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Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance.
- Source :
-
PloS one [PLoS One] 2016 Aug 02; Vol. 11 (8), pp. e0160091. Date of Electronic Publication: 2016 Aug 02 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- 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.
- Subjects :
- Amodiaquine analogs & derivatives
Amodiaquine chemistry
Amodiaquine metabolism
Amodiaquine pharmacology
Antimalarials metabolism
Biological Transport
Chloroquine analogs & derivatives
Chloroquine chemistry
Chloroquine metabolism
Chloroquine pharmacology
Drug Design
Drug Resistance
Heme antagonists & inhibitors
Heme metabolism
Hemin metabolism
Hydrophobic and Hydrophilic Interactions
Plasmodium falciparum metabolism
Quinolines chemistry
Quinolines metabolism
Quinolines pharmacology
Structure-Activity Relationship
Vacuoles metabolism
Antimalarials chemistry
Antimalarials pharmacology
Hemin antagonists & inhibitors
Plasmodium falciparum drug effects
Vacuoles drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 11
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 27483471
- Full Text :
- https://doi.org/10.1371/journal.pone.0160091