European Journal of Medicinal Chemistry 2013-06-01

Synthesis and antimalarial testing of neocryptolepine analogues: addition of ester function in SAR study of 2,11-disubstituted indolo[2,3-b]quinolines.

Wen-Jie Lu, Kathryn J Wicht, Li Wang, Kento Imai, Zhen-Wu Mei, Marcel Kaiser, Ibrahim El Tantawy El Sayed, Timothy J Egan, Tsutomu Inokuchi

Index: Eur. J. Med. Chem. 64 , 498-511, (2013)

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Abstract

This report describes the synthesis, and in vitro and in vivo antimalarial evaluations of certain ester-modified neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives. The modifications were carried out by introducing ester groups at the C2 and/or C9 position on the neocryptolepine core and the terminal amino group of the 3-aminopropylamine substituents at the C11 position with a urea/thiourea unit. The antiplasmodial activities of our 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 the ester modified neocryptolepine derivatives have higher antiplasmodial activities against both strains and a low cytotoxic activity against normal cells. The best results were achieved by compounds 9c and 12b against the NF54 strain with the IC50/SI value as 2.27 nM/361 and 1.81 nM/321, respectively. While against K1 strain, all the tested compounds showed higher activity than the well-known antimalarial drug chloroquine. Furthermore, the compounds were tested for β-haematin inhibition and 12 were found to be more active than chloroquine (IC50 = 18 μM). Structure activity relationship studies exposed an interesting linear correlation between polar surface area of the molecule and β-haematin inhibition for this series. In vivo testing of compounds 7 and 8a against NF54 strain on Plasmodium berghei female mice showed that the introduction of the ester group increased the antiplasmodial activity of the neocryptolepine core substantially.Copyright © 2013 Elsevier Masson SAS. All rights reserved.