1-2-6-7-tetraoxaspiro(7.11)nonadecane and Malaria--Falciparum

Topics: Alkylation; Antimalarials; Artemisinins; Cysteine Proteinase Inhibitors; Drug Resistance; Drug Stability; Drug Therapy, Combination; Heme; Humans; Malaria, Falciparum; Oxidative Stress; Prodrugs; Sesquiterpenes

Plasmodium falciparum, the major causative parasite for the disease, has acquired resistance to most of the antimalarial drugs used today, presenting an immediate need for new antimalarial drugs. Here, we report the in vitro and in vivo antimalarial activities of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against P. falciparum and Plasmodium berghei parasites. The N-251 showed high antimalarial potencies both in the in vitro and the in vivo tests (EC(50) 2.3×10(-8) M; ED(50) 15 mg/kg (per oral)). The potencies were similar to that of artemisinin in vitro and greater than artemisinin's activity in vivo (p.o.). In addition, N-251 has little toxicity: a single oral administration at 2000 mg/kg to a rat gave no health problems to it. Administration of N-251 to mice bearing 1% of parasitemia (per oral 68 mg/kg, 3 times a day for 3 consecutive days) resulted in a dramatic decrease in the parasitemia: all the 5 mice given N-251 were cured without any recurrence, with no diarrhea or weight loss occurring in the 60 days of experiment. N-251 deserves more extensive clinical evaluation, desirably including future trials in the human.

Topics: Administration, Oral; Animals; Antimalarials; Artemisinins; Cell Line, Tumor; Drug Therapy, Combination; Erythrocytes; Heterocyclic Compounds, 2-Ring; Hexanols; Humans; Malaria; Malaria, Falciparum; Mice; Mice, Inbred ICR; Molecular Structure; Parasitemia; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Rats; Spiro Compounds; Survival Analysis; Tetraoxanes

Of several bis(alkyldioxy)alkanes and the related acyclic peroxides prepared in this study, 1,1-bis(methyldioxy)cyclododecane showed the most notable antimalarial activity particularly in vivo (almost a half of that of artemisinin).

Topics: Alkanes; Animals; Antimalarials; Cycloparaffins; Humans; Hydrocarbons, Cyclic; Malaria, Falciparum; Mice; Peroxides; Plasmodium falciparum; Tumor Cells, Cultured