Analogues of the phenol compound

[david1597]

Alongside the chemical synthesis of the biosynthesised phenol compound OSM-S-412 -
OpenSourceMalaria/OSM_To_Do_List#525 - I also plan to make the analogues shown below: bioisosteres, positional isomers and a halogen bond as a hydrogen bond mimic (following a suggestion through Twitter).

[MFernflower]

LHS lactones anyone? @mcoster

also is your ELN up yet?

[david1597]

My ELN.

[david1597]

Priority for now is OSM-S-412, with those other five structures which have bioisosteres of phenol as time permits.

Additional ideas for playing around with the LHS, including those lactones, will probably wait until the first batch are made and we have some data on them.

[mattodd]

Good review as source of inspiration for this question of phenol isosteres
http://pubs.acs.org/doi/abs/10.1021/jm1013693
@drc007 (you may have already suggested this)

[mcoster]

My two cents... I'd suggest exploring SAR around the phenol itself, in addition to bioisosteres. Even in the (excellent) bioisostere review (thx @mattodd ), there's examples of med chemists getting around problems with phenols by tinkering with substituents on the aromatic or doing phenyl -> pyridyl. Substituting around the phenol ring may also positively impact it's binding role and/or ADMET properties. Below are a few ideas. Also included is CHF2 (as a lipophilic H-bond donor), and CF3. My rationale on the latter is simply that we saw CF3 as a phenol replacement work well in our work on the natural product angelmarin (no idea why!). In that work, there was only a ~3.5-fold increase in potency from -H to -OH on the phenyl ring, but CF3 was ~3.5x more potent still. I've also thrown in a '4-hydroxypyridazine' compound as a bit of a lark. :)

[MFernflower]

Para sf5 on the benzene ring might be neat to try @mcoster https://user-images.githubusercontent.com/3164942/33584763-e22373c2-d92e-11e7-82af-dc040ca3fce5.png

[mcoster]

I don't know much about these new-fangled SF₅ bioisosteres, but I do remember Nicholas Meanwell, in a workshop here, say that SF₅building blocks are expensive. Not to say it wouldn't be possible, but would be a factor to consider, since there would be a number of steps from the commercial SF₅ building block to the target compound. @MFernflower

[MFernflower]

Just throwing ideas around Update 12/5/17: @mcoster The SF5 building block that @david1597 would couple to diethyl malonate is really cheap! (50 USD a gram is best price I have found) https://t.co/JhsMaxO43I http://www.combi-blocks.com/cgi-bin/find.cgi?QA-6968

[david1597]

@mcoster - I like it. I put an order in earlier today for some chemicals to pursue ideas around this phenol area...maybe I should have included some more! I'll post a update to this later in the week once our summer scholar, Josh, introduces what he plans to do in his project.

I also agree with OpenSourceMalaria/OSM_To_Do_List#551, it'd be neat to have a way to collectively agree on the best targets to aim for from suggestions such as the above.

[david1597]

As promised, an update to this is over at OpenSourceMalaria/OSM_To_Do_List#555 - a discussion about which compounds we should target next as part of this family. It includes some of the compounds suggested above.

[david1597]

The pCF3 analogue, suggested above by @mcoster and voted for as a 'High Priority Target' in the poll, has been synthesised:

pCF3 scheme.zip

ELN links:
DGS 44-1
DGS 45-1
DGS 51-2

Names/strings:
DGS 51-2
OSM-S-486
FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=CC=C(C(F)(F)F)C=C4)N32
InChI=1S/C22H17F5N4O3/c23-21(24)34-17-7-3-14(4-8-17)20-30-29-18-9-28-10-19(31(18)20)33-12-15(11-32)13-1-5-16(6-2-13)22(25,26)27/h1-10,15,21,32H,11-12H2
PDJUGAPLRLVSPE-UHFFFAOYSA-N

[mcoster]

Well done! I hope it's super active! 😉

[david1597]

The meta analogue has been synthesised:

meta.zip

ELN links:
DGS 19-2
DGS 30-1
DGS 33-1
DGS 32-1

Names/strings:
DGS 32-1
OSM-S-533
FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(CO)C4=CC=CC(O)=C4)N32
InChI=1S/C21H18F2N4O4/c22-21(23)31-17-6-4-13(5-7-17)20-26-25-18-9-24-10-19(27(18)20)30-12-15(11-28)14-2-1-3-16(29)8-14/h1-10,15,21,28-29H,11-12H2
OKGRHDYGIKFDNY-UHFFFAOYSA-N