Synthesis, β-haematin inhibition, and in vitro antimalarial testing of isocryptolepine analogues: SAR study of indolo[3,2-c]quinolines with various substituents at C2, C6, and N11.
A series of indolo[3,2-c]quinolines were synthesized by modifying the side chains of the ω-aminoalkylamines at the C6 position and introducing substituents at the C2 position, such as F, Cl, Br, Me, MeO and NO2, and a methyl group at the N11 position for an SAR study. The in vitro antiplasmodial activities of the derivative agents against two different strains (CQS: NF54 and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that compounds 6k and 6l containing the branched methyl groups of 3-aminopropylamino at C6 with a Cl atom at C2 exhibited a very low cytotoxicity with IC50 values above 4000 nM, high antimalarial activities with IC50 values of about 11 nM for CQS (NF54), IC50 values of about 17 nM for CQR (K1), and RI resistance indices of 1.6. Furthermore, the compounds were tested for β-haematic inhibition, and QSAR revealed an interesting linear correlation between the biological activity of CQS (NF54) and three contributing factors, namely solubility, hydrophilic surface area, and β-haematin inhibition for this series. In vivo testing of 6l showed a reduction in parasitaemia on day 4 with an activity of 38%.
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
Ning
N
Wang
Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa.
Kathryn J
KJ
Wicht
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
Kento
K
Imai
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
Ming-Qi
MQ
Wang
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
Tran
T
Anh Ngoc
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
Ryo
R
Kiguchi
Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; University Basel, Petersplatz 1, CH-4003 Basel, Switzerland.
Marcel
M
Kaiser
Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa. Electronic address: Timothy.Egan@uct.ac.za.
Timothy J
TJ
Egan
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan. Electronic address: inokuchi@cc.okayama-u.ac.jp.
Tsutomu
T
Inokuchi
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006427:Hemin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D007211:Indoles / Q000737:chemistry; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship
D000962:Antimalarials; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C577868:isocryptolepine; D006427:Hemin
Antiplasmodial activity; C9-alkylamino-substituted isocryptolepine; Chloroquine sensitive and resistant; In vitro test; Indolo[3,2-c]quinoline; β-Haematin inhibition