title: Novel 2H-isoquinolin-3-ones as antiplasmodial falcipain-2 inhibitors.
abstract: A series of 1-aryl-6,7-disubstituted-2H-isoquinolin-3-ones (2-10) was synthesized and evaluated for their inhibition against Plasmodium falciparum cysteine protease falcipain-2, as well as against cultured P. falciparum strain FCBR parasites. All compounds displayed inhibitory activity against recombinant falcipain-2 and against in vitro cultured intraerythrocytic P. falciparum, with the exception of 9. The new compounds exhibited no selectivity against human cysteine proteases such as cathepsins B and L. The inhibitory activity of the synthesized compounds was also evaluated against another protozoal cysteine protease, namely rhodesain of Trypanosoma brucei rhodesiense.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata 98168, Messina, Italy. nmicale@pharma.unime.it
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.forename: Astrid
authors.initials: A
authors.lastname: Evers
authors.forename: Christoph
authors.initials: C
authors.lastname: Gelhaus
authors.forename: Matthias
authors.initials: M
authors.lastname: Leippe
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D007546:Isoquinolines; D003546:Cysteine Endopeptidases; C416224:falcipain 2