Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues.
Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds.
Laboratory of Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
Gitte
G
Van Baelen
Steven
S
Hostyn
Liene
L
Dhooghe
Pál
P
Tapolcsányi
Péter
P
Mátyus
Guy
G
Lemière
Roger
R
Dommisse
Marcel
M
Kaiser
Reto
R
Brun
Paul
P
Cos
Louis
L
Maes
György
G
Hajós
Zsuzsanna
Z
Riedl
Ildikó
I
Nagy
Bert U W
BU
Maes
Luc
L
Pieters
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D026121:Indole Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
D000962:Antimalarials; D000970:Antineoplastic Agents; D026121:Indole Alkaloids