BISQUINOLINES - 2 - ANTIMALARIAL N,N-BIS(7-CHLOROQUINOLIN-4-YL)HETEROALKANEDIAMINES

N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesiz ed and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. These bisquinolines had IC50 values from 1 to 100 nM against P. falciparum in vitro. Six of the 11 bisquinolines were signi ficantly more potent against the chloroquine-resistant W2 clone compar ed to the chloroquine-sensitive D6 clone. For bisquinolines 1-11 there was no relationship between the length of the bisquinoline heteroalka ne bridge and antimalarial activity and no correlation between in vitr o and in vivo antimalarial activities. Bisquinolines with alkyl ether and piperazine bridges were substantially more effective than bisquino lines with alkylamine bridges against P. berghei in vivo. Bisquinoline s 1-10 were potent inhibitors of hematin polymerization with IC50 valu es falling in the narrow range of 5-20 mu M, and there was a correlati on between potency of inhibition of hematin polymerization and inhibit ion of parasite growth. Compared to alkane-bridged bisquinolines (Venn erstrom et al., 1992), none of these heteroalkane-bridged bisquinoline s had sufficient antimalarial activity to warrant further investigatio n of the series.