Reversal activity of the naturally occurring chemosensitizer malagashaninein Plasmodium malaria

Malagashanine (MG) is the parent compound of a new type of indole alkaloids , the NbC(21)-secocuran, isolated so far from the Malagasy Strychnos specie s traditionally used as chloroquine adjuvants in the treatment of chronic m alaria. Previously, it was shown to have weak in vitro intrinsic antiplasmo dial activity (IC50 = 146.5 +/- 0.2 mu M), but did display marked in vitro chloroquine-potentiating action against the FcM29 chloroquine-resistant str ain of Plasmodium falciparum. The purpose of the present study was to furth er investigate its reversal activity. Thus, the previous in vitro results w ere tested in vivo. The interaction of MG with several antimalarials agains t various strains of P. falciparum was also assessed. As expected, MG enhan ced the effect of chloroquine against the resistant strain W2, but had no a ction on the susceptible strain 3D7 and two sensitive isolates. interesting ly, MG was found to exhibit significant chloroquine-potentiating action aga inst the FcB1 strain formerly described as a resistant strain but one which has since lost its resistance for unknown reasons. One other relevant resu lt that arose from our study was the observation of the selective enhancing action of MG on quinolines (chloroquine, quinine, and mefloquine), aminoac ridines (quinacrine and pyronaridine), and a structurally unrelated drug (h alofantrine), all of which are believed to exert their antimalarial effect by binding with haematin. MG was finally found to specifically act with chl oroquine on the old trophozoite stage of the P. falciparum cycle. Similarit ies and differences between verapamil and MG reversal activity are briefly presented. (C) 2000 Elsevier Science Inc.