OpenSourceMalaria:Triazolopyrazine (TP) Series

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===PfATP4 Activity===
===PfATP4 Activity===
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The following five compounds were evaluated. Structures, potency and metabolism/solubility are here.
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The following five compounds were evaluated. Structures, potency, metabolism/solubility and raw PfATP4 assay data are [http://malaria.ourexperiment.org/biological_data/7934/ here].
[[Image:Original PfATP4 Activities.tif|thumb|center|600px|The Five Compounds Initially Evaluated for PfATP4 activity]]
[[Image:Original PfATP4 Activities.tif|thumb|center|600px|The Five Compounds Initially Evaluated for PfATP4 activity]]
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MMV669000: (potency: inactive)
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MMV669000: no (potency: inactive)
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MMV669304: (potency: 280 nM)
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MMV669304: yes (potency: 280 nM)
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MMV669360: (potency: 356 nM)
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MMV669360: yes (potency: 356 nM)
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MMV669542: (potency: 185 nM)
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MMV669542: yes (potency: 185 nM)
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MMV669848: (potency: 114 nM)
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MMV669848: yes (potency: 114 nM)
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(Note the correlation: compound inactive in PfATP4 assay is the inactive analog)
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MMV669000 did not dissipate the plasma membrane Na+ gradient or increase the plasma membrane pH gradient consistent with it not inhibiting PfATP4 at the concentration tested.
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The other compounds dissipated the plasma membrane Na+ gradient and increased the plasma membrane pH gradient at a concentration of 2 μM, consistent with them being PfATP4 inhibitors.
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(i.e. note the correlation: compound inactive in PfATP4 assay is the inactive analog)
Strings<br>
Strings<br>

Revision as of 00:36, 28 August 2013

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Contents

Open Source Malaria Series 4: The Triazolopyrazine (TP) Series

Introduction

Preamble

This series of compounds arises from industrial work that cannot be disclosed, followed by some hit-to-lead work funded directly by MMV which can. The series is based on a triazolopyrazine core. There is evidence that these compounds may be PfATP4 inhibitors. OSM started to look at this series following a decision by MMV to release their data into the public domain.

Current Aims

Further hit-to-lead work. Validate PfATP4 activity. Improve potency and drug likeness.

Prior Knowledge of the Series

Potency of Hits and Analogs

PfATP4 Activity

The following five compounds were evaluated. Structures, potency, metabolism/solubility and raw PfATP4 assay data are here.

The Five Compounds Initially Evaluated for PfATP4 activity
The Five Compounds Initially Evaluated for PfATP4 activity

MMV669000: no (potency: inactive)

MMV669304: yes (potency: 280 nM)

MMV669360: yes (potency: 356 nM)

MMV669542: yes (potency: 185 nM)

MMV669848: yes (potency: 114 nM)

MMV669000 did not dissipate the plasma membrane Na+ gradient or increase the plasma membrane pH gradient consistent with it not inhibiting PfATP4 at the concentration tested.

The other compounds dissipated the plasma membrane Na+ gradient and increased the plasma membrane pH gradient at a concentration of 2 μM, consistent with them being PfATP4 inhibitors.

(i.e. note the correlation: compound inactive in PfATP4 assay is the inactive analog)

Strings
MMV669000: O=C(N1CC(C=CC=C2)=C2C1)C3=CN=CC4=NN=C(C5=CC=C(OC(F)F)C=C5)N43; InChI=1S/C21H15F2N5O2/c22-21(23)30-16-7-5-13(6-8-16)19-26-25-18-10-24-9-17(28(18)19)20(29)27-11-14-3-1-2-4-15(14)12-27/h1-10,21H,11-12H2
MMV669304: FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(CCCC4=CC=CC=C4)N32; InChI=1S/C21H18F2N4O/c22-21(23)28-18-11-9-16(10-12-18)20-26-25-19-14-24-13-17(27(19)20)8-4-7-15-5-2-1-3-6-15/h1-3,5-6,9-14,21H,4,7-8H2
MMV669360: FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(COCC4=CC=C(F)C(F)=C4)N32; InChI=1S/C20H14F4N4O2/c21-16-6-1-12(7-17(16)22)10-29-11-14-8-25-9-18-26-27-19(28(14)18)13-2-4-15(5-3-13)30-20(23)24/h1-9,20H,10-11H2
MMV669542: FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(C(NC4=CC=CC(Cl)=C4)=O)N32; InChI=1S/C19H12ClF2N5O2/c20-12-2-1-3-13(8-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-4-6-14(7-5-11)29-19(21)22/h1-10,19H,(H,24,28)
MMV669848: FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(CN4CC(C=CC=C5)=C5C4)N32; InChI=1S/C21H17F2N5O/c22-21(23)29-18-7-5-14(6-8-18)20-26-25-19-10-24-9-17(28(19)20)13-27-11-15-3-1-2-4-16(15)12-27/h1-10,21H,11-13H2

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