α,α-Difluoromethyl Ketone Moiety: A Promising Functional Group for Targeting Druggable Enzymes

α,α-Difluoromethyl ketones (DFMKs) have gained nowadays some relevance in the field of medicinal chemistry as the functionalization of the methyl ketone group with two fluorine atoms induces profound changes in the physicochemical properties and reactivity of the related substrates. In principle, the presence of these fluorine atoms enhances considerably the electrophilicity of the adjacent carbonyl group, then its susceptibility to undergo nucleophilic attack, a feature that might be exploited in the design of cysteine and serine protease inhibitors. Additionally, the ability of the terminal -CHF2 group to behave as a lipophilic and weakly acidic hydrogen bond donor is enabled, making the DFMK moiety a valid bioisostere of the -COOH group. In this regard, on the basis of preliminary docking studies, we successfully applied the chemistry of direct and chemoselective halomethylation - under nucleophilic regime - on peptidic substrates to obtain a pseudodipeptide bearing the DFMK moiety as C-terminal electrophilic warhead with activity against coronaviruses. Later on, we shifted our synthetic methodology to heterocyclic scaffolds (isoxazole and pyrazole) to obtain effective COX inhibitors in which the DFMK moiety has been envisaged as bioisosteric replacement of the -COOH group.