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

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. © 2013 The Pharmaceutical Society of Japan.