Many antimalarial agents have a common structural feature: a quinoline ring or an
acridine ring (which is a quinoline ring with an extra benzene ring appended to it).
The other major class of antimalarials are the folate synthesis antagonists. There is a
considerable difference in the drug sensitivity and affinity of dihydrofolate reductase
enzyme (DHFR) between humans and the Plasmodiumparasite. The parasite can there-
fore be eliminated successfully without excessive toxic effects to the human host. DHFR
inhibitors block the reaction that transforms deoxyuridine monophosphate (dUMP) to
deoxythymidine monophosphate (dTMP) at the end of the pyrimidine-synthetic pathway.
This reaction, a methylation, requires N^5 ,N^10 -methylene-tetrahydrofolate as a carbon car-
rier, which is oxidized to dihydrofolate. If the dihydrofolate cannot then be reduced back
to tetrahydrofolate (THF), this essential step in DNA synthesis will come to a standstill.
The DHFR-inhibitor antimalarial drugs are competitive inhibitors and therefore
structural analogs of folate. They are either diaminobenzyl- or diaminophenyl-pyrimidines
(trimethoprim (9.113); pyrimethamine (9.114)) or triazines such as cycloguanil (9.115),
which is the active form of chlorguanide (9.116), a pro-drug that undergoes an oxida-
tive ring closure in vivo. The replacement of the folate 6-OH by an amino group in these
analogs increases their affinity for the enzyme by a factor of 1 × 104 to 5 × 104 as com-
pared to folate. Some very insoluble derivatives of cycloguanil show a protective effect
for several months after a single intramuscular injection, and may play an important
role in the eradication of malaria. Because of the emergence of many resistant strains of
Plasmodium, combination chemotherapy is imperative. Eradication of the insect vector,
theAnophelesmosquito, is also an important but elusive goal if endemic malarial areas
in Africa and Southeast Asia are to be cleared.
Malaria is still one of the major health problems in tropical countries, where tens of
millions of people suffer from this debilitating disease. Drug design for malaria is a
research area with the capacity to blossom in coming years. Due to environmental
changes such as global warming, the distribution of this disease may change, leading to
malaria occurrences in the southern portions of North America and Europe. This will
undoubtedly be a motivating factor to drive new research directions.
EXOGENOUS PATHOGENS AND TOXINS 587