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.
Van Baelen
Gitte
G
Laboratory of Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
Hostyn
Steven
S
Dhooghe
Liene
L
Tapolcsányi
Pál
P
Mátyus
Péter
P
Lemière
Guy
G
Dommisse
Roger
R
Kaiser
Marcel
M
Brun
Reto
R
Cos
Paul
P
Maes
Louis
L
Hajós
György
G
Riedl
Zsuzsanna
Z
Nagy
Ildikó
I
Maes
Bert U W
BU
Pieters
Luc
L
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