In vitro inhibition of beta-haematin formation, DNA interactions, antiplasmodial activity, and cytotoxicity of synthetic neocryptolepine derivatives.
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.
Van Miert
Sabine
S
Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. sabine.vanmiert@ua.ac.be
Jonckers
Tim
T
Cimanga
Kanyanga
K
Maes
Louis
L
Maes
Bert
B
Lemière
Guy
G
Dommisse
Roger
R
Vlietinck
Arnold
A
Pieters
Luc
L
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
D000470:Alkaloids; D000962:Antimalarials; D006420:Hemeproteins; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C414982:neocryptolepine; C020753:hemozoin; C024015:cryptolepine; D004247:DNA