Utility of alkylaminoquinolinyl methanols as new antimalarial drugs

Antimicrob Agents Chemother. 2006 Dec;50(12):4132-43. doi: 10.1128/AAC.00631-06. Epub 2006 Sep 11.


Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the "opening" of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.

Publication types

  • Comparative Study
  • Evaluation Study

MeSH terms

  • 3T3 Cells
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / economics
  • Antimalarials / metabolism
  • Antimalarials / pharmacokinetics
  • Antimalarials / pharmacology*
  • Antimalarials / toxicity
  • Aotidae
  • Computer Simulation
  • Drug Evaluation, Preclinical
  • Erythrocytes / parasitology
  • Female
  • Hydrogen-Ion Concentration
  • Inhibitory Concentration 50
  • Male
  • Mefloquine / analogs & derivatives*
  • Mefloquine / chemical synthesis
  • Mefloquine / chemistry
  • Mefloquine / economics
  • Mefloquine / metabolism
  • Mefloquine / pharmacokinetics
  • Mefloquine / pharmacology*
  • Mefloquine / toxicity
  • Mice
  • Microscopy, Confocal
  • Molecular Structure
  • Neurons / drug effects
  • Neurons / metabolism
  • Parasitemia / drug therapy
  • Plasmodium berghei / drug effects
  • Plasmodium falciparum / drug effects
  • Plasmodium vivax / drug effects
  • Solubility
  • Structure-Activity Relationship


  • Antimalarials
  • Mefloquine