Structure-activity relationships for antiplasmodial activity among 7-substituted 4-aminoquinolines

Aminoquinolines (AQs) with diaminoalkane side chains (-HNRNEt2) shorter or longer than the isopentyl side chain [-HNCHMe(CH2)(3)NEt2] of chloroquine a re active against both chloroquine-susceptible and -resistant Plasmodium fa lciparum. (De, D.; et al. Am. J. Trop. Med. Hyg. 1996, 55, 579-583). In the studies reported here, we examined structure-activity relationships (SARs) among AQs with different N,N-diethyldiaminoalkane side chains and differen t substituents at the 7-position occupied by Cl in chloroquine. 7-Iodo- and 7-bromo-AQs with diaminoalkane side chains [-HN(CH2)(2)NEt2, -HN(CH2)(3)NE t2, or -HNCHMeCH2NEt2] were as active as the corresponding 7-chloro-AQs aga inst both chloroquine-susceptible and -resistant P. falciparum (IC(50)s of 3-12 nM). In contrast, with one exception, 7-fluoro-AQs and 7-trifluorometh yl-AQs were less active against chloroquine-susceptible P. falciparum (IC(5 0)s of 15-50 nM) and substantially less active against chloroquine-resistan t P. falciparum (IC(50)s of 18-500 nM). Furthermore, most 7-OMe-AQs were in active against both chloroquine-susceptible (IC(50)s of 17-150 nM) and -res istant P. falciparum (IC(50)s of 90-3000 nM).