title: High antiplasmodial activity of novel plasmepsins I and II inhibitors.
abstract: The aim of this study was to develop new antiplasmodial compounds acting through distinct mechanisms during both the liver and the blood stages of the parasite life cycle. Compounds were designed on the basis of the "double-drug" approach: primaquine, which has been linked to statine-based inhibitors of plasmepsins (PLMs), the plasmodial aspartic proteases involved in degradation of hemeoglobin. The compounds were tested in vitro for anti-PLM I/PLM II activities and against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of P. falciparum. An antiplasmodial activity (IC(50)) as low as 0.1 microM was obtained, an excellent improvement in comparison with inhibitors previously reported (IC(50) = 2-20 microM). The killing activity was equally directed against both P. falciparum strains and was correlated to lipophilicity (calculated as ALogP), for all compounds but one (9). All compounds inhibited PLM I and PLM II in the nanomolar range (K(i) = 1-700 nM). The most promising compounds (2, 6, 10) were not cytotoxic against human fibroblasts at 100 microM and were highly selective for PLMs vs human cathepsin D.
authors.affiliation: Department of Pharmacological Sciences, School of Pharmacy, University of Milan, Milan 20100, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Dell'Agli
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Germana
authors.initials: G
authors.lastname: Galli
authors.forename: Nadia
authors.initials: N
authors.lastname: Vaiana
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Ben M
authors.initials: BM
authors.lastname: Dunn
authors.forename: Enrica
authors.initials: E
authors.lastname: Bosisio
authors.forename: Sergio
authors.initials: S
authors.lastname: Romeo
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D015800:Protozoan Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C517238:2-(2-(4-(4-((1-(1-(butylamino)-3-hydroxy-6-methyl-1-oxoheptan-4-ylamino)-3-methyl-1-oxopentan-2-yl)carbamoyl)phenoxy)benzamido)propanamido)-6-(tert-butoxycarbonyl)hexanoic acid propyl ester; C517237:4-(2-(4-(4-((1-(1-(4-(6-methoxyquinolin-8-ylamino)pentylamino)-1-oxopropan-2-ylamino)-4-methyl-1-oxopentan-2-yl)carbamoyl)phenoxy)benzamido)-3-methylpentanamido)-3-hydroxy-6-methylheptanoic acid butylamide; C517236:4-(2-(4-(4-((1-(4-(6-methoxyquinolin-8-ylamino)pentylamino)-4-methyl-1-oxopentan-2-yl)carbamoyl)phenoxy)benzamido)-3-methylpentanamido)-3-hydroxy-6-methylheptanoic acid butylamide; D000634:Aminoquinolines; D000962:Antimalarials; D004151:Dipeptides; D015800:Protozoan Proteins; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin; C100637:plasmepsin II; D002402:Cathepsin D; D007930:Leucine