OpenSourceMalaria:Triazolopyrazine (TP) Series

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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

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

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