OSDDMalaria:OSDD Malaria Paper 1

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Emergence of resistance to artemisinin on the Thai-Myanmar border: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960484-X/abstract.
Emergence of resistance to artemisinin on the Thai-Myanmar border: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960484-X/abstract.
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Description of how the open project worked.
==Synthesis==
==Synthesis==
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==Evaluation==
==Evaluation==
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The first round of compounds were evaluated against 3D7 (drug-sensitive) and K1 (resistant). The screen was repeated in three different institutions using different assays. These identified 2-iminothiazolidinone aryl pyrroles as active anti-malarial compounds and confirmed GSK Tres Cantos data set compounds TCMDC-123812 and TCMDC-123794 as active, although less than previously reported. The parent ester and aldehyde compounds were found to be inactive against malaria, indicating that hydrolysis of TCMDC-123* does not result in increased activity, but could result in deactivation. HEK293
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The second round focused on a wider range of 2-iminothiazolidinone analogues. A number of highly active compounds were identified but the most active compounds suffer from poor solubility and high logP. Also the 2-iminothiazolidinone component was shown to be inactive on its own (ZYH 23-1), indicating that both the aryl pyrrole and the 2-iminothiazolidinone are required for activity.
==Conclusions==
==Conclusions==
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The original lab notebook entries and data can be found [http://malaria.ourexperiment.org/ here]
The original lab notebook entries and data can be found [http://malaria.ourexperiment.org/ here]
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=== Pyrroles ===
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=== Pyrrole aldehydes ===
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=== Pyrrole esters ===
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=== Pyrrole amides ===
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=== Pyrrole acids ===
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=== Thiazolidinones ===
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=== Pyrrole Thiazolidinones ===
==Experimental Details for Biological Evaluation==
==Experimental Details for Biological Evaluation==
Description of the biological evaluation can be found [http://malaria.ourexperiment.org/biological_data here]
Description of the biological evaluation can be found [http://malaria.ourexperiment.org/biological_data here]
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=== GSK Assay ===
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=== Avery Assays ===
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=== Bio21 Assays ===
==Supporting Information Section==
==Supporting Information Section==

Current revision

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Contents

Open Source Drug Discovery for Malaria - Highly Potent Compounds Derived from the GSK Arylpyrrole Set

Vicky Avery
Felix Calderon
Sandra Duffy
Javier Gamo
Zoe Hungerford, School of Chemistry, The University of Sydney, NSW 2006, Australia
James Pham
Stuart Ralph
Matthew H. Todd, School of Chemistry, The University of Sydney, NSW 2006, Australia
Paul Willis
Paul Ylioja, School of Chemistry, The University of Sydney, NSW 2006, Australia

Additional authors - add alphabetically if you contribute something substantial. Please include some public place you can be contacted, e.g. a G+ account.

The licence for this page is CC BY 3.0

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Introduction

Possible background to include: lead-oriented synthesis paper (tenuous) and decline of R&D efficiency paper (good).

Malaria's continuing impact.

Emergence of resistance to artemisinin on the Thai-Myanmar border: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960484-X/abstract.

Description of how the open project worked.

Synthesis

The initial targets were TCMDC-123812 and its 4-aminoantipyrine derivative TCMDC-123794. The aryl pyrrole core was obtained via a Paal-Knorr cyclisation using 4-fluoroaniline and 2,5-hexanedione. This gave multi-gram quantities of the pyrrole that could be furnished with an aldehyde in good yield using Vilsmeier-Haack conditions. Unfortunately, the subsequent oxidation of this aldehyde failed to give the desired carboxylic acid in synthetically useful yields. Instead ethyl 2-acetyl-4-oxopentanoate was synthesised and cyclised to the desired pyrrole ester. Hydrolysis followed by conversion to the acid chloride and coupling with glycolamide side chains (xxx and xxx) gave both TCMDC-123812 and TCMDC-123794 in xxx and xxx% yield respectively.

Proposed Synthesis Strategy
Proposed Synthesis Strategy

The 2-iminothiazolidinone analogues were obtained from the pyrrole aldehyde and 2-phenyliminothiazolidin-4-one using conditions used by Roberts. These could then be converted to the acyl, cyclohexyl and acetonitrile derivatives...

Evaluation

The first round of compounds were evaluated against 3D7 (drug-sensitive) and K1 (resistant). The screen was repeated in three different institutions using different assays. These identified 2-iminothiazolidinone aryl pyrroles as active anti-malarial compounds and confirmed GSK Tres Cantos data set compounds TCMDC-123812 and TCMDC-123794 as active, although less than previously reported. The parent ester and aldehyde compounds were found to be inactive against malaria, indicating that hydrolysis of TCMDC-123* does not result in increased activity, but could result in deactivation. HEK293

The second round focused on a wider range of 2-iminothiazolidinone analogues. A number of highly active compounds were identified but the most active compounds suffer from poor solubility and high logP. Also the 2-iminothiazolidinone component was shown to be inactive on its own (ZYH 23-1), indicating that both the aryl pyrrole and the 2-iminothiazolidinone are required for activity.

Conclusions

Acknowledgements

Experimental Details for Novel Compounds

Identities of compounds are here

The original lab notebook entries and data can be found here

Pyrroles

Pyrrole aldehydes

Pyrrole esters

Pyrrole amides

Pyrrole acids

Thiazolidinones

Pyrrole Thiazolidinones

Experimental Details for Biological Evaluation

Description of the biological evaluation can be found here

GSK Assay

Avery Assays

Bio21 Assays

Supporting Information Section

Insert details for known compounds here.

References

(Use PLoS style - see Gamo et al for an example, or the official guidelines are here. Arrange references below in alphabetical order of first author)

  • Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E et al (2010) Thousands of chemical starting points for antimalarial lead identification. Nature 465: 305-310 (DOI: 10.1038/nature09107)
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