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opensourceantibiotics / Series-2-Diarylimidazoles

Open Source Antibiotics Series 2
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OSA Series 2 Meeting Apr 6th #114

Open mattodd opened 2 years ago

mattodd commented 2 years ago

This post is draft till this text is removed

Meeting April 6th at 4pm UK time at https://ucl.zoom.us/j/92800004715. Follows on from #113

Recording: https://youtu.be/r0jlMNrJTr0

On the call: @mattodd @edwintse @danielgedder @loriferrins @drc007 Lee Graves, Thomas Gilbert, Maria Dichiara

PREVIOUS ACTIONS

Today:

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danielgedder commented 2 years ago

Hello everyone, update done at #112. I will talk more about the new analogs during the meeting.

danielgedder commented 2 years ago

Actions

MFernflower commented 2 years ago

If I'm not mistaken @lferrins has the direct DNDI contact

On Thu, Apr 7, 2022, 5:39 AM Daniel Gedder @.***> wrote:

Actions

-

ACTION ITEM: Set a date for the next MRSA biological assay (maybe April 22nd) for @danielgedder https://github.com/danielgedder and Maria's compounds;

ACTION ITEM: @MFernflower https://github.com/MFernflower check with DNDi the availability to test the new set of compounds against T. Cruzi, T.brucei, Leishmania, and mammalian cytotoxicity

ACTION ITEM: @danielgedder https://github.com/danielgedder searches the targets mentioned by Lee and checks information about potential inhibitors and research groups working with these targets;

— Reply to this email directly, view it on GitHub https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/issues/114#issuecomment-1091434693, or unsubscribe https://github.com/notifications/unsubscribe-auth/AAYEWDTWKK2JUN56PZG6HLTVD2UNVANCNFSM5ST7UY6A . You are receiving this because you were mentioned.Message ID: <opensourceantibiotics/Series-2-Diarylimidazoles/issues/114/1091434693@ github.com>

lferrins commented 2 years ago

@MFernflower you are right, thanks ;)

Yes, if you would like to ship more compounds to DNDi I can certainly help get that done!

danielgedder commented 2 years ago

Sorry @MFernflower, I tagged you by mistake. @lferrins I would like to test the 8 diarylimidazoles derivatives that I am working on here, plus 10 indazol derivatives synthesized in Brazil. All the 18 compounds will be tested against MRSA and I would like to send them to DNDi as well. I have a collaboration with professor Maes and Guy from Antwerp. I don't know which lab you usually send the samples to, but if you are going to send them to the University of Antwerp (Laboratory of Microbiology, Parasitology and Hygiene), I can contact professor Maes and Guy, in case you prefer. Please, let me know! Thank you!

danielgedder commented 2 years ago

REPORT Hello everyone, I have made some researchers based on Lee’s presentation and some of the target that he spoken about. The starting point was a screening of GlaxoSmithKline internal library collection for inhibitors of the transforming growth factor β1 (TGF- β1) type I receptor (ALK5), it was identified 2-Diarylimidazoles as a promising hit (compound 7 IC50 of 0.46 µM against ALK5 and non-inhibition against p38 kinase). ALK5 is the receptor of TGF-β and plays a pivotal role in the canonical TGF-β signaling pathway. The inhibitor 7 inhibits TGF- β1- induced fibronectin (FN) mRNA (IC50 of 0.50 µM) in A498 cells. Further optimizations lead to selective inhibitor 14 (IC50 of 0.094 µM against ALK5 and non inhibition against p38 kinase, LD50 > 30 uM), which inhibits TGF-β1-induced fibronectin mRNA (IC50 of 0.05 µM) formation while displaying no measurable cytotoxicity in the 48 h XTT assay. ¹ image

The second publication was in 2009, the authors described that the compound OSA_812 is TGFR1 inhibitor. image

http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50110206

Analogue DGS245 is known selective inhibitor of ALK5: image

I have done a search at ChEMBL database to filter only compounds selectively potent against NEK2, NEK3, CSNK1E and TGFRB1with the available bioactivities. The database containing about 9 thousand molecules with available bioactivities were extracted (NEK2 – 3324 compounds; NEK3 – 817 compounds; CSNK1E – 1207; TGFRB1 – 3536). I have attached the file.

After applying appropriated filters, I have found 103 compounds containing 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, similar to OSA compounds. These pyrrolo[1,2-b]pyrazole derivatives showed activity against TGF-beta receptor type 1. For example compounds DGS_5727 and 4636. image image

One pyrrolo[1,2-b]pyrazole derivative was also tested against Serine/threonine-protein kinase NEK2, but it was inactive.

image

5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole kinase assays reveal high activity towards ALK5.

Mechanism of action in cells corresponds to ALK5 inhibition. Compounds display low cytotoxicity in cell lines. ²

Many other examples have the pyridine attached to the core ring and it resulted in activity against TGF-beta receptor type I in different assays. See the compounds below:

image image image image

Other compounds did not have the pyridine moiety but it showed high activity against TGF-beta receptor type I:

image image

Pyrrolo[1,2-a]imidazole derivatives were tested against Serine/threonine-protein kinase (NEK2), but no activity was detected.

image image

A set of 109 Pyrrolo[1,2-a]pyrazine derivatives were tested against CSNK1E and it showed to be a promising inhibitor. Eight compounds showed IC50 of 1 nM.

image image

  1. Callahan, J. F.; Burgess, J. L.; Fornwald, J. A.; Gaster, L. M.; Harling, J. D.; Harrington, F. P.; Heer, J.; Kwon, C.; Lehr, R.; Mathur, A.; Olson, B. A.; Weinstock, J.; Laping, N. J., Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem 2002, 45 (5), 999-1001.
  2. Řezníčková, E.; Tenora, L.; Pospíšilová, P.; Galeta, J.; Jorda, R.; Berka, K.; Majer, P.; Potáček, M.; Kryštof, V., ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. European Journal of Medicinal Chemistry 2017, 127, 632-642. CDD Excel Export - 2022-04-21 08h21m25s.xlsx
danielgedder commented 2 years ago

Hi everyone! I have done research on potential collaborators for enzyme assays; so far, I have found this list below. I sent an e-mail to Tania asking her if she could assay the compounds. She works in FioCruz in Brazil. She has published papers with Sabine from France with ALK5 assays. Maybe I can send an e-mail to Sabine as well.

ALK5 TGF-B assays

Tania C. Araujo-Jorge - Brazil

taniaaj@ioc.fiocruz.br [taniaaj@ioc.fiocruz.br](mailto:taniaaj@ioc.fiocruz.br);

Sabine Bailly - France

sbailly@cea.fr [sbailly@cea.fr](mailto:sbailly@cea.fr);

There is a group in UCN that runs biological assays for all the targets we are interested in assay our compounds.

Group in UNC

https://pharmacy.unc.edu/research/centers/sgc-unc/resources/

NEK2/3

Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Hong-yuLia

HLi2@uams.edu