jm701141u_si_001.pdf (114.77 kB)
Download file

Development of Peptidomimetics with a Vinyl Sulfone Warhead as Irreversible Falcipain-2 Inhibitors

Download (114.77 kB)
journal contribution
posted on 28.02.2008, 00:00 by Roberta Ettari, Emanuela Nizi, Maria Emilia Di Francesco, Marie-Adrienne Dude, Gabriele Pradel, Radim Vičík, Tanja Schirmeister, Nicola Micale, Silvana Grasso, Maria Zappalà
This paper describes the synthesis of a new class of peptidomimetic cysteine protease inhibitors based on a 1,4-benzodiazepine scaffold and on an electrophilic vinyl sulfone moiety. The former was introduced internally to a peptide sequence that mimics the fragment d-Ser-Gly; the latter was built on the P1-P1′ site and reacts as a classical “Michael acceptor”, leading to an alkylated enzyme by irreversible addition of the thiol group of the active site cysteine. The introduction of the vinyl sulfone moiety has been accomplished by olefin cross-metathesis, a powerful tool for the formation of carbon−carbon double bonds. New compounds 23 have been proven to be potent and selective inhibitors of falcipain-2, a cysteine protease isolated from Plasmodium falciparum, displaying antiplasmodial activity.