSDDMalaria:GSK_Arylpyrrole_Series:desired_compounds|desired]] compounds.
 +
 
 +
=== The two known TCMDC series starting points ===
 +
 
Compounds are [http://www.thesynapticleap.org/node/345 commercially-available]<br>
Compounds are [http://www.thesynapticleap.org/node/345 commercially-available]<br>
-
Series was [http://pubs.acs.org/doi/abs/10.1021/ml200135p listed as one of the most promising leads] from TCAMS set (though lacking aryl F)<br>
 
-
2) The two known series examples:<br>
+
Series was released in a [http://www.nature.com/nature/journal/v465/n7296/full/nature09107.html large dataset] by GSK and later [http://pubs.acs.org/doi/abs/10.1021/ml200135p listed as one of the most promising leads] from TCAMS set (though lacking aryl F)<br>
-
'''TCMDC 123812'''<br>
+
==== TCMDC 123812 ====
-
[[Image:Arylpyrrole 1.png|none|left|260px|TCMDC123812]]<br>
+
[[Image:Arylpyrrole 1.png|thumb|center|260px|TCMDC123812]]
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<br>
+
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)<br>
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)<br>
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Resynthesis:<br>
Resynthesis:<br>
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'''TCMDC 123794'''<br>
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==== TCMDC 123794 ====
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[[Image:Arylpyrrole 2.png|none|left|260px|TCMDC123794]]<br>
+
[[Image:Arylpyrrole 2.png|thumb|center|260px|TCMDC123794]]
-
<br>
+
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)<br>
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)<br>
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The proposed resynthesis strategy for these two compounds:<br>
The proposed resynthesis strategy for these two compounds:<br>
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[[Image:arylpyrrolesynth.png|none|600px|left|Proposed Strategy]]<br>
 
-
3) Known "Near Neighbours" contained in the Tres Cantos set
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[[Image:arylpyrrolesynth.png|thumb|450px|center|Proposed Synthesis Strategy]]
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[[Image:Near neighbours.png|none|600px|left|Known GSK Arylpyrrole Near Neighbours]]<br>
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=== The Near-Neighbour Sub-series ===
 +
 
 +
==== Known "[[OSDDMalaria:GSK_Arylpyrrole_Series:Near Neighbours|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 [http://www.thesynapticleap.org/node/349 the synaptic leap].
 +
 
 +
[[Image:Near neighbours.png|thumb|450px|center|Known GSK Arylpyrrole Near Neighbours]]<br>
Data/links for these compounds:
Data/links for these compounds:
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CCn1c(cc(c1C)C=C2C(=O)NC(=Nc3ccccc3)S2)C
CCn1c(cc(c1C)C=C2C(=O)NC(=Nc3ccccc3)S2)C
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Potential synthesis strategy toward near-neighbours:
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==== Initial synthesis strategy toward near-neighbours ====
 +
 
 +
[[Image:Nearneighbour.png|thumb|center|450px|Initial synthesis of near neighbours]]
 +
 
 +
Experimental information available from [http://malaria.ourexperiment.org/uri/32 PMY 13-1], [http://malaria.ourexperiment.org/uri/33 PMY 14-1] and [http://malaria.ourexperiment.org/uri/39 PMY 16-1], [http://malaria.ourexperiment.org/uri/41 PMY 14-3].
 +
 
 +
==== Current synthesis strategy toward near-neighbours ====
 +
 
 +
[[Image:Nearneighbour2.png|thumb|center|450px|Current synthesis of near neighbours]]
 +
Synthesis method taken from [http://dx.doi.org/10.1016/j.bmcl.2011.09.049 this paper].
 +
 
 +
 
 +
=== Alternative side-chains ===
 +
 
 +
Some alternative heterocyclic side-chain ideas have been proposed [http://www.thesynapticleap.org/node/367 here] at the Synaptic Leap.
 +
 
 +
==== Oxazoles ====
 +
 
 +
The [http://en.wikipedia.org/wiki/Oxazole|oxazole] side chain would target ester isosteres (see TCMDC-123812) but with greater biological stability.
 +
 
