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

• Published in: Journal of medicinal chemistry 2008-02, Vol.51 (4), p.988-996
• Main Authors: Ettari, Roberta, Nizi, Emanuela, Di Francesco, Maria Emilia, Dude, Marie-Adrienne, Pradel, Gabriele, Vičík, Radim, Schirmeister, Tanja, Micale, Nicola, Grasso, Silvana, Zappalà, Maria
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Biological and medical sciences; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Cathepsin B - antagonists & inhibitors; Cathepsin B - chemistry; Cathepsin L; Cathepsins - antagonists & inhibitors; Cathepsins - chemistry; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Humans; Kinetics; Medical sciences; Molecular Mimicry; Peptides - chemistry; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Stereoisomerism; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701141u

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 2–3 have been proven to be potent and selective inhibitors of falcipain-2, a cysteine protease isolated from Plasmodium falciparum, displaying antiplasmodial activity.