Michael J. DascombeMichael G.B. DrewHarry MorrisPrapon WilairatSaranya AuparakkitanonWendy A. MouleSaid Alizadeh-ShekalgourabiPhilip G. EvansMichael LloydAnthony M. DyasPamela CarrFyaz M.D. IsmailUniversity of ManchesterUniversity of ReadingLiverpool John Moores UniversityMahidol UniversityUniversity of Hertfordshire2018-06-212018-06-212005-08-25Journal of Medicinal Chemistry. Vol.48, No.17 (2005), 5423-5436002226232-s2.0-23944500763https://repository.li.mahidol.ac.th/handle/20.500.14594/16301Resistant 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyPharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1021/jm0408013