Purchased analogues of the original hit#2: RA-0020083-01

[HadiaAmahli]

We received the 8 purchased analogues of the original hit #2: RA-0020083-01 from Mcule at UCL, the structures are as follow:

On 19th April, these analogues were sent to Nick Heaton's lab for testing against SARS-Cov-2-NSP14.

[HadiaAmahli]

The new data released in July 2024 from our collaborator Prof. Nick Heaton showed that non of the original hit https://github.com/StructuralGenomicsConsortium/CNP27-SARS-CoV-2-NSP14/issues/2: RA-0020083-01analogues (either purchased or https://github.com/StructuralGenomicsConsortium/CNP27-SARS-CoV-2-NSP14/issues/1#issuecomment-2116642846 compounds) showed a similar or greater activity to the original hit RA-0020084-01.

The most active purchased compound RA-0138504 looks like it's the most promising compounds since it's activity is slightly lower than the original hit #2 RA-0020083-01 and has a better activity than all other purchased and synthetic compounds for all hits that's why we are interested in developing its structure to build up a higher molecular weight compound with improved activity.

After conducting analogues search, the only commercially available analogues we found are 6 analogues which have been ordered for testing.

[HadiaAmahli]

We are also decided to synthesize the following analogues which could lead to variable analogues and new binding interactions with the virus target.

The suggested synthetic route is as following:

[HadiaAmahli]

On 23rd August, we shipped the following synthetic and purchased compounds to be tested as well . The new data from Nick Heaton lab showed an impressive activity of RA-0138504-02 which has been synthesized at UCL (by Hadia) and interestingly other batches of this compound purchased from Mcule and Enamine did not show similar activity. We are waiting for more results to come in the upcoming weeks.

[HadiaAmahli]

Our plan of synthesis is as follows: