pwkenny

Hi @JSPEN my understanding is that the methoxy dihydroquinolones eliminate methanol and I’d expect fluoro dihydroquinolones to eliminate HF in analogous manner. I don’t know how well characterized the elimination of methanol is or whether the problem is restricted to dihydroquinolones. My view is that is would be worth looking at acetylenyl as a configuration lock because it can potentially eclipse the amide NH more effectively than methyl. Another option would be to insert methylene between the chiral center and the oxygen of the methoxy which would take out the amide NH with an intramolecular hydrogen bond. I submitted these as PET-UNK-7955f415 and the submission includes proposed binding modes for the designs.

JSPEN

Sure. Good points. What about CF3 or CHF2?

1 reply

pwkenny

Fluorine is a weak hydrogen bond acceptor and I would favor CF2F over CHF2 or CF3 since adding fluorine will reduce hydrogen bond basicity. In case it’s of interest, there’s a section on hydrogen bond basicity in this article.

miko_a

CF2H is hydrogen bond donor, so I suppose this even could make things worse by stabilizing wrong conformation, like this: CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolines - Chemical Communications (RSC Publishing)

1 reply

JSPEN

Nice paper and good reference thanks!

pwkenny

Thanks for the reference @miko_a because I’d been looking for something like this for a hydrogen bond donor article that I’m working on. In case it’s of interest to you or @JSPEN here’s a link to my talk from the UK-QSAR group autumn meeting last week.