Synthesis and antiplasmodial activity of aminoalkylamino-substituted neocryptolepine derivatives.
A series of chloro- and aminoalkylamino-substituted neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives were synthesized and evaluated as antiplasmodial agents. The evaluation also included cytotoxicity (MRC5 cells), inhibition of beta-hematin formation, and DNA interactions (DNA-methyl green assay). Introduction of aminoalkylamino chains increased the antiplasmodial activity of the neocryptolepine core substantially. The most efficient compounds showed antiplasmodial activities in the nanomolar range. N(1),N(1)-Diethyl-N(4)-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine 11c showed an IC(50) of 0.01 microM and a selectivity index of 1800.
Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein, 1, 2610, Antwerp, Belgium.
Ibrahim
I
El Sayed
Pieter
P
Van der Veken
Koen
K
Steert
Liene
L
Dhooghe
Steven
S
Hostyn
Gitte
G
Van Baelen
Guy
G
Lemière
Bert U W
BU
Maes
Paul
P
Cos
Louis
L
Maes
Jurgen
J
Joossens
Achiel
A
Haemers
Luc
L
Pieters
Koen
K
Augustyns
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000378:metabolism; D015195:Drug Design; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000470:Alkaloids; D000962:Antimalarials; D016054:DNA, Protozoan; D011804:Quinolines; C414982:neocryptolepine