amino acid at one location in dihydrofolate reductase. Proguanil resistance is associated with substitution at a different amino acid location, and strains resistant to both drugs show substitutions at both sites (Peterson et al., 1990).
A detailed understanding of the inhibitor-enzyme interaction offers an opportunity for rational drug design or discovery. It should be possible to identify compounds that bind to dihydrofolate reductase but are unaffected by the mutations associated with pyrimethamine and proguanil resistance. Drugs derived from such a program would restore the usefulness of this strategy for treating falciparum malaria.
Proguanil (Chlorguanil) and Chlorproguanil The discovery of antimalarial activity of the biguanides predates the development of the diaminopyrimidines. These compounds were initially prepared as acyclic analogs of a series of anilino pyrimidines under investigation at Imperial Chemical Industries in the United Kingdom. Like pyrimethamine, proguanil is a causal prophylactic agent for P. falciparum, but it acts slowly against the blood-stage parasite. It is not particularly useful for treating vivax malaria. Unlike pyrimethamine, proguanil has a short half-life, and so prophylactic use requires daily dosing. Strains of P. falciparum resistant to proguanil are common, seriously limiting its use in therapy.
Chlorproguanil contains one more chlorine atom than proguanil, which increases the drug's potency and half-life (Peters, 1990b). Neither drug is currently marketed as a single oral dose in combination with a PABA anti-metabolite, however, and clinical trials conducted in Thailand with proguanil in combination with sulfonamide suggest that these drugs may have utility in areas endemic for multidrug-resistant malaria (Karwacki et al., 1990). Neither proguanil nor chlorproguanil is marketed in the United States.
The mechanism of action of the biguanides is the same as that of pyrimethamine. Technically, the biguanides are “prodrugs” that must be metabolically converted by the human host to a cyclic compound, cycloguanil, that inhibits dihydrofolate reductase (Webster, 1990).
Mefloquine The development of mefloquine was a collaborative achievement of the U.S. Army Medical Research and Development Command, the World Health Organization (WHO), and Hoffman-LaRoche, Inc. The drug was recently licensed in the United States and several other countries. A 4-quinoline methanol, mefloquine may be considered a quinine analog. It was first synthesized by the Army's medicinal chemistry program in the late 1960s.
Clinical and field trials during the past 17 years have confirmed the effectiveness of a single dose of mefloquine for rapidly clearing P. falciparum parasitemia and alleviating symptoms. Preliminary studies of mefloquine