Publication: Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: Design, construction, characterization, and pharmacology of metaquine
Issued Date
2005-08-25
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ISSN
00222623
Other identifier(s)
2-s2.0-23944500763
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Medicinal Chemistry. Vol.48, No.17 (2005), 5423-5436
Suggested Citation
Michael J. Dascombe, Michael G.B. Drew, Harry Morris, Prapon Wilairat, Saranya Auparakkitanon, Wendy A. Moule, Said Alizadeh-Shekalgourabi, Philip G. Evans, Michael Lloyd, Anthony M. Dyas, Pamela Carr, Fyaz M.D. Ismail 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. Vol.48, No.17 (2005), 5423-5436. doi:10.1021/jm0408013 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/16301
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Title
Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: Design, construction, characterization, and pharmacology of metaquine
Abstract
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 ID50of 25 μmol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 μM). 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. © 2005 American Chemical Society.