Investigation of Strychnos (Loganiaceae) shrubs and trees was initiated by their traditional uses of their inherent
poisons on arrows: this led to the discovery of
strychnine and
curare alkaloids. Subsequently,
phytochemical investigation of several Strychnos species has shown great structural diversity of the
alkaloid constituent which also display various
biological effects, i.e. convulsive and relaxant effects on muscles, and antimicrobial, antitumor and
antihypertensive properties. Ethnobotanical field work conducted in different regions of Madagascar revealed that infusion of three Strychnos species, S. mostueoides, S. myrtoides and S. diplotricha, is used in association with subcurative doses of
chloroquine to treat
chronic malaria. Bioassayfractionation led to the isolation of two major bioactive components,
strychnobrasiline and
malagashanine. Whereas
strychnobrasiline is a previously known chemical compound,
malagashanine is the first in a series of a new subtype of Strychnos
alkaloids. These two
alkaloids are devoid of intrinsic
antimalarial effects, both in vitro (IC50 = 73.0 micrograms/ml for
strychnobrasiline and 69.1 micrograms/ml for
malagashanine) and in vivo (10 mg/kg conferred a 5% suppression of
parasitemia). When these
alkaloids are combined with
chloroquine at doses much lower than required for antiplasmodial effects, they greatly enhance the
chloroquine action in a dose dependent manner as seen by the isobologram method. Several minor
alkaloids structurally related to
malagashanine were also isolated from Madagascan Strychnos. They all enhance, to greater or lesser degrees, the
chloroquine effectiveness. Interestingly, there is a positive correlation between the ethnomedical use of the three Strychnos species as
chloroquine adjuvants and the
chloroquine-potentiating effects of
malagashanine and
strychnobrasiline isolated from them. After preliminary toxicological studies, infusion of stem barks of S. myrtoides in association with
chloroquine was successfully evaluated in a clinical setting. Additional chemical, pharmacological and toxicological work is being conducted on these
alkaloids with the aim of developing purified and standardized extracts for clinical trials. These trials will be carried out in the
chloroquine-resistant regions of Madagascar which are in need of inexpensive and efficient drugs for the treatment of
chloroquine-resistant
malaria.