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

Ning Wang; Kathryn Jean Wicht; Li Wang; Wen-Jie Lu; Ryuhei Misumi; Ming-qi Wang; Ahmed Abdel Aleem El Gokha; Marcel Kaiser; Ibrahim El Tantawy El Sayed; Timothy John Egan; Tsutomu Inokuchi

doi:10.1248/cpb.c13-00639

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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

Ning Wang, Kathryn Jean Wicht, Li Wang, Wen-Jie Lu, Ryuhei Misumi, Ming-qi Wang, Ahmed Abdel Aleem El Gokha, Marcel Kaiser, Ibrahim El Tantawy El Sayed, Timothy John Egan, Tsutomu Inokuchi

Author information

Ning Wang
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University
Kathryn Jean Wicht
Department of Chemistry, University of Cape Town
Li Wang
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University
Wen-Jie Lu
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University
Ryuhei Misumi
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University
Ming-qi Wang
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University
Ahmed Abdel Aleem El Gokha
Chemistry Department, Faculty of Science, El Menoufeia University
Marcel Kaiser
Swiss Tropical and Public Health Institute
Ibrahim El Tantawy El Sayed
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University
Chemistry Department, Faculty of Science, El Menoufeia University
Timothy John Egan
Department of Chemistry, University of Cape Town
Tsutomu Inokuchi Corresponding author
Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University

Keywords: 6H-indolo[2,3-b]quinolone, neocryptolepine congener, antiplasmodial activity, ester-substituted; ω-aminoalkylamino-substituted, β-haematin inhibition

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2013 Volume 61 Issue 12 Pages 1282-1290

DOI https://doi.org/10.1248/cpb.c13-00639

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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 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 IC₅₀/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 IC₅₀ 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.

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