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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

Wang, N. and Wicht, K. J. and Wang, L. and Lu, W. J. and Misumi, R. and Wang, M. Q. and El Gokha, A. A. and Kaiser, M. and El Sayed, T. and Egan, T. J. and Inokuchi, T.. (2013) 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. Chemical and pharmaceutical bulletin, Vol. 61, H. 12. pp. 1282-1290.

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Official URL: http://edoc.unibas.ch/dok/A6223298

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Abstract

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 ?-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 IC50/SI values as of 86 nM/20 and 317 nM/370, respectively. Furthermore, the compounds were tested for ?-haematin inhibition. Twelve were found to have IC50 values below 100 µM and a linear correlation between the ?-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.
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 (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Pharmaceutical Society of Japan
ISSN:0009-2363
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:27 Mar 2014 13:12
Deposited On:27 Mar 2014 13:12

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