title: In vitro inhibition of beta-haematin formation, DNA interactions, antiplasmodial activity, and cytotoxicity of synthetic neocryptolepine derivatives.
abstract: Neocryptolepine, a minor alkaloid of Cryptolepis sanguinolenta, was investigated as a lead for new antiplasmodial agents, because of its lower cytotoxicity than cryptolepine, the major alkaloid. Synthetic 2- or 3-substituted neocryptolepine derivatives were evaluated for their biological activity. In addition to the antiplasmodial activity (Plasmodium falciparum chloroquine-sensitive and -resistant) also the cytotoxicity (MRC-5 cells) was determined. Several compounds such as 2-bromoneocryptolepine showing higher and more selective antiplasmodial activity than neocryptolepine were obtained. Several functional assays and in vitro tests were used to obtain additional information on the mechanism of action, i.e., the beta-haematin formation inhibitory assay (detoxification of haem) and the DNA-methylgreen displacement assay (interaction with DNA). It could be demonstrated that the 2- or 3-substituted neocryptolepine derivatives investigated here have about the same potency to inhibit the beta-haematin formation as chloroquine, indicating that inhibition of haemozoin formation makes at least an important contribution to their antiplasmodial activity, although their in vitro antiplasmodial activity is still less than chloroquine.
authors.affiliation: Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. sabine.vanmiert@ua.ac.be
authors.forename: Sabine
authors.initials: S
authors.lastname: Van Miert
authors.forename: Tim
authors.initials: T
authors.lastname: Jonckers
authors.forename: Kanyanga
authors.initials: K
authors.lastname: Cimanga
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Bert
authors.initials: B
authors.lastname: Maes
authors.forename: Guy
authors.initials: G
authors.lastname: Lemière
authors.forename: Roger
authors.initials: R
authors.lastname: Dommisse
authors.forename: Arnold
authors.initials: A
authors.lastname: Vlietinck
authors.forename: Luc
authors.initials: L
authors.lastname: Pieters
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D031106:Cryptolepis; D004247:DNA / Q000378:metabolism*; D006420:Hemeproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D006420:Hemeproteins; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C414982:neocryptolepine; C020753:hemozoin; C024015:cryptolepine; D004247:DNA