miko_a

Alpha-perfluoroalkylated ketones can sometimes form stable hydrates and/or trap cysteine which could mimic transition state nicely. That would be something like c2ccc1nccc1c2C(=O)C(F)(F)c(c3)cncc3Cl

1 reply

pwkenny

I believe that trifluoromethyl ketones have been described as covalent serine protease inhibitors. Peptidomimetic SARS-CoV-2 main protease inhibitors that target the catalytic cysteine with aldehyde and alpha-ketoamide warheads have been described. These designs, which are based on a fragment-derived inhibitor, also target the the catalytic cysteine and the trifluoromethyl ketone warhead could be substituted for the aldehyde. These design notes may be of interest.

JSPEN

Good points. C(H)CF3 or a direct CF2 would hopefully lead to a “Micky Finn” Chloral hydrate like structure with a tetrahedral dihydrate instead of ketone.

1 reply

miko_a

Turning that linker around, that is something similiar to c13ccnc1cccc3C(F)(F)C(=O)c(c2)cncc2Cl would lead to much stronger electrophile. One known preparation of 3-trifluoroacetylpyridine involves azeotropic dehydratation of ketone hydrate formed during aqueous workup, which is not needed in case of trifluoroacetophenone. I’ve also noticed that hydrate easily forms in storage. I’m not sure how that would bind though