The online version of this article (doi:10.1186/1475-2875-11-65) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
CM carried out the β-haematin and peroxidation studies, performed the statistical analysis and drafted the manuscript. AJ carried out the synthesis of 4-aminoalcohol quinoline derivatives. CD performed the Plasmodium falciparum susceptibility assays. NT participated to the Plasmodium falciparum susceptibility assays and helped to draft the manuscript. PS participated in the design and coordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript.
A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs.
The (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ.
The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro.
Additional file 1: Peroxidative degradation of haemin at pH 7.0. The data provided represent the mean values (± SD) of the peroxidative degradation of haemin performed at pH 7.0 along with the statistical analysis. (DOC 38 KB)12936_2011_2032_MOESM1_ESM.DOC
Authors’ original file for figure 112936_2011_2032_MOESM2_ESM.pdf
Douglas NM, Nosten F, Ashley EA, Phaiphun L, van Vugt M, Singhasivanon P, White NJ, Price RN: Plasmodium vivax recurrence following falciparum and mixed species malaria: risk factors and effect of antimalarial kinetics. Clin Infect Dis. 2011, 52: 612-620. 10.1093/cid/ciq249. PubMedCentralCrossRefPubMed
Dow GS, Heady TN, Bhattacharjee AK, Caridha D, Gerena L, Gettayacamin M, Lanteri CA, Obaldia N, Roncal N, Shearer T, Smith PL, Tungtaeng A, Wolf L, Cabezas M, Yourick D, Smith KS: Utility of alkylaminoquinolinyl methanols as new antimalarial drugs. Antimicrob Agents Chemother. 2006, 50: 4132-4143. 10.1128/AAC.00631-06. PubMedCentralCrossRefPubMed
Milner E, McCalmont W, Bhonsle J, Caridha D, Cobar J, Gardner S, Gerena L, Goodine D, Lanteri C, Melendez V, Roncal N, Sousa J, Wipf P, Dow GS: Anti-malarial activity of a non-piperidine library of next-generation quinoline methanol. Malar J. 2010, 9: 51-10.1186/1475-2875-9-51. PubMedCentralCrossRefPubMed
Shepherd J: Use of (+) mefloquine for the treatment of malaria. 1998, International patent WO98/39003
Jonet A, Dassonville-Klimpt A, Da Nascimento S, Léger JM, Guillon J, Sonnet P: First enantioselective synthesis of 4-aminoalcohol quinoline derivatives through a regioselective SN2 epoxide opening mechanism. Tetrahedron-Asymmetry. 2011, 22: 138-148. 10.1016/j.tetasy.2011.01.003. CrossRef
Jonet A, Dassonville-Klimpt A, Mullié C, Taudon N, Sonnet P: Enantioselective synthesis method 4-aminoalcoholquinoline derivatives and the use. European Patent. 2011, N11154229-
Lowry R: VassarStats: Website for Statistical Computation. [ http://faculty.vassar.edu/lowry/VassarStats.html]
Mullié C, Jonet A, Dassonville-Klimpt A, Gosmann G, Sonnet P: Inhibitory effect of ursolic acid derivatives on hydrogen peroxide--and glutathione-mediated degradation of hemin: a possible additional mechanism of action for antimalarial activity. Exp Parasitol. 2010, 125: 202-207. 10.1016/j.exppara.2010.01.016. CrossRefPubMed
Kutter D, Chibale K, Egan TJ: Linear free energy relationships predict coordination and π-stacking interactions of small molecules with ferriprotoporphyrin IX. J Inorg Biochem. 2011, 105: 684-692. 10.1016/j.jinorgbio.2011.02.008. CrossRef
Wandhammer M, Carletti E, Van der Schans M, Gillon E, Nicolet Y, Masson P, Goeldner M, Noort D, Nachon F: Structural study of the complex stereoselectivity of human butyrylcholinesterase for the neurotoxic V-agents. J Biol Chem. 2011, 286: 16783-16789. 10.1074/jbc.M110.209569. PubMedCentralCrossRefPubMed
Sanchez CP, Rotmann A, Stein WD, Lanzer M: Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum. Mol Microbiol. 2008, 70: 786-798. PubMed
Phompradit P, Wisedpanichkij R, Muhamad P, Chaijaroenkul W, Na-Bangchang K: Molecular analysis of pfatp6 and pfmdr1 polymorphisms and their association with in vitro sensitivity in Plasmodium falciparum isolates from the Thai-Myanmar border. Acta Trop. 2011, 120: 130-135. 10.1016/j.actatropica.2011.07.003. CrossRefPubMed
de Lagerie Barraud S, Comets E, Gautrand C, Fernandez C, Auchere D, Singlas E, Mentre F, Gimenez F: Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice. Br J Pharmacol. 2004, 141: 1214-1222. 10.1038/sj.bjp.0705721. CrossRef
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