 +
*Synthesis: [http://dx.doi.org/10.1021/ol101145t oxazole synthesis]
 +
*Pyrrole core acid to amide: [http://dx.doi.org/10.1021/jm100504d Amide Synthesis]
 +
 
 +
=== Other known incidences of these molecules/this series ===
 +
 
 +
Related compounds are known to inhibit the proteasome, according to [http://www.nature.com/nature/journal/v467/n7312/abs/nature09299.html this Nature paper].
 +
 
 +
According to [http://dx.doi.org/10.1016/j.bmcl.2011.09.049 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, [http://dx.doi.org/10.1021/jm2003359 Imidazolopiperazines].
 +
 
 +
Misc papers to digest/assimilate regarding antimycobacterial/tuberculosis activity: [http://dx.doi.org10.1021/jm701560p Antimycobacterial 1,5-diphenyl pyrroles], [http://dx.doi.org/10.1016/j.ejmech.2009.06.005 10.1016/j.ejmech.2009.06.005], [http://dx.doi.org/10.1016/j.bmc.2010.09.006 10.1016/j.bmc.2010.09.006], [http://dx.doi.org/10.1002/cmdc.201000526 10.1002/cmdc.201000526]<br>
 +
 
 +
''' ChEMBL-NTD '''
 +
 
 +
Searches on [https://www.ebi.ac.uk/chemblntd/compound/structure_home ChEMBL-NTD] reveal:
 +
* 19 iminothiazolidinones
 +
* 55 2,5-dialkylpyrroles
 +
* 58 rhodanines. These do not contain any biological data, presumably omitted due to promiscuity/PAINS issues.
 +
 
 +
'''Scifinder Search:'''
 +
2,4,5-alkyl-1-aryl-pyrrole: 77552 hits, 905 biological studies:
 +
 
 +
[http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&adjacent=true&locale=en_EP&FT=D&date=20111013&CC=WO&NR=2011127333A2&KC=A2 WO 2011127333  (A2)]
 +
[[Image:CXCR4.png|thumb|none|CXCR4 active compound]]
 +
 
 +
[http://worldwide.espacenet.com/publicationDetails/description?CC=US&NR=2011251184A1&KC=A1&FT=D&date=20111013&DB=EPODOC&locale=en_EP US 2011251184  (A1)]
 +
[[Image:HDAC6.png|thumb|none|HDAC6 inhibitor]]
 +
 
 +
Obesity/diabetes GIP receptor inhibitor [http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&adjacent=true&locale=en_EP&FT=D&date=20110922&CC=JP&NR=2011184298A&KC=A JP 2011184298  (A)]
 +
[[Image:Obesity_diabetes.png|thumb|none|GIP inhibitor]]
 +
 
 +
Proteasome [http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&adjacent=true&locale=en_EP&FT=D&date=20110804&CC=WO&NR=2011094545A2&KC=A2 WO 2011094545  (A2)]
 +
[[Image:Proteasome.png|thumb|none|Proteasome agonist]]
 +
 
 +
[http://www.wipo.int/patentscope/search/en/WO2006076202 WO2006076202] Steroid nuclear receptor ligands
 +
 
 +
[http://worldwide.espacenet.com/publicationDetails/description?CC=WO&NR=2011075684A1&KC=A1&FT=D&date=20110623&DB=EPODOC&locale=en_EP WO 2011075684  (A1)] Inhibitors of Plasma [http://en.wikipedia.org/wiki/Kallikrein Kallikrein]/Protease
 +
 
 +
[http://worldwide.espacenet.com/publicationDetails/biblio?FT=D&date=20091112&DB=EPODOC&locale=en_EP&CC=WO&NR=2009137133A2&KC=A2&ND=5 WO 2009137133 (A2)] 5-Substituted-2-Imino-Thiazolidinone Compounds And Their Use As Inhibitors Of Bacterial Infection
 +
[[Image:WO2009137133A2.png|thumb|none|Bacterial inhibitor]]
 +
 
