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In vitro inhibition of beta-haematin formation, DNA interactions, antiplasmodial activity, and cytotoxicity of synthetic neocryptolepine derivatives.

Authors :
Van Miert S
Jonckers T
Cimanga K
Maes L
Maes B
Lemière G
Dommisse R
Vlietinck A
Pieters L
Source :
Experimental parasitology [Exp Parasitol] 2004 Nov-Dec; Vol. 108 (3-4), pp. 163-8.
Publication Year :
2004

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.

Details

Language :
English
ISSN :
0014-4894
Volume :
108
Issue :
3-4
Database :
MEDLINE
Journal :
Experimental parasitology
Publication Type :
Academic Journal
Accession number :
15582513
Full Text :
https://doi.org/10.1016/j.exppara.2004.08.006