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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/16301
Title: Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: Design, construction, characterization, and pharmacology of metaquine
Authors: 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
University of Manchester
University of Reading
Liverpool John Moores University
Mahidol University
University of Hertfordshire
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 25-Aug-2005
Citation: Journal of Medicinal Chemistry. Vol.48, No.17 (2005), 5423-5436
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.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=23944500763&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/16301
ISSN: 00222623
Appears in Collections:Scopus 2001-2005

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