 +
== Biology ==
 +
 
 +
=== Malaria Assays ===
 +
==== '''''In vitro''''' ====
 +
Current tested compounds and their biological activities are summarised on a Google [http://bit.ly/OSDDcompounds spreadsheet]
 +
 
 +
The results are collected on [http://malaria.ourexperiment.org/biological_data malaria.ourexperiment.org].
 +
 
 +
==== '''''In vivo''''' ====
 +
 
 +
TCMDC-123812, TCMDC-123794 and near neighbour ZYH 3-1 have been [http://www.thesynapticleap.org/node/395 submitted] for study oral ''in vivo'' mouse model. Unfortunately it was found that the compounds possess zero oral efficacy (Results available [http://malaria.ourexperiment.org/uri/ed here]) in this initial trial.
 +
 
 +
=== Mode of action ===
 +
==== ''In silico'' prediction ====
 +
 
 +
''In silico'' prediction of targets has been carried out by [https://plus.google.com/u/0/b/114702323662314783325/115238763121035691959/posts Iain Wallace] and summarised by [[User:Matthew_Todd|Mat]] on [http://www.thesynapticleap.org/node/387 the synaptic leap]. Detail on the procedure is given on the [http://malaria.ourexperiment.org/in_silico_prediction/2675 ELN]. The following targets were identified from data derived from the ChEMBL database:
 +
 
 +
* Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1
 +
* Dihydroorotate dehydrogenase (DHODH)[in progress at GSK Tres Cantos]
 +
* SUMO-activating enzyme subunit 2
 +
* SUMO-activating enzyme subunit 1
 +
* Cyclin-dependent kinase 1
-
Experimental information available from [http://malaria.ourexperiment.org/uri/32 PMY 13-1], [http://malaria.ourexperiment.org/uri/33 PMY 14-1] and [http://malaria.ourexperiment.org/uri/39 PMY 16-1].
+
Collaborators are invited to investigate these targets to confirm if these are targeted by our compounds.
-
4) Other known incidences of these molecules/this series<br>
+
==== ''In vitro'' ====
-
Related compounds are known to inhibit the proteasome, according to [http://www.nature.com/nature/journal/v467/n7312/abs/nature09299.html this Nature paper].<br>
+
GSK Tres Cantos have offered to assay our compounds against dihydroorotate dehydrogenase (DHODH).

Revision as of 00:29, 6 June 2012

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Contents

The Arylpyrrole Series

This page contains a summary of all the data associated with this open source project. A more human-readable summary is available.

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
GSK Tres Cantos Arylpyrrole Generic Structure
Near Neighbour 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 released in a large dataset by GSK and later listed as one of the most promising leads from TCAMS set (though lacking aryl F)

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

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
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.


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

ChEMBL-NTD

Searches on ChEMBL-NTD reveal:

  • 19 iminothiazolidinones
  • 55 2,5-dialkylpyrroles
  • 58 rhodanines. These do not contain any biological data, presumably omitted due to promiscuity/PAINS issues.

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

Bacterial inhibitor
Bacterial inhibitor

Biology

Malaria Assays

In vitro

Current tested compounds and their biological activities are summarised on a Google spreadsheet

The results are collected on malaria.ourexperiment.org.

In vivo

TCMDC-123812, TCMDC-123794 and near neighbour ZYH 3-1 have been submitted for study oral in vivo mouse model. Unfortunately it was found that the compounds possess zero oral efficacy (Results available here) in this initial trial.

Mode of action

In silico prediction

In silico prediction of targets has been carried out by Iain Wallace and summarised by Mat on the synaptic leap. Detail on the procedure is given on the ELN. The following targets were identified from data derived from the ChEMBL database:

  • Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1
  • Dihydroorotate dehydrogenase (DHODH)[in progress at GSK Tres Cantos]
  • SUMO-activating enzyme subunit 2
  • SUMO-activating enzyme subunit 1
  • Cyclin-dependent kinase 1

Collaborators are invited to investigate these targets to confirm if these are targeted by our compounds.

In vitro

GSK Tres Cantos have offered to assay our compounds against dihydroorotate dehydrogenase (DHODH).

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