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 ID(50) of 25 micromol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 microM). 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.
authors.affiliation: Faculty of Life Sciences, Stopford Building 1.124, The University of Manchester, Oxford Road, Manchester M13 9PT, U.K. mike.dascombe@manchester.ac.uk
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dascombe
authors.forename: Michael G B
authors.initials: MG
authors.lastname: Drew
authors.forename: Harry
authors.initials: H
authors.lastname: Morris
authors.forename: Prapon
authors.initials: P
authors.lastname: Wilairat
authors.forename: Saranya
authors.initials: S
authors.lastname: Auparakkitanon
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Moule
authors.forename: Said
authors.initials: S
authors.lastname: Alizadeh-Shekalgourabi
authors.forename: Philip G
authors.initials: PG
authors.lastname: Evans
authors.forename: Michael
authors.initials: M
authors.lastname: Lloyd
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Dyas
authors.forename: Pamela
authors.initials: P
authors.lastname: Carr
authors.forename: Fyaz M D
authors.initials: FM
authors.lastname: Ismail
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016208:Databases, Factual; D015195:Drug Design; D006418:Heme / Q000737:chemistry; D006427:Hemin / Q000737:chemistry; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010655:Phenylenediamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010962:Plasmodium berghei / Q000187:drug effects; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C504518:N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine; D010655:Phenylenediamines; D011804:Quinolines; D006418:Heme; D006427:Hemin