Cryptolepine and development of new antimalarial agents

Natural product-derived drugs exemplified by quinine, isolated from South American Cinchona species and artemisinin discovered in China are of immense importance for the treatment of malaria. Although malaria parasites resistant to artemisinin have not yet been found in malaria patients, the need for new antimalarial agents remains. The burden of malaria is heaviest in Africa where over a million children die of the disease each year, but although many medicinal plants are used in African traditional medicines for the treatment of malaria, none has yet yielded and effective antimalarial compound. Cryptolepis sanguinolenta (Periplocaceae), is a West African climbing shrub used traditionally for the treatment of malaria. Cryptolepine, an indoloquinoline alkaloid is the major constituent of the roots of C. sanguinolenta and has potent activity against malaria parasites in vitro, but it is cytotoxic on account of its abilities to inhibit topoisomerase II and to intercalate into DNA and it is also toxic to mice in vivo. However, the antimalarial mode of action of cryptolepine appears to involve a quinine-like mechanism (inhibition of ?-haematin formation) that is independent of interactions with DNA. This opens up the possibility that it may be feasible to prepare analogues of cryptolepine that do not interact with DNA (and hence may be less cytotoxic) but that retain or have enhanced antiplasmodial activities. Using various synthetic routes, a number of substituted cryptolepine analogues have been made and evaluated for their potential as leads to new antimalarial agents. Compounds were assessed for in-vitro activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and for cytotoxic activities. Some compounds have been assessed for their abilities to interact with DNA and a number of compounds has also been assessed for antimalarial activity against P. berghei in mice. Several cryptolepine analogues were found to have potent antiplasmodial activities (IC50 < 0.1 µM) against chloroquine-resistant P. falciparum (IC50 for chloroquine = 0.44 µM), but they are generally of similar cytotoxicity to cryptolepine. However, while cryptolepine is toxic to mice, a number of analogues have been shown to have promising antimalarial activities in the mouse-malaria model with no apparent toxicity. In view of this, derivatives of cryptolepine appear to be worthy of further investigation as potential antimalarial agents. In this lecture, the current status of antimalarial cryptolepine research will be reviewed and the potential of cryptolepine as a lead to new antimalarial agents will be discussed.