title: Structure-activity relationships for inhibition of cysteine protease activity and development of Plasmodium falciparum by peptidyl vinyl sulfones.
abstract: The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P(2) leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA. bshenai@itsa.ucsf.edu
authors.forename: Bhaskar R
authors.initials: BR
authors.lastname: Shenai
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Lee
authors.forename: Alejandro
authors.initials: A
authors.lastname: Alvarez-Hernandez
authors.forename: Pek Y
authors.initials: PY
authors.lastname: Chong
authors.forename: Cory D
authors.initials: CD
authors.lastname: Emal
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D013450:Sulfones; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3