The OSM Blog

I'm Paul, a third year chemistry student at the University of Sydney. I have been working with Alice in the lab for some time now but so far, I have only made the simpler compounds.

Over the next few weeks, I will be working on derivatising molecules (SGS 7-1, SGS 9-1, SGS 8-1, SGS ?) that were synthesised by students from Sydney Grammar School. The purity of these molecules will checked with NMR and if necessary, will be purified.

Derivitisation of these molecules will be with an alcohol, by displacing the chlorine, with the general scheme below.

Work Up (SGS 6-2)

SGS 6-2 was fully dissolved by adding ethyl acetate (~300 mL), dichloromethane (~10 mL), methanol (~10 mL), and washed with water (~30 mL) then brine (~70 mL). The organic layer was collected and dried with sodium sulfate and the solvent was removed.

Work Up (SGS 8-1)

Ethyl acetate (~100 mL) was added, the solvents were removed, and the SGS 8-1 left under high vacuum.

Work Up (SGS 7-2)

Ethyl acetate (~100 mL) was added, the solvent was removed

NMR Data

¹H NMR 300 MHz 24th June

SGS 2 DMSO

SGS 2-2 CDCl3

SGS 5-1 DMSO

SGS 7-1 CDCl3

SGS 7-2 CDCl3

SGS 8-1 CDCl3

9.38 (1H, s), 8.91 (1H, s), 8.84 (1H, d, J 4.9 Hz), 8.05 (1H, d, J 7.9 Hz), 7.93 (1H, s), 7.53 (1H, dd, J 5.0, 7.8 Hz), 7.25 (1H, s).

¹H NMR 300 MHz 24th June

SGS 9-1 DMSO

 

 

OSM recently received data from Syngene on the latest set of Series 4 compounds screened against the malaria parasite. While no 'killer' compounds were discovered, the data has provided some interesting SAR data. 

This post aims to stimulate discussion about the 10-30 compounds that we should aim to synthesise next. Comments below, on GitHub or via Twitter are very welcome - email should be avoided but you are also always welcome to contact us at opensourcemalaria@gmail.com. Over the next week or so, this list will be refined following input from the community, here are some suggestions based on the data.

I'm going to use letters to label each compound to prevent any mix-up with the previous target molecules.

Triazolopyrazine Core

1. Remaining 'Top Ten' Compounds

A few compounds from the previous wish list remain unsynthesised.

The latest data showed compounds featuring an aliphatic group at Y to be inactive. Two remaining compounds featuring a heterocyclic aliphatic substituent (A and B) should be synthesised to further investigate substitution at this position. Additionally, the proposed compound (C) featuring an aliphatic replacement at X should also be synthesised.

 

2. Exploration of substituted pyridines at X and or Y

Different unsubstituted pyridine isomers at Y were found to be inactive, whereas the 2-CF3 substituted compound OSM-S-278 showed promising activity in the initial screen. This result suggests that tempering the electronics of the pyridine ring could provide some promising results. A range of 2-, 3- and 4-substituted pyridine aldehydes are commercially available and so compounds of type D could be synthetically accessible.

Question Is 2-substitution typically preferred?

 

Compound E is a composite of MMV688895 and MMV67093 andis proposed a compound with lower CLogP and potentially greater activity.

3. Polar Benzylic Groups

The latest screen confirmed the activity of compounds containing a polar benzylic group. However, mono methylated amine OSM-S- 281 showed no activity. Despite potential metabolic flags, compound F could be synthesised to evaluate the activity of a disubstituted amine and confirm the pattern of results shown for MMV671651 MMV670763 and MMV670437 with regard to amine substitution. Compounds G-J would probe the effect of extending the polar side chain. MMV670947, the 3,4-difluorophenyl analogue of G displayed potency of 25 nM a promising starting point for optimisation. 

 

4. Additional substitution on side chain X

 Further substitition on side chain X could also be explored.

5. Modification to the core

The initial CRO/Pfizer data set revealed a potent compound MMV669846 containing an imidazopyrazine core. This has been under explored so far. The presence of one less nitrogen serves to increase the CLogP and so further analogues could be designed to include substituted pyridines to decrease the lipophilicity (O and P).

Jamie Scott at The University of Edinburgh synthesised some ether triazolopyridine analogues, which although active were found to be less potent than their corresponding triazolopyrazine. One interesting result can be found in comparison of potency data for JS16-1 and MMV670994. This data would suggest that in the case of amides, changing core from triazolopyrazine to triazolopyridine destroys activity.

6. Suggestions from Dr Mrinalkanti Kundu, Associate Director TCG Lifesciences, India.

Mrinal Suggested several compounds following the last OSM synthesis consultation. These thoughtful suggestions will be considered for the next round of synthesis.

Post originally authored by Alice Williamson

Strings

OSM-S-275  InChI=1S/C19H22N4O2/c24-16(14-7-3-1-4-8-14)13-25-18-12-20-11-17-21-22-19(23(17)18)15-9-5-2-6-10-15/h1,3-4,7-8,11-12,15-16,24H,2,5-6,9-10,13H2

OSM-S-276  InChI=1S/C15H16N4O2/c1-2-13-17-18-14-8-16-9-15(19(13)14)21-10-12(20)11-6-4-3-5-7-11/h3-9,12,20H,2,10H2,1H3

A  InChI=1S/C18H21N5O2/c24-15(13-5-2-1-3-6-13)12-25-17-11-20-10-16-21-22-18(23(16)17)14-7-4-8-19-9-14/h1-3,5-6,10-11,14-15,19,24H,4,7-9,12H2

B  InChI=1S/C16H16N4O3/c21-13(11-4-2-1-3-5-11)10-23-15-7-17-6-14-18-19-16(20(14)15)12-8-22-9-12/h1-7,12-13,21H,8-10H2

C  InChI=1S/C17H18F2N4O3/c1-17(2,24-3)10-25-14-9-20-8-13-21-22-15(23(13)14)11-4-6-12(7-5-11)26-16(18)19/h4-9,16H,10H2,1-3H3

OSM-S-258  InChI=1S/C18H14ClN5O/c19-15-4-2-1-3-13(15)7-10-25-17-12-21-11-16-22-23-18(24(16)17)14-5-8-20-9-6-14/h1-6,8-9,11-12H,7,10H2

OSM-S-278 InChI=1S/C19H14F3N5O2/c20-19(21,22)15-7-6-13(8-24-15)18-26-25-16-9-23-10-17(27(16)18)29-11-14(28)12-4-2-1-3-5-12/h1-10,14,28H,11H2

D

MMV670936  InChI=1S/C19H12F5N5O/c20-13-3-1-11(7-14(13)21)5-6-30-17-10-25-9-16-27-28-18(29(16)17)12-2-4-15(26-8-12)19(22,23)24/h1-4,7-10H,5-6H2

E  InChI=1S/C19H12F5N5O2/c20-12-3-1-10(5-13(12)21)14(30)9-31-17-8-25-7-16-27-28-18(29(16)17)11-2-4-15(26-6-11)19(22,23)24/h1-8,14,30H,9H2

OSM-S-279  InChI=1S/C20H16F2N4O3/c21-20(22)29-15-8-6-14(7-9-15)19-25-24-17-10-23-11-18(26(17)19)28-12-16(27)13-4-2-1-3-5-13/h1-11,16,20,27H,12H2

OSM-S-283  InChI=1S/C20H17F2N5O2/c21-20(22)29-15-8-6-14(7-9-15)19-26-25-17-10-24-11-18(27(17)19)28-12-16(23)13-4-2-1-3-5-13/h1-11,16,20H,12,23H2

OSM-S-281  InChI=1S/C21H19F2N5O2/c1-24-17(14-5-3-2-4-6-14)13-29-19-12-25-11-18-26-27-20(28(18)19)15-7-9-16(10-8-15)30-21(22)23/h2-12,17,21,24H,13H2,1H3

F  InChI=1S/C22H21F2N5O2/c1-28(2)18(15-6-4-3-5-7-15)14-30-20-13-25-12-19-26-27-21(29(19)20)16-8-10-17(11-9-16)31-22(23)24/h3-13,18,22H,14H2,1-2H3

MMV670947  InChI=1S/C21H16F4N4O3/c22-16-6-3-13(7-17(16)23)14(10-30)11-31-19-9-26-8-18-27-28-20(29(18)19)12-1-4-15(5-2-12)32-21(24)25/h1-9,14,21,30H,10-11H2

G  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

H InChI=1S/C21H19F2N5O2/c22-21(23)30-17-8-6-15(7-9-17)20-27-26-18-11-25-12-19(28(18)20)29-13-16(10-24)14-4-2-1-3-5-14/h1-9,11-12,16,21H,10,13,24H2

I  InChI=1S/C21H19F2N5O3/c22-21(23)31-16-8-6-15(7-9-16)20-27-26-18-10-25-11-19(28(18)20)29-12-17(30-13-24)14-4-2-1-3-5-14/h1-11,17,21H,12-13,24H2

J  InChI=1S/C21H18F2N4O4/c22-21(23)31-16-8-6-15(7-9-16)20-26-25-18-10-24-11-19(27(18)20)29-12-17(30-13-28)14-4-2-1-3-5-14/h1-11,17,21,28H,12-13H2

K  InChI=1S/C22H20F2N4O3/c1-14(18(13-29)15-5-3-2-4-6-15)30-20-12-25-11-19-26-27-21(28(19)20)16-7-9-17(10-8-16)31-22(23)24/h2-12,14,18,22,29H,13H2,1H3

L  InChI=1S/C20H16F2N4O4/c21-20(22)29-14-8-6-13(7-9-14)18-25-24-15-10-23-11-16(26(15)18)30-19(28)17(27)12-4-2-1-3-5-12/h1-11,17,19-20,27-28H

M  InChI=1S/C20H16F2N4O3/c21-20(22)28-15-8-6-14(7-9-15)19-25-24-16-11-23-12-17(26(16)19)29-18(27)10-13-4-2-1-3-5-13/h1-9,11-12,18,20,27H,10H2

N  InChI=1S/C20H17F2N5O2/c21-20(22)28-15-8-6-14(7-9-15)19-26-25-17-11-24-12-18(27(17)19)29-16(23)10-13-4-2-1-3-5-13/h1-9,11-12,16,20H,10,23H2

MMV669846  InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)18-10-25-19-11-24-12-20(26(18)19)27-8-7-13-1-6-16(22)17(23)9-13/h1-6,9-12H,7-8H2  

O  InChI=1S/C20H15F3N4O2/c21-20(22,23)17-7-6-14(8-25-17)15-9-26-18-10-24-11-19(27(15)18)29-12-16(28)13-4-2-1-3-5-13/h1-11,16,28H,12H2

P  InChI=1S/C19H15F4N5O2/c1-29-15(13-3-5-17(20)27-8-13)10-30-18(6-24)28-11-25-9-14(28)12-2-4-16(26-7-12)19(21,22)23/h2-9,11,15H,10H2,1H3/b18-6+

JS 16-1  InChI=1S/C20H11F3N6O/c21-20(22,23)16-10-14(8-9-25-16)26-19(30)15-2-1-3-17-27-28-18(29(15)17)13-6-4-12(11-24)5-7-13/h1-10H,(H,25,26,30)

MMV670944  InChI=1S/C18H11F3N6O2/c19-14-7-11(5-6-23-14)24-17(28)13-8-22-9-15-25-26-16(27(13)15)10-1-3-12(4-2-10)29-18(20)21/h1-9,18H,(H,23,24,28)

MK-001: 1/C20H14F2N6O2/c1-29-17(12-3-5-15(21)16(22)6-12)11-30-19-10-24-9-18-26-27-20(28(18)19)13-2-4-14(7-23)25-8-13/h2-6,8-10,17H,11H2,1H3/t17-/m0/s1

MK-002: 1/C20H12F4N6O2/c21-14-4-2-11(5-15(14)22)16(32-20(23)24)10-31-18-9-26-8-17-28-29-19(30(17)18)12-1-3-13(6-25)27-7-12/h1-5,7-9,16,20H,10H2/t16-/m0/s1

MK-003: 1/C20H15ClF2N4O2/c1-28-17(13-4-7-15(22)16(23)8-13)11-29-19-10-24-9-18-25-26-20(27(18)19)12-2-5-14(21)6-3-12/h2-10,17H,11H2,1H3/t17-/m0/s1

MK-004: 1/C21H16ClN5O2/c1-28-18(16-4-2-3-5-17(16)22)13-29-20-12-24-11-19-25-26-21(27(19)20)15-8-6-14(10-23)7-9-15/h2-9,11-12,18H,13H2,1H3/t18-/m0/s1

MK-005: 1/C21H15F2N5O2/c1-29-18(15-6-16(22)8-17(23)7-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3/t18-/m0/s1

MK-006: 1/C20H15ClF3N5O2/c1-30-15(13-6-7-26-16(8-13)20(22,23)24)11-31-18-10-25-9-17-27-28-19(29(17)18)12-2-4-14(21)5-3-12/h2-10,15H,11H2,1H3/t15-/m0/s1

MK-007: 1/C19H13ClF3N5O/c20-14-3-1-13(2-4-14)18-27-26-16-10-24-11-17(28(16)18)29-8-6-12-5-7-25-15(9-12)19(21,22)23/h1-5,7,9-11H,6,8H2

MK-008: 1/C21H16F5N5O3/c1-32-15(13-6-7-28-16(8-13)21(24,25)26)11-33-18-10-27-9-17-29-30-19(31(17)18)12-2-4-14(5-3-12)34-20(22)23/h2-10,15,20H,11H2,1H3/t15-/m0/s1

MK-009: 1/C20H14F5N5O2/c21-19(22)32-14-3-1-13(2-4-14)18-29-28-16-10-26-11-17(30(16)18)31-8-6-12-5-7-27-15(9-12)20(23,24)25/h1-5,7,9-11,19H,6,8H2

MK-010: 1/C21H15F3N6O2/c1-31-16(15-6-7-27-17(8-15)21(22,23)24)12-32-19-11-26-10-18-28-29-20(30(18)19)14-4-2-13(9-25)3-5-14/h2-8,10-11,16H,12H2,1H3/t16-/m0/s1

MK-011: 1/C21H13F5N6O2/c22-20(23)34-15(14-5-6-29-16(7-14)21(24,25)26)11-33-18-10-28-9-17-30-31-19(32(17)18)13-3-1-12(8-27)2-4-13/h1-7,9-10,15,20H,11H2/t15-/m0/s1

MK-012: 1/C20H13F3N6O/c21-20(22,23)16-9-13(5-7-26-16)6-8-30-18-12-25-11-17-27-28-19(29(17)18)15-3-1-14(10-24)2-4-15/h1-5,7,9,11-12H,6,8H2

MK-001: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC)c1cnc(cc1)C#N
MK-002: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC(F)F)c1cnc(cc1)C#N
MK-003: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC)c1ccc(cc1)Cl
MK-004: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1ccccc1Cl)OC)c1ccc(cc1)C#N
MK-005: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(cc(c1)F)F)OC)c1ccc(cc1)C#N
MK-006: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(ncc1)C(F)(F)F)OC)c1ccc(cc1)Cl
MK-007: N1=CC2=NN=C(N2C(=C1)OCCc1cc(ncc1)C(F)(F)F)c1ccc(cc1)Cl
MK-008: O(c1ccc(cc1)C1=NN=C2N1C(=CN=C2)OC[C@H](c1cc(ncc1)C(F)(F)F)OC)C(F)F
MK-009: O(c1ccc(cc1)C1=NN=C2N1C(=CN=C2)OCCc1cc(ncc1)C(F)(F)F)C(F)F
MK-010: O([C@H](c1cc(ncc1)C(F)(F)F)COC1=CN=CC2=NN=C(N12)c1ccc(cc1)C#N)C
MK-011: O([C@H](c1cc(ncc1)C(F)(F)F)COC1=CN=CC2=NN=C(N12)c1ccc(cc1)C#N)C(F)F
MK-012: N1=CC2=NN=C(N2C(=C1)OCCc1cc(ncc1)C(F)(F)F)c1ccc(cc1)C#N

Last semester at Sydney Uni, Alice Williamson created a new lab course in what's known as the "Special Studies Program" in Chemistry - high achieving undergrads who are given the freedom to try something new and challenging. Alice, working with Adam Bridgeman and Peter Rutledge in the School of Chemistry, designed a set of experiments based on where we're up to with the chemistry in OSM's Series 4 - a research project funded by the ARC and MMV.

The lab manual is openly available, and the students had to keep open lab notebooks. Here they are! I'm not sure there's ever been a lab class quite like it. Students engaged in real research, where everything is shared. We're now going to incorporate what they discovered into OSM itself.

Excitingly, I think this would scale. One can imagine lab courses based around current needs in any open source drug discovery and development project, meaning we could, with proper mentorship, bring to bear very large levels of skilled human resource to tackle actual project needs, with global coordination between cohorts. Undergrads in other countries have already contributed to OSM.

The students had to make short videos talking about any aspect of their project - they were given complete creative control. I had the pleasure of watching these during a showing in one of our lecture theatres last month - I was deeply impressed (and, occasionally, slightly disturbed). Here's the full playlist.

These students have done a fantastic job, and Alice deserves enormous kudos for driving this through from scratch. Well done!