Synthesis, antimalarial activity and inhibition of haem detoxification of novel bisquinolines

The synthesis of novel bisquinoline compounds comprising 4-(4-diethylamino-1-methylbutyl)aminoquinoline units joined through the 2-position by a (CH2)(n) linker is described. Their ability to inhibit the growth of both chloroquine-sensitive (D10) and chloroquine-resistant (K1) strains of Plasmodium falciparum, the hydrogen peroxide-mediated pathway for decomposition of haem, and the conversion of haem to beta -haematin have been measured. The activity was affected by the length of the linker and the most active (6c, n = 12) showed effects similar to chloroquine in three of the assays. However, it was even more active against the resistant strain [IC50, 17 nM (K1); 43 nM (D10)], much superior to chloroquine (IC50, 540 nM) and slightly better than mefloquine (IC50, 30 nM) in this regard. (C) 2001 Elsevier Science Ltd. All rights reserved.