Reversal activity of the naturally occurring chemosensitizer malagashanine in Plasmodium malaria

• Published in: Biochemical pharmacology Vol. 59; no. 9; pp. 1053 - 1061
• Main Authors: Rafatro, Herintsoa, Ramanitrahasimbola, David, Rasoanaivo, Philippe, Ratsimamanga-Urverg, Suzanne, Rakoto-Ratsimamanga, Albert, Frappier, François
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.05.2000; Elsevier Science
• Subjects: Alkaloids - chemistry; Alkaloids - pharmacology; Alkaloids - therapeutic use; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - pharmacology; Antimalarials - therapeutic use; Antiparasitic agents; Biological and medical sciences; chemosensitizer; Chloroquine - pharmacology; Disease Models, Animal; Drug Interactions; Drug Resistance; indole alkaloid; malagashanine; malaria chemotherapy; Malaria, Falciparum - drug therapy; Medical sciences; Mice; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Plasmodium yoelii - drug effects; reversal activity; Solubility; Verapamil - pharmacology; indole alkaloid; malaria chemotherapy; malagashanine; reversal activity; chemosensitizer; Protozoa; Apicomplexa; Drug combination; Chloroquine; Rodentia; Molecular interaction; In vitro; Resistance; In vivo; Plasmodium falciparum; Vertebrata; Alkaloid; Chemotherapy; Mammalia; Mouse; Animal; Parasiticid; Subcutaneous administration; Drug interaction; Indole derivatives; Chemosensitizing agent
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(99)00400-1

Malagashanine (MG) is the parent compound of a new type of indole alkaloids, the N bC(21)-secocuran, isolated so far from the Malagasy Strychnos species traditionally used as chloroquine adjuvants in the treatment of chronic malaria. Previously, it was shown to have weak in vitro intrinsic antiplasmodial activity ( ic 50 = 146.5 ± 0.2 μM), but did display marked in vitro chloroquine-potentiating action against the FcM29 chloroquine-resistant strain of Plasmodium falciparum. The purpose of the present study was to further investigate its reversal activity. Thus, the previous in vitro results were tested in vivo. The interaction of MG with several antimalarials against various strains of P. falciparum was also assessed. As expected, MG enhanced the effect of chloroquine against the resistant strain W2, but had no action on the susceptible strain 3D7 and two sensitive isolates. Interestingly, MG was found to exhibit significant chloroquine-potentiating action against the FcB1 strain formerly described as a resistant strain but one which has since lost its resistance for unknown reasons. One other relevant result that arose from our study was the observation of the selective enhancing action of MG on quinolines (chloroquine, quinine, and mefloquine), aminoacridines (quinacrine and pyronaridine), and a structurally unrelated drug (halofantrine), all of which are believed to exert their antimalarial effect by binding with haematin. MG was finally found to specifically act with chloroquine on the old trophozoite stage of the P. falciparum cycle. Similarities and differences between verapamil and MG reversal activity are briefly presented.