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opensourceantibiotics / Series-2-Diarylimidazoles

Open Source Antibiotics Series 2
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OSA Series 2 Meeting June 10th #115

Open mattodd opened 2 years ago

mattodd commented 2 years ago

Meeting June 10th at 2pm UK time at https://ucl.zoom.us/j/92800004715. Follows on from #114

Recording: https://youtu.be/3pg-LIElt10

On the call: @mattodd @edwintse @danielgedder @loriferrins Maria Dichiara

HI @opensourceantibiotics/series-2-diarylimidazoles - time to finish up the tox, DNA binding, MoA experiments and to advance the paper writing towards a submission.

Active Priorities for Discussion

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danielgedder commented 2 years ago

Hi everyone, we re-tested some OSA_975 derivatives against MRSA and MSSA and we got the same results. OSA001052 was 16mcg/mL against both strains. OSA001053, OSA001072-OSA001077 was >32 mcg/mL against both strains. OSA000821 and OSA000822, showed MIC values of 4 mcg/mL against both strains (MSSA and MRSA). Vancomycin MIC was 1 mcg/mL for both strains.

osa_meeting10-06-22

mariadichiara commented 2 years ago

Hi @danielgedder, this is a summary of NEU synthesis/purification

image

We decided to cancel the following molecule since the alkylation of the intermediate has occurred at the undersired N-position

image

mattodd commented 2 years ago

Welcome aboard @mariadichiara

danielgedder commented 2 years ago

Hi @mariadichiara, these are the conditions that worked well for Suzuki coupling and also for purification:

Procedure:

3-Bromo-2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (76 mg, 0.28 µmol, 1 eq.) was dissolved in 1,4-dioxane/ethanol/water (v/v/v, 7:3:4, 5 mL) and treated with appropriated boronic acid (64 mg, 0.43 µmol, 1.5 eq.), PdCl2(dppf) (155 mg, 0.05 eq.), and K2CO3 (155 mg, 1.12 µmol, 4 eq). The vial was sealed and microwaved with stirring at 100 °C for 4 h. (4 bar pressure). The reaction mixture was cooled to room temperature, then diluted with MeOH, filtered through celite, and rotovapped. The crude material was purified by chromatography column (100%-95% Chloroform; 0-5% MeOH in 1% Et3N) to afford the title compound.

Purification tip: you can prepare your MeOH solution in 1%Et3N and use it for purification. I always decrease the flow rate for half of what is settled up in biotage. For example, 10g column, I use a 6 mL flow rate instead of 12 mL. I have attached the biotage PDF file.

RGS249_CHLOR_MEOH_1%ET3N_frac.pdf

danielgedder commented 2 years ago

@mariadichiara could you please share your synthetic routes? I have done a condensation reaction yesterday in DMF and that seems to work. Maybe you could try the same conditions as I suggested during the meeting.

mariadichiara commented 2 years ago

Thanks @danielgedder! These are the conditions I used

image

In all three conditions I was not able to see any tiny signal of my final compound. I m trying with protected imidazole now, maybe this is the problem. I could try your conditions too

danielgedder commented 2 years ago

@mariadichiara, I guess you using the protected imidazole is a great strategy.

MFernflower commented 2 years ago

@mariadichiara maybe try johnphos?

On Wed, Jun 15, 2022, 7:09 AM Daniel Gedder @.***> wrote:

@mariadichiara https://github.com/mariadichiara, I guess you using the protected imidazole is a great strategy.

— Reply to this email directly, view it on GitHub https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/issues/115#issuecomment-1156334989, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDRVQQQ23PXGFVJXEDDVPG2V7ANCNFSM5XKAKBNA . You are receiving this because you are on a team that was mentioned.Message ID: <opensourceantibiotics/Series-2-Diarylimidazoles/issues/115/1156334989 @github.com>