title: Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents.
abstract: The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of beta-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg(-1) day(-1) ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (DeltaT(m) value) or toxicity in the mouse-malaria model.
authors.affiliation: The School of Pharmacy, University of Bradford, West Yorkshire, BD7 1DP, UK. c.w.wright@bradford.ac.uk
authors.forename: C W
authors.initials: CW
authors.lastname: Wright
authors.forename: J
authors.initials: J
authors.lastname: Addae-Kyereme
authors.forename: A G
authors.initials: AG
authors.lastname: Breen
authors.forename: J E
authors.initials: JE
authors.lastname: Brown
authors.forename: M F
authors.initials: MF
authors.lastname: Cox
authors.forename: S L
authors.initials: SL
authors.lastname: Croft
authors.forename: Y
authors.initials: Y
authors.lastname: Gökçek
authors.forename: H
authors.initials: H
authors.lastname: Kendrick
authors.forename: R M
authors.initials: RM
authors.lastname: Phillips
authors.forename: P L
authors.initials: PL
authors.lastname: Pollet
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006361:Heating; D006427:Hemin / Q000737:chemistry; D026121:Indole Alkaloids; D007211:Indoles; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D009691:Nucleic Acid Denaturation; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C435938:2,7-dibromocryptolepine; D000470:Alkaloids; D000962:Antimalarials; D000970:Antineoplastic Agents; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C024015:cryptolepine; D006427:Hemin; D004247:DNA