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.
Highlights
In the search for chloroquine (CQ) analogues, which could retain their antimalarial activity against the increasingly prevalent CQ-resistant strains [1] of Plasmodium falciparum, a group of bis-quinolines was synthesized [2, 3]
Earlier we found molecular modelling using AM1 [13] helpful in interpreting stoichiometry of interactions with haematin [13], and to test expectations of resonance within the para (4)aminopyridine ring and the para-aminopyridinium ion formed on protonation of the aromatic ring N1
The original question was whether two bis quinolines (3 and 6) of similar molecular weight (535 for 3 vs. 523 for 6) might owe their biological properties to identical physicochemical parameters in respect of their acid-base character and lipid solubility
Summary
In the search for chloroquine (CQ) analogues, which could retain their antimalarial activity against the increasingly prevalent CQ-resistant strains [1] of Plasmodium falciparum, a group of bis-quinolines was synthesized [2, 3]. We measured the pKa and log P values of DCQ, in comparison with those of PQ and CQ.
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