Next batch of compounds sent for biological testing Jul 2019

[edwintse]

A set of 16 compounds have just been sent to Dundee for screening against P. falciparum.

THE PREDICTIVE MODELLING COMPETITION HAS CONCLUDED (HERE). THE RESULTS FOR THIS BATCH ARE POSTED BELOW

• Control compounds: 698 as the reference compound (#572) and 155 control synthesised by my masters student.
• Phenyl bioisosteres: the last two phenyl bioisosteres that I will make. p-carborane 644 to complete the set and BCP 642 from starting materials provided by Pfizer.
• Benzylic primary alcohol derivatives: compounds made as precursors to the hERG Evador derivatives
• tele-substitution products: compounds isolated as by-products from the diol coupling reactions
• hERG Evador derivatives: two compounds with EWG 640 and EDG 641 to see the effects on potency compared to the original hERG Evador (#26)

MMV Number	SMILES	InChI	InChI Key
MMV897698	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4=CC=CC=C4)N32	InChI=1S/C20H16F2N4O2/c21-20(22)28-16-8-6-15(7-9-16)19-25-24-17-12-23-13-18(26(17)19)27-11-10-14-4-2-1-3-5-14/h1-9,12-13,20H,10-11H2	AVBCIJLYABLIRW-UHFFFAOYSA-N
MMV693155	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=CC=CC=C4)N32	InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2	MGANJQKOPZQELF-UHFFFAOYSA-N
MMV1794644	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCCC4567[BH]89%10[BH]%11%124[BH]8%13%14[BH]%11%15%16[CH]%13%17%18[BH]%149%19[BH]%105%20[BH]%21%226[BH]%17%15([BH]%22%12%167)[BH]%18%19%20%21)N32	InChI=1S/C16H22B10F2N4O2/c27-14(28)34-10-3-1-9(2-4-10)13-31-30-11-7-29-8-12(32(11)13)33-6-5-16-22-17-15-18(17,22)20(15)21(15)19(15,17)23(16,17,22)25(16,19,21)26(16,20,21)24(16,18,20)22/h1-4,7-8,14-15,17-26H,5-6H2	CKBIQPOPXAGIEF-UHFFFAOYSA-N
MMV1794642	FC(F)C1(C2)CC2(COC3=CN=CC4=NN=C(C5=CC=C(OC(F)F)C=C5)N43)C1	InChI=1S/C19H16F4N4O2/c20-16(21)19-7-18(8-19,9-19)10-28-14-6-24-5-13-25-26-15(27(13)14)11-1-3-12(4-2-11)29-17(22)23/h1-6,16-17H,7-10H2	PXXUWBAUMUWHOT-UHFFFAOYSA-N
MMV1794631	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=C(F)C=CC=C4)N32	InChI=1S/C21H17F3N4O3/c22-17-4-2-1-3-16(17)14(11-29)12-30-19-10-25-9-18-26-27-20(28(18)19)13-5-7-15(8-6-13)31-21(23)24/h1-10,14,21,29H,11-12H2	ABSBXVNECYEKEY-UHFFFAOYSA-N
MMV1794632	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(OCC(CO)C4=CC=CC(F)=C4)=NC=CN32	InChI=1S/C21H17F3N4O3/c22-16-3-1-2-14(10-16)15(11-29)12-30-20-19-27-26-18(28(19)9-8-25-20)13-4-6-17(7-5-13)31-21(23)24/h1-10,15,21,29H,11-12H2	PLYCVTLKERZMOF-UHFFFAOYSA-N
MMV1794633	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=C(OC)C=CC=C4)N32	InChI=1S/C22H20F2N4O4/c1-30-18-5-3-2-4-17(18)15(12-29)13-31-20-11-25-10-19-26-27-21(28(19)20)14-6-8-16(9-7-14)32-22(23)24/h2-11,15,22,29H,12-13H2,1H3	UTULOEBHNZHAOG-UHFFFAOYSA-N
MMV1794634	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=CC(OC)=CC=C4)N32	InChI=1S/C22H20F2N4O4/c1-30-18-4-2-3-15(9-18)16(12-29)13-31-20-11-25-10-19-26-27-21(28(19)20)14-5-7-17(8-6-14)32-22(23)24/h2-11,16,22,29H,12-13H2,1H3	JHTYHNMJMLESBY-UHFFFAOYSA-N
MMV1794635	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=CC(C(F)(F)F)=CC=C4)N32	InChI=1S/C22H17F5N4O3/c23-21(24)34-17-6-4-13(5-7-17)20-30-29-18-9-28-10-19(31(18)20)33-12-15(11-32)14-2-1-3-16(8-14)22(25,26)27/h1-10,15,21,32H,11-12H2	RSUSOBALBASKRU-UHFFFAOYSA-N
MMV1794636	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=C(F)C=C(F)C=C4F)N32	InChI=1S/C21H15F5N4O3/c22-13-5-15(23)19(16(24)6-13)12(9-31)10-32-18-8-27-7-17-28-29-20(30(17)18)11-1-3-14(4-2-11)33-21(25)26/h1-8,12,21,31H,9-10H2	UTKUNEDKHGJWFZ-UHFFFAOYSA-N
MMV1794637	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=C(F)C=C(F)C(F)=C4)N32	InChI=1S/C21H15F5N4O3/c22-15-6-17(24)16(23)5-14(15)12(9-31)10-32-19-8-27-7-18-28-29-20(30(18)19)11-1-3-13(4-2-11)33-21(25)26/h1-8,12,21,31H,9-10H2	VNWHTGHTARECMP-UHFFFAOYSA-N
MMV1794638	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(OCC(CO)C4=CC(F)=C(F)C=C4F)=NC=CN32	InChI=1S/C21H15F5N4O3/c22-15-8-17(24)16(23)7-14(15)12(9-31)10-32-20-19-29-28-18(30(19)6-5-27-20)11-1-3-13(4-2-11)33-21(25)26/h1-8,12,21,31H,9-10H2	NEIRZOMSGQEPFH-UHFFFAOYSA-N
MMV1794639	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=CC=C(OC)C=C4)N32	InChI=1S/C22H20F2N4O4/c1-30-17-6-2-14(3-7-17)16(12-29)13-31-20-11-25-10-19-26-27-21(28(19)20)15-4-8-18(9-5-15)32-22(23)24/h2-11,16,22,29H,12-13H2,1H3	WPBMLSOEVMUHGX-UHFFFAOYSA-N
MMV1794640	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C(O)=O)C4=C(F)C=C(F)C=C4F)N32	InChI=1S/C21H13F5N4O4/c22-11-5-14(23)18(15(24)6-11)13(20(31)32)9-33-17-8-27-7-16-28-29-19(30(16)17)10-1-3-12(4-2-10)34-21(25)26/h1-8,13,21H,9H2,(H,31,32)	OTUKSSDCGFNGTE-UHFFFAOYSA-N
MMV1794641	FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C(O)=O)C4=CC=C(OC)C=C4)N32	InChI=1S/C22H18F2N4O5/c1-31-15-6-2-13(3-7-15)17(21(29)30)12-32-19-11-25-10-18-26-27-20(28(18)19)14-4-8-16(9-5-14)33-22(23)24/h2-11,17,22H,12H2,1H3,(H,29,30)	BGONQZJCXFSVTQ-UHFFFAOYSA-N
MMV1794643	FC(F)OC(C=C1)=CC=C1C2=NN=C3C(OCC(CO)C4=CC=CC=C4)=NC=CN32	InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)18-25-26-19-20(24-10-11-27(18)19)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2	HFXALRWXEQXCJL-UHFFFAOYSA-N

Dundee Compounds 170719.zip

[MFernflower]

Really like the new bicyclic that Pfizer gave us!

[mattodd]

Yes, it's neat, right? We just got approval that we could mention it in public - there was a condition applied to their gift of one of the starting materials. Really great to have these samples on the way to Dundee, well done @edwintse !

[edwintse]

In case you're wondering about the results, we have received them BUT will not be revealing them at this stage. They will be used as part of the test set to judge the final models from the predictive modelling competition happening here so they will be posted after the conclusion of the competition.

[edwintse]

UPDATE: The predictive modelling competition has concluded so we can now post the results from this batch.

---

Brief comments:

• The potency of the control compounds is as expected.
• The p-carborane compound is the least potent of the set (ortho = 0.05 uM, meta = 0.12 uM). This appears to be in line with the hydrophobicity and polarity changes between the three isomers.
• The BCP analogue is roughly equipotent with the corresponding benzyl ether compound (2.24 uM). Encouragingly, the BCP compound showed improved metabolic stability (#72). I'm currently trying to make the BCP derivative with an extra methylene unit in the ether chain - the BCP analogue of the control compound MMV897698
• The benzylic primary alcohol derivatives are generally quite potent. The meta-substituted derivatives are the most potent amongst the set.
• Unsurprisingly, the tele-substitution products are inactive. The potency for the 3-F derivative could not be obtained as there was too little compound for the assay.
• Substitution on the phenyl ring of the hERG Evador (3.88 uM) was not tolerated well with both ED and EW groups resulting in potency drops.

[MFernflower]

Great! Also lends credence to an idea I had involving the BCP fuctional group being used in the mycetoma compounds @fantasy121

@maratsydney when will the results of the anthacene compound be made public?

[edwintse]

Could be interesting for sure but it'd be up to @fantasy121 if he want's to give it a shot. Unfortunately I won't be able to provide any of the BCP alcohol or the acid as those compounds were part of an agreement we had with Pfizer.

I've let @maratsydney know that the competition has concluded so he will post the results of the August batch soon.

[MFernflower]

@edwintse @fantasy121

That pretty much puts the nail in the coffin for my idea - considering what I'm proposing to test would need these two rather expensive intermediates (since none of the Pfizer share can be used)!

[MFernflower]

I'm just spitballing but if you have any 4-fluorobicyclo[2.2.2]octane-1-carbaldehyde left I think it would not be to hard to react that with phenyllithium

@edwintse @fantasy121