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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

Wang, Ning and Wicht, Kathryn J. and Imai, Kento and Wang, Ming-Qi and Anh Ngoc, Tran and Kiguchi, Ryo and Kaiser, Marcel and Egan, Timothy J. and Inokuchi, Tsutomu. (2014) 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. Bioorganic & medicinal chemistry, 22 (9). pp. 2629-2642.

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Official URL: http://edoc.unibas.ch/dok/A6263112

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Abstract

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 4000nM, high antimalarial activities with IC50 values of about 11nM for CQS (NF54), IC50 values of about 17nM 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%.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0968-0896
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Dec 2017 14:01
Deposited On:15 Aug 2014 07:16

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