wr-225448 and Malaria

Topics: Animals; Antimalarials; Humans; Life Cycle Stages; Liver; Malaria; Plasmodium; Structure-Activity Relationship

Topics: Aminoquinolines; Animals; Antimalarials; Artemisinins; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Malaria; Mefloquine; Mice; Naphthoquinones; Plasmodium falciparum; Pyrimethamine; Quinolines; Sesquiterpenes; Sulfadoxine

A series of 2-substituted analogues of the exceptional drug 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3- (trifluoromethyl)phenoxy]quinoline (I) were prepared and evaluated for both suppressive and prophylactic antimalarial activity. The preparation of analogues of compound I was of interest due to the high level of both blood and tissue schizonticidal activity demonstrated by this compound. One analogue, 8a, was found to be both more active and less toxic than the parent compound I. In addition, three analogues of example 8a were prepared. Although two of the three analogues showed significant antimalarial activity, both were inferior to compound 8a.

Topics: Aminoquinolines; Animals; Antimalarials; Chemical Phenomena; Chemistry; Malaria; Mice; Plasmodium berghei; Structure-Activity Relationship

Five 4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues were synthesized and tested for radical curative activity against Plasmodium cynomolgi in Rhesus monkeys and for blood schizonticidal antimalarial activity against Plasmodium berghei in mice. In addition, they were evaluated for causal prophylactic antimalarial activity against Plasmodium berghei yoelii in mice. One compound, 4-ethyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2b), showed radical curative activity equivalent to 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2a). A second compound showed radical curative activity slightly less than 2a and 2b; the remaining three compounds were not active against P. cynomolgi. All five compounds showed much higher blood schizonticidal activity and less toxicity than primaquine; however, none of the compounds were as active as 2a. Three of four compounds tested showed high activity against P. berghei yoelii.

Topics: Animals; Chemical Phenomena; Chemistry; Macaca mulatta; Malaria; Mice; Plasmodium; Primaquine; Structure-Activity Relationship

Two isomeric sulfur-interrupted 8-amino side chain analogues of 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2) were prepared and tested for antimalarial activity. The compounds were evaluated for blood schizonticidal activity against Plasmodium berghei in mice and radical curative activity against Plasmodium cynomolgi in rhesus monkeys. In addition, they were evaluated for causal prophylactic activity against Plasmodium berghei yoelii in mice. Both compounds were more active and less toxic than primaquine in the P. berghei screen. One of the compounds showed radical curative activity similar to primaquine but was less active than 2. One of the compounds was active at 160 mg/kg in the P. berghei yoelii screen; the other was not active.

Topics: Aminoquinolines; Animals; Chemical Phenomena; Chemistry; Macaca mulatta; Malaria; Mice; Plasmodium; Primaquine

Two new Mannich base antimalarials, WR 194,965 and 228,258 exhibit blood schizontocidal action against Plasmodium berghei in vivo. This action is retained also against the P. berghei NS line which has a low level of resistance to chloroquine. While WR 228,258 is also active against the highly chloroquine-resistant RC line, WR 194,965 is not. Both compounds show slightly reduced activity against the highly mefloquine-resistant N/1100 line. WR 225,448, an 8-aminoquinoline, is as active against blood stages of the NS, RC and N/1100 lines of P. berghei as against the N strain, and more so on a dose/weight basis than the first two compounds. It shows a low level of cross-resistance against the primaquine-resistant P line. WR 225,448 has a clear causal prophylactic effect on the pre-erythrocytic schizonts of P. yoelii nigeriensis. While WR 194,965 and 228,258 also appeared to act on these stages, the effect is most probably due to residual action on emerging erythrocytic merozoites since pre-erythrocytic schizonts in treated animals were morphologically indistinguishable from those of the untreated control.

Topics: Aminoquinolines; Animals; Antimalarials; Blood; Butylated Hydroxytoluene; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Malaria; Male; Mice; Plasmodium

Light microscope and ultrastructural studies show that WR 225,448, an 8-aminoquinoline related to primaquine, causes substantial damage to developing pre-erythrocytic (EE) schizonts of Plasmodium yoelii yoelii in the liver of young rats. In addition to lesions of the mitochondria and nuclear membranes, secretory granules in the parasite fail to reach the surrounding host cell cytoplasm across the parasite membrane. The effective dose of WR 225,448 is much lower than that of primaquine. However, hepatic damage is also seen in treated animals. This may be the summation of damage produced by the experimental inoculation of a large quantity of infective salivary gland tissue from mosquitoes (which is also seen in untreated animals) plus toxic effects of the drug itself. Particular attention would have to be directed to this aspect in preclinical toxicity testing of the compound.

Topics: Aminoquinolines; Animals; Antimalarials; Dose-Response Relationship, Drug; Liver; Malaria; Microscopy, Electron; Mitochondria, Liver; Plasmodium; Rats; Rats, Inbred Strains