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

J Med Chem. 1998 Dec 3;41(25):4918-26. doi: 10.1021/jm980146x.

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).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminoquinolines / chemical synthesis*
  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Chloroquine / chemistry
  • Chloroquine / pharmacology
  • Drug Resistance
  • Inhibitory Concentration 50
  • Plasmodium falciparum / drug effects*
  • Structure-Activity Relationship

Substances

  • Aminoquinolines
  • Antimalarials
  • Chloroquine