Pyridinium cationic-dimer antimalarials, unlike chloroquine, act selectively between the schizont stage and the ring stage of Plasmodium falciparum.
Malaria is a leading cause of death in developing countries, and the emergence of strains resistant to the main therapeutic agent, chloroquine, has become a serious problem. We have developed cationic-dimer type antimalarials, MAP-610 and PMAP-H10, which are structurally different from chloroquine. In this study, we introduced several substituents on the terminal phenyl rings of PMAP-H10. The electronic and hydrophobic properties of the substituents were correlated with the antimalarial activity and cytotoxicity of the compounds, respectively. Studies with synchronized cultures of malarial plasmodia showed that our cationic-dimers act selectively between the schizont stage and the ring stage of the parasitic cycle, unlike chloroquine, which has a stage-independent action. Thus, the mechanism of action of our antimalarials appears to be different from that of chloroquine, and our compounds may be effective against chloroquine-resistant strains.
Yoshikawa
Mai
M
Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
Motoshima
Kazunori
K
Fujimoto
Kanji
K
Tai
Akihiro
A
Kakuta
Hiroki
H
Sasaki
Kenji
K
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000633:toxicity*; D002412:Cations; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000737:chemistry / Q000633:toxicity*; D019281:Dimerization; D004351:Drug Resistance; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development*; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000633:toxicity*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D002412:Cations; D011726:Pyridinium Compounds; D002738:Chloroquine