Fourth expansion
Please go to Researchers involved for a list of researchers who contributed to this work
2024-10-23
To continue to explore the SAR around RA-3301 we returned to the binding pose of the compound to try to elicit a way forward. The headgroup, and specifically the benzene ring, faces a very lipophilic pocket and thus we don't expect to improve activity by changing this part of the molecule. As show in previous expansions, the hydroxy group seems to form a very favorable hydrogen bond with the proposed pose offering multiple side-chain options (not shown). Upon looking at the side-chain space around the molecule a lysine appeared to be within reach of the molecule to establish another hydrogen bond. The follow list of compounds were proposed for the fourth expansion based on this (looking also at suitable starting materials).
2024-12-20
In a parallel project for the SARS-CoV2 NSP15 a very similar quinoline-core has been used and a number of these compounds were included in the fourth expansion to help further the SAR around RA-3301, and specifically RA-188637.
Due to time constraints, not all of the above suggested compounds to be synthesized for the fourth expansion were available to send at the deadline and thus the list of 11 compounds is as shown below. Notably, a 9 compounds were not active, showing less than 50% inhibition at 10 μM. Four compounds were studied in dose-response, but as with the third expansion the antiviral effect was poor and thus the compounds need to be retested to confirm activity.
Next steps:
- Retest compounds.
- Complete synthesis of the proposed compounds.