Pyronaridine: A new antimalarial drug

The worldwide spread of strains of Plasmodium falciparum that are resistant to chloroquine has highlighted the urgent need for new antimalarial drugs, particularly in less developed tropical countries. However, in the current economic climate the pharmaceutical giants in the developed world are withdrawing from tropical disease research. Consequently, the following article from Fu Sui and Xiao Shuhuo is of particular interest, not only because it summarizes work on on alternative antimalarial drug that is efficacious against multiply resistant Plasmodium but also because this drug has been developed primarily from Chinese research efforts, the results of which have largely only been published in the Chinese scientific literature. The drug under scrutiny is pyronaridine, and is the product of 30 years of chemistry that began with the mepacrine nucleus. This nucleus was selected as the starting point in the search for a chloroquine alternative because the various derivatives synthesized were active against chloroquine-resistant parasites. However, mepacrine itself also needed replacing as it is too toxic for mass use. After synthesizing and screening a huge series of substitutions, the addition of an amodiaquine side-chain to this nucleus was found to give the greatest activity for fewest adverse effects. Being aware of the rapid selection of pyronaridine-resistant Plasmodium strains that occurs in the laboratory, the Chinese efforts have also investigated the use of drug combinations to circumvent or delay the development of drug resistance. In addition to the triple combination described here, pyronaridine and primaquine combinations are under trial against both P. vivax and P. falciparum. Pyronaridine is a highly active blood schizonticide like chloroquine and amodiaquine. It has already undergone extensive trials in humans against both P. falciparum and P. vivax. However, nothing is known of its mode of action, nor the basis for the development of resistance and although it is active against chloroquine-resistant strains of parasite, paradoxically, pyronaridine-resistant Plasmodium is resistant to chloroquine.