wr-243251 and floxacrine

To improve upon the activity and properties of the 3-aryl-7-chloro-3,4- dihydro-1,9(2H,10H)-acridinediones, a variety of 1-[(alkylamino)alkylene]imino derivatives (3) were prepared and shown to be highly active antimalarial agents in both rodents and primates. Among structural modifications prepared, including N10-alkyl and C2-substituted analogs, removal of the C9 oxygen, and introduction of an imino side chain at C9, the imines of the N10-H acridinediones were the most active compounds obtained. The [3-(N,N- dimethylamino)propyl]imino derivative of 7-chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)- acridinedione (9aa) proved to be highly active in advanced studies in primates.

Topics: Acridines; Animals; Antimalarials; Haplorhini; Malaria; Mice; Plasmodium berghei; Structure-Activity Relationship

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