title: Antimalarial activity of crambescidin 800 and synthetic analogues against liver and blood stage of Plasmodium sp.
abstract: Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC50=490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC50 = 8.5-59 microM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC50 = 9.2 microM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.
authors.affiliation: Marine Science Institute, University of the Philippines, Diliman 1101, Quezon City, Philippines. jlazaro@uap.edu.ph
authors.forename: J Enrico H
authors.initials: JE
authors.lastname: Lazaro
authors.forename: Josiane
authors.initials: J
authors.lastname: Nitcheu
authors.forename: Nassira
authors.initials: N
authors.lastname: Mahmoudi
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Ibana
authors.forename: Gina C
authors.initials: GC
authors.lastname: Mangalindan
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Black
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Howard-Jones
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Moore
authors.forename: Dafydd A
authors.initials: DA
authors.lastname: Thomas
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Chris M
authors.initials: CM
authors.lastname: Ireland
authors.forename: Gisela P
authors.initials: GP
authors.lastname: Concepcion
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Murphy
authors.forename: Bertrand
authors.initials: B
authors.lastname: Diquet
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000469:parasitology; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D022781:Hepatocytes / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D010967:Plasmodium yoelii / Q000187:drug effects*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D016019:Survival Analysis
chemical_list: D000962:Antimalarials; D013141:Spiro Compounds; C490355:crambescidin 800; D019791:Guanidine