Medicinal Chemistry

9.6.1 Antiparasitic Drugs Targeting Protozoans

Although there is a variety of protozoan infestations, malaria is probably the most
important on a world-wide scale. Four species of the plasmodium parasite cause malaria
in humans:Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and
Plasmodium ovale; P. falciparum is responsible for most of the deaths. Malaria parasites
have a very complex life cycle and can exist in many different forms (sporozoite, sch-
izont, merozoite, trophozoite, gametocyte). When a human is bitten by an Anopheline
mosquito, the parasite is introduced in its sporozoite form. This rapidly invades the liver
where it matures first into a schizont and then into a merozoite. This merozoite form of
the parasite leaves the liver and then invades red blood cells (erythrocytes). Within ery-
throcytes the merozoite is sequentially transformed into a trophozoite, then into a sch-
izont, and finally back to a merozoite, which ruptures out of the erythrocyte to inoculate
other erythrocytes. Within the erythrocyte, some merozoites also develop into gameto-
cytes, which are taken up by mosquitoes, where they are matured back into infective
sporozoites—thereby initiating the infective process all over again. This circuitous life
cycle, shown in figure 9.5, offers a number of targets for antimalarial drugs.
There are four major types of compounds that exhibit activity against malaria:

1. Quinoline and acridine antimalarials


2. Folate synthesis antagonists


3. Atovaquone compounds that inhibit mitochondrial electron transport in the parasite


4. Artemisia derivatives that kill parasites via carbon-centered free radicals

Of these four groups of compounds, the quinoline/acridine class is the most widely used.

586 MEDICINAL CHEMISTRY

Figure 9.5 Malaria parasites have a complex life cycle, existing in many different forms between
humans and mosquitoes. This offers a number of targets for drug design.