Aryl methylene ketones and fluorinated methylene ketones as reversible inhibitors for severe acute respiratory syndrome (SARS) 3C-like proteinase

Zhang, Jianmin; Huitema, Carly; Niu, Chunying; Yin, Jiang; James, Michael N.G.; Eltis, Lindsay D.; Vederas, John C.

The severe acute respiratory syndrome (SARS) virus depends on a chymotrypsin-like cysteine proteinase (3CL(pro)) to process the translated polyproteins to functional viral proteins. This enzyme is a target for the design of potential anti-SARS drugs. A series of ketones and corresponding mono- and di-fluoro ketones having two or three aromatic rings were synthesized as possible reversible inhibitors of SARS 3CL(pro). The design was based on previously established potent inhibition of the enzyme by oxa analogues (esters), which also act as substrates. Structure–activity relationships and modeling studies indicate that three aromatic rings, including a 5-bromopyridin-3-yl moiety, are key features for good inhibition of SARS 3CL(pro). Compound 11d, 2-(5-bromopyridin-3-yl)-1-(5-(4-chlorophenyl)furan-2-yl)ethanone and its α-monofluorinated analogue 12d, gave the best reversible inhibition with IC(50) values of 13 μM and 28 μM, respectively. In contrast to inhibitors having two aromatic rings, α-fluorination of compounds with three rings unexpectedly decreased the inhibitory activity.