Activity of piperaquine and other 4-aminoquinoline antiplasmodial drugs against chloroquine-sensitive and resistant blood-stages of Plasmodium falciparum. Role of β-haematin inhibition and drug concentration in vacuolar water- and lipid-phases

David C. Warhurst, John C. Craig, Ipemida S. Adagu, R. Kiplin Guy, Peter B. Madrid, Quinton L. Fivelman

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Abstract

Chloroquine (CQ), a 4-aminoquinoline, accumulates in acidic digestive vacuoles of the malaria parasite, preventing conversion of toxic haematin to β-haematin. We examine how bis 4-aminoquinoline piperaquine (PQ) and its hydroxy-modification (OH-PQ) retain potency on chloroquine-resistant (CQ-R) Plasmodium falciparum. For CQ, PQ, OH-PQ and 4 and 5, representing halves of PQ, β-haematin inhibitory activity (BHIA) was assayed, while potency was determined in CQ-sensitive (CQ-S) and CQ-R P. falciparum. From measured pKas and the pH-modulated distribution of base between water and lipid (log D), the vacuolar accumulation ratio (VAR) of charged drug from plasma water (pH 7.4) into vacuolar water (pH 4.8) and lipid accumulation ratio (LAR) were calculated. All agents were active in BHIA. In CQ-S, PQ, OH-PQ and CQ were equally potent while 4 and 5 were 100 times less potent. CQ with two basic centres has a VAR of 143,482, while 4 and 5, with two basic centres of lower pKas have VARs of 1287 and 1966. In contrast PQ and OH-PQ have four basic centres and achieve VARs of 104,378 and 19,874. This confirms the importance of VAR for potency against CQ-S parasites. Contrasting results were seen in CQ-R. 5, PQ and OH-PQ with LARs of 693; 973,492 and 398,118 (compared with 8.25 for CQ) showed similar potency in CQ-S and CQ-R. Importance of LAR for potency against CQ-R parasites probably reflects ability to block efflux by hydrophobic interaction with PfCRT but may relate to β-haematin inhibition in vacuolar lipid.

Original languageEnglish
Pages (from-to)1910-1926
Number of pages17
JournalBiochemical Pharmacology
Volume73
Issue number12
DOIs
StatePublished - Jun 15 2007

Bibliographical note

Funding Information:
The work was carried out while D.C. Warhurst and J.C. Craig were Emeritus Professors at: 1. The Department of Infectious and Tropical Diseases (Pathogen Molecular Biology 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. Ipemida S. Adagu was a lecturer in Parasitology at LSHTM and Quinton L. Fivelman was supported there by a Commonwealth Research Fellowship. R. Kiplin Guy (associate professor) and Peter B. Madrid (postgraduate student, now a PhD) were working at the University of California, San Francisco.

Keywords

  • 4-Aminoquinolines
  • Drug-resistance
  • Hydrophobicity
  • Lysosomotropism
  • Piperaquine
  • Plasmodium

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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