naphthoquinones and menoctone

Malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. The diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of

Topics: Animals; Anopheles; Antimalarials; Atovaquone; Cytochromes b; DNA, Protozoan; Drug Resistance; Female; Malaria, Falciparum; Mice; Mice, Inbred BALB C; Mutation; Naphthoquinones; Plasmodium berghei; Plasmodium falciparum

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: Animals; Antiprotozoal Agents; Drug Interactions; Folic Acid Antagonists; Hypoxanthines; Naphthoquinones; Plasmodium falciparum; Proguanil; Pyrimethamine; Triazines

Ten naphthoquinones, including parvaquone (993C) (Clexon; Wellcome) and menoctone, were tested for activity in cattle artificially infected with Theileria parva, the causative organism of East Coast fever (ECF). Parvaquone cured all 14 cattle treated with a single dose of 20 mg/kg intramuscularly and all five treated twice with 10 mg/kg intramuscularly. Menoctone cured seven of 10 cattle treated with a single dose of 5 mg/kg intramuscularly. Of 25 untreated control cattle, 22 died of ECF. None of the remaining eight naphthoquinones was as active as parvaquone. Three esters of active naphthoquinones, designed as 'prodrugs' of their parent compounds, showed little or no activity in infected cattle despite being highly active in vitro against T parva. These results were instrumental in the selection of parvaquone for development as the first specifically active remedy for ECF.

Topics: Animals; Cattle; Injections, Intramuscular; Male; Naphthoquinones; Theileriasis

Groups of cattle were infected with Theileria parva by the injection of stabilate material prepared from infected Rhipicephalus appendiculatus ticks. The cattle were treated with the hydroxy alkylated naphthoquinone, menoctone, which was administered intravenously (i/v), intramuscularly (i/m), or orally (p/o) up to 4 days after the disease became apparent. The disease was rapidly controlled and all the treated cattle (15) recovered following (i/v) or i/m injection of a single dose of menoctone at 10 mg/kg body weight but control was incomplete with lower dosages in single or multiple dose regimens. The i/m route was slightly more effective than i/v. The p/o administration of menoctone had only a slight and transient beneficial effect and 10 cattle treated by this route all died of theileriosis. Twelve of 18 untreated controls also died. Following injection of menoctone, schizonts degenerated within the lymphoid cells and piroplasms were destroyed within the erythrocytes. The level and duration of antitheilerial activity in the serum following treatment was assayed by an in vitro culture method and was shown to correlate closely with the efficacy of treatment.

Topics: Administration, Oral; Animals; Antiprotozoal Agents; Apicomplexa; Body Temperature; Cattle; Injections, Intramuscular; Injections, Intravenous; Naphthoquinones; Theileriasis; Ticks

Topics: Animals; Antimalarials; Chloroquine; Dimethylpolysiloxanes; Drug Implants; Malaria; Male; Mefloquine; Mice; Mice, Inbred Strains; Naphthoquinones; Piperidines; Plasmodium berghei; Primaquine; Proguanil; Pyrimethamine; Quinolines; Silicone Elastomers; Sulfadiazine; Triazines

Among various ubiquinone (Q) isoprenologues tested, only Q7 was more efficient than menadione in promoting the oxidation of 5-methyltetrahydrofolate (CH3FH4) by 5,10-methylenetetrahydrofolate reductase isolated from adult Brugia pahangi, whereas Q10 was the best cofactor in the same reaction catalysed by the analogous enzyme from adult Dirofilaria immitis. Menoctone (3-[1-cyclohexyloctyl] -2-hydroxy-1,4-naphthoquinone) was a strong competitive inhibitor of both these ubiquinone isoprenologues in the respective reactions. When incubated in the presence of D,L-[14C]-mevalonate, adult B. pahangi and D. immitis synthesized radiolabelled Q9 only, in addition to other isoprenoid derivatives in the neutral lipid fraction. In view of the inability of Q9 to promote the oxidation of CH3FH4 by 5,10-methylenetetrahydrofolate reductase from B. pahangi, it seems unlikely that this filaria uses Q9 as a cofactor in this reaction. Conceivably, D. immitis could use Q9 as a cofactor in its enzymatic oxidation of CH3FH4, since in this circumstance, it was a better cofactor than menadione.

Topics: Brugia; Dirofilaria; Filarioidea; Naphthoquinones; Tetrahydrofolates; Ubiquinone; Vitamin K

A tissue culture method was used to screen compounds for activity against Theileria parva, and demonstrated that the hydroxy-alkylated naphthoquinones, 'menoctone' and 993C were highly active, with ED50 values around 0,005 mg/l. When injected into cattle artificially infected the T. parva, menoctone cured all of 7 cattle at a total dosage of 10 mg/kg injected intravenously (i.v.). A further trial showed that injection of menoctone, 10 mg/kg, as a single dose gby the intramuscular (i.m.) route was more effective than when a similar dose was given by the i.v. route. Titration of serum from these cattle in the in vitro system showed that inhibitory levels of drug persisted for three days after i.v. injection and six days when menoctone was injected i.m. The minimum effective dose level of 993C was 20 mg/kg i.m. either as a single dose, or as two doses of 10 mg/kg with an interval of 48 hours.

Topics: Animals; Antimalarials; Cattle; Naphthoquinones; Theileriasis

Bovine lymphoblastoid cell cultures permanently infected with Theileria parva and T. annulata were used in an in vitro screen to test a wide range of compounds for chemotherapeutic activity against these parasites. Only two compounds, menoctone and methotrexate, showed significant activity, which has subsequently been confirmed by tests in infected cattle. Menoctone was about 100 times more active than methotrexate. Mixtures of menoctone and various other other compounds were tested, but showed no potentiation. The activity of menoctone was antagonized by cycloguanil and methotrexate. The in vitro test represents a rapid, cheap, and apparently reliable method of screening compounds for activity against Theileria.

Topics: Animals; Apicomplexa; Cattle; Cell Line; Drug Combinations; Drug Evaluation, Preclinical; Methotrexate; Naphthoquinones; Theileriasis