Malagashanine (MG) is the parent compound of a new type of
indole alkaloids, the N(b)C(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 microM), 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.