naphthoquinones and tafenoquine

Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.

Topics: Aminoquinolines; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Clinical Trials as Topic; Dapsone; Drug Combinations; Drug Design; Drug Resistance; Ethanolamines; Flavonoids; Fluorenes; Fosfomycin; Global Health; Humans; Lumefantrine; Malaria; Naphthoquinones; Naphthyridines; Plasmodium falciparum; Proguanil; Sesquiterpenes

U.S. military aviators are currently restricted to the use of chloroquine or doxycycline for malaria prophylaxis. Ground forces are allowed the additional option of taking mefloquine. These medications are begun before deployment, must be taken for 4 weeks after leaving the malarious area, and primaquine must be added to the regimen the last 2 of those 4 weeks. Compliance with this regimen is often poor, especially in populations who travel abroad frequently for short periods of time. Causal malaria prophylaxis offers potential benefits of decreased length of postdeployment regimens and obviates the need for a second medication for terminal prophylaxis. Potential obstacles include adverse drug reactions, cost, and rapid development of resistance to new medications by Plasmodium species, which should be weighed against the risks to health and mission success in each deployment.

Topics: Aminoquinolines; Antimalarials; Atovaquone; Aviation; Chloroquine; Doxycycline; Drug Combinations; Humans; Malaria; Mefloquine; Military Personnel; Naphthoquinones; Primaquine; Proguanil; United States

Topics: Aminoquinolines; Antimalarials; Artemisinins; Atovaquone; Chemical Phenomena; Chemistry; Drug Design; Drug Evaluation, Preclinical; Drug Resistance; Humans; Malaria; Naphthoquinones; Research; Sesquiterpenes

A reversed-phase high-performance liquid chromatographic technique for the determination of dihydroorotate dehydrogenase in Plasmodium falciparum was developed. The assay was applied to the evaluation of the effects of several antimalarial drugs on the enzyme. Treatment of both the asexual and gametocyte stages of P. falciparum in culture with menoctone, primaquine or the primaquine derivative WR 238605 led to depression of the enzyme activity, although the drugs did not appear to inhibit the enzyme directly.

Topics: Aminoquinolines; Animals; Antimalarials; Chromatography, High Pressure Liquid; Dihydroorotate Dehydrogenase; Enzyme Activation; Naphthoquinones; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Plasmodium falciparum; Primaquine

The gametocytocidal and sporontocidal activity of three 8-aminoquinolines (primaquine, WR-238605, and WR-242511), three dihydroacridine-diones (floxacrine, WR-250547, and WR-250548), a 1,4-naphthoquinone (menoctone), a synthetic aminoalcohol (halofantrine), and a guanide (WR-182393) was determined against a cloned line of Plasmodium berghei ANKA. Gametocytocidal activity was assessed by treating mice with a single intraperitoneal inoculation of a given compound (25 mg base drug/kg mouse body weight) four days after the mice were infected with P. berghei. Thin blood smears were made every other day, and the percent parasitemia and macrogametocyte and microgametocyte rates were determined. Floxacrine, menoctone, WR-242511, WR-250547, and WR-250548 effectively cleared sexual and asexual parasites from the peripheral circulation within six days of drug administration. Halofantrine, primaquine, WR-182393, and WR-238605 were ineffective at clearing P. berghei ANKA from circulating erythrocytes at the doses tested; however, mice survival time increased markedly with these compounds when compared with the controls. Significant numbers of macrogametocytes and microgametocytes were present throughout the duration of the infection in mice treated with halofantrine, primaquine, WR-182393, and WR-238605. Sporontocidal activity was evaluated by allowing Anopheles stephensi mosquitoes to feed on P. berghei-infected mice 90 min after treatment with a particular drug. Halofantrine and WR-182393 exhibited no sporontocidal activity, while floxacrine, menoctone, primaquine, WR-238605, WR-242511, WR-250547, and WR-250548 exhibited significant activity. Minimum effective doses (mg base drug/kg of mouse body weight) that prevented mosquitoes from developing sporozoite-infected salivary glands were 0.1563 mg/kg for WR-250547, 0.625 mg/kg for menoctone, 1.25 mg/kg for primaquine, 10 mg/kg for floxacrine, 10 mg/kg for WR-242511, 10 mg/kg for WR-250548, and 25 mg/kg for WR-238605.

Topics: Acridines; Aminoquinolines; Analysis of Variance; Animals; Anopheles; Antimalarials; Female; Germ Cells; Guanidines; Imidazoles; Mice; Mice, Inbred ICR; Naphthoquinones; Phenanthrenes; Plasmodium berghei; Primaquine

Topics: Aminoquinolines; Amodiaquine; Antimalarials; Artemisinins; Calcium Channel Blockers; Chloroquine; Humans; Malaria; Mefloquine; Naphthoquinones; Phenanthrenes; Primaquine; Quinine; Sesquiterpenes; Sulfadoxine