Structure−Activity Relationships for Antiplasmodial Activity among 7-Substituted 4-Aminoquinolines

Abstract

Aminoquinolines (AQs) with diaminoalkane side chains (−HNRNEt₂) shorter or longer than the isopentyl side chain [−HNCHMe(CH₂)₃NEt₂] of chloroquine are active against both chloroquine-susceptible and -resistant Plasmodium falciparum. (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 different substituents at the 7-position occupied by Cl in chloroquine. 7-Iodo- and 7-bromo-AQs with diaminoalkane side chains [−HN(CH₂)₂NEt₂, −HN(CH₂)₃NEt₂, or −HNCHMeCH₂NEt₂] were as active as the corresponding 7-chloro-AQs against both chloroquine-susceptible and -resistant P. falciparum (IC₅₀s of 3−12 nM). In contrast, with one exception, 7-fluoro-AQs and 7-trifluoromethyl-AQs were less active against chloroquine-susceptible P. falciparum (IC₅₀s of 15−50 nM) and substantially less active against chloroquine-resistant P. falciparum (IC₅₀s of 18−500 nM). Furthermore, most 7-OMe-AQs were inactive against both chloroquine-susceptible (IC₅₀s of 17−150 nM) and -resistant P. falciparum (IC₅₀s of 90−3000 nM).