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Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine

Dascombe, M.J., Drew, M.G.B., Morris, H., Wilairat, P., Auparakkitanon, S., Moule, W.A., Alizadeh-Shekalgourabi, S., Evans, P.G., Lloyd, M., Dyas, A.M., Carr, P. and Ismail, F.M.D. (2005) Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine. Journal of Medicinal Chemistry, 48 (17). pp. 5423-5436. ISSN 0022-2623

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To link to this item DOI: 10.1021/jm0408013

Abstract/Summary

Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID50 of 25 mu mol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 mu M). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G*) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1: 1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
ID Code:11178
Uncontrolled Keywords:QUANTITATIVE STRUCTURE-ACTIVITY, INHOMOGENEOUS ELECTRON-GAS, BETA-HEMATIN FORMATION, QUINOLINE ANTIMALARIALS, MALARIA PIGMENT, FERRIPROTOPORPHYRIN-IX, PLASMODIUM-FALCIPARUM, CHLOROQUINE RESISTANCE, RECEPTOR ANTAGONISTS, MEDICINAL CHEMISTRY

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