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.

A pulse radiolysis study of free radicals formed by one-electron oxidation of the antimalarial drug pyronaridine

“…This eliminates oxidative stress due to free heme and allows the parasite to survive. Compounds that inhibit heme biocrystallization also possess antimalarial activity [18]. Recent results indicate that pyronaridine forms a complex with hematin that inhibits further biocrystallization [19].…”

Interaction of Iron(III)-5,10,15,20-Tetrakis (4-Sulfonatophenyl) Porphyrin with Chloroquine, Quinine and Quinidine

“…The coordination of the iron center of Ferri-porphyrin by the alcohol/alkoxy functionality and an intramolecular hydrogen bond formed between the protonated quaternary quinuclidine nitrogen atom of a drug molecule and the negatively charged propionate side chain of the Ferri-porphyrin have been also mentioned as additional forces stabilizing the complex [12] [15] [19] [20]. Growing resistance of the Plasmodium to the quinoline antimalarials spurred the development of a new antimalarial pharmacological approach based on designing new molecules [21] [22]. A new antimalarial chemotherapy has been reported based on choline analogues with novel mechanisms of action [7] [23].…”

Antiplasmodial Evaluation of One Compound from <i>Calophyllum flavoranulum</i>

“…The appearance of drug resistant Plasmodium falciparum since 1960 has made the treatment of malaria increasingly problematic and apparently the battle against malaria has not been successful [2]. Drugs which are employed in the treatment of malaria are becoming increasingly ineffective due to the spread of resistant parasite strains threaten to increas the annual death tool [3][4].…”

“…Calophyllum is one of the most important medicine plants, because Calophyllum as a source of new active compound for treatment of malaria [2][3][4]. Four species of Plasmodium: P. falciparum, P. vivax, P. ovale and P. Malariae can produce malaria in human.…”