Warhurst, DC, Craig, JC and Raheem, KS. 2016. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance. [Online]. Figshare. Available from: https://doi.org/10.1371/journal.pone.0160091.
Warhurst, DC, Craig, JC and Raheem, KS. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance [Internet]. Figshare; 2016. Available from: https://doi.org/10.1371/journal.pone.0160091.
Warhurst, DC, Craig, JC and Raheem, KS (2016). Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance. [Data Collection]. Figshare. https://doi.org/10.1371/journal.pone.0160091.
Description
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.
Data capture method | Experiment |
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Date (Date published in a 3rd party system) | 2 August 2016 |
Language(s) of written materials | English |
Data Creators | Warhurst, DC, Craig, JC and Raheem, KS |
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LSHTM Faculty/Department | Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology |
Participating Institutions | London School of Hygiene & Tropical Medicine, University of California San Francisco, University of Westminster |
Date Deposited | 19 Aug 2016 13:19 |
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Last Modified | 09 Jul 2021 11:22 |
Publisher | Figshare |
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Filename: S1Table_Excel.XLSX
Description: Physicochemical and other parameters for the compounds studied (MS Excel)
Content type: Dataset
File size: 25kB
Mime-Type: application/vnd.openxmlformats-officedocument.spreadsheetml.sheet
Filename: S1Table-CSV.csv
Description: Physicochemical and other parameters for the compounds studied (CSV format)
Content type: Dataset
File size: 6kB
Mime-Type: text/plain