Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance

PLoS One. 2016 Aug 2;11(8):e0160091. doi: 10.1371/journal.pone.0160091. eCollection 2016.


Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p-aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications.

MeSH terms

  • Amodiaquine / analogs & derivatives
  • Amodiaquine / chemistry
  • Amodiaquine / metabolism
  • Amodiaquine / pharmacology
  • Antimalarials / chemistry*
  • Antimalarials / metabolism
  • Antimalarials / pharmacology*
  • Biological Transport
  • Chloroquine / analogs & derivatives
  • Chloroquine / chemistry
  • Chloroquine / metabolism
  • Chloroquine / pharmacology
  • Drug Design
  • Drug Resistance
  • Heme / antagonists & inhibitors
  • Heme / metabolism
  • Hemin / antagonists & inhibitors*
  • Hemin / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / metabolism
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Quinolines / pharmacology
  • Structure-Activity Relationship
  • Vacuoles / drug effects*
  • Vacuoles / metabolism


  • Antimalarials
  • Quinolines
  • Amodiaquine
  • Heme
  • Hemin
  • desethylamodiaquine
  • 3-methylchloroquine
  • Chloroquine
  • piperaquine

Grants and funding

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Part of this work was carried out while DCW and JCC were emeritus professors at 1. The Department of Infectious and Tropical Diseases (Pathogen Molecular Unit) of the London School of Hygiene and Tropical Medicine (LSHTM) (University of London) and 2. The Department of Pharmaceutical Chemistry of the University of California, San Francisco, respectively. Miscellaneous external analysis costs were paid personally by these authors, but both have acknowledged the continuing essential logistical support of these distinguished research institutes.