Synthesis and in vitro testing of antimalarial activity of non-natural-type neocryptolepines: structure–activity relationship study of 2,11- and 9,11-disubstituted 6-methylindolo[2,3-b]quinolines.
This report describes the synthesis and in vitro anti-malarial evaluations of certain C2 or C8 and C11-disubstituted 6-methyl-5H-indolo[2,3-b]quinoline (neocryptolepine congener) derivatives. To attain higher activities, the structure–activity relationship (SAR) studies were conducted by varying the kind of alkylamino or ω-aminoalkylamino stubstituents at C11 and with Cl at the C2 position, or CO2Me at the C9 position. The anti-malarial activities of the tested compounds were significantly increased compared to the 11-non(alkylamino) derivatives. The 3-aminopropylamino group at C11 was further modified to urea and thiourea, which improved the cytotoxicity against normal cells. The best results were achieved with compounds 8 and 9d against the NF54 strain with the IC(50)/SI values as of 86 nM/20 and 317 nM/370, respectively. Furthermore, the compounds were tested for β-haematin inhibition. Twelve were found to have IC(50) values below 100 µM and a linear correlation between the β-haematin inhibition and cell growth inhibition in the NF54 strain was found for those derivatives with basic amino side chains. A second correlation was identified between the NF54 activity and physico-chemical factors related to solvation and polarity.
Ning
N
Wang
Kathryn Jean
KJ
Wicht
Li
L
Wang
Wen-Jie
WJ
Lu
Ryuhei
R
Misumi
Ming-qi
MQ
Wang
Ahmed Abdel Aleem
AA
El Gokha
Marcel
M
Kaiser
Ibrahim El Tantawy
Iel T
El Sayed
Timothy John
TJ
Egan
Tsutomu
T
Inokuchi
D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000962:Antimalarials; D007211:Indoles; D011804:Quinolines; C414982:neocryptolepine