1-2-6-7-tetraoxaspiro(7.11)nonadecane and artemisinin

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

Metronidazole is well known for medicine against Trichomonas vaginalis infection, but it has side effects though it is effective, and especially because reports of metronidazole-tolerant species are increasing, the development of new medicine is being required. Here, we noticed the killing effects of endoperoxide compounds, N-89 and N-251 as new antimalarial drug candidates, on T. vaginalis and searched the possibility of development of new medicine. We added each of metronidazole, artemisinin, and two of new endoperoxides (N-89 and N-251) to metronidazole-resistant and -sensitive species and compared its anti-trichomonal efficacy. For metronidazole, IC

Topics: Antiprotozoal Agents; Artemisinins; Drug Resistance; Heterocyclic Compounds, 2-Ring; Inhibitory Concentration 50; Metronidazole; Spiro Compounds; Tetraoxanes; Trichomonas vaginalis

We have reported that two endoperoxides, N-89 and N-251, synthesized in 2001, possess potent antimalarial activities. Aiming at their eventual use for curing malaria in humans, we have been investigating various aspects of their antimalarial actions. Here we show that N-89 and N-251 inhibit the growth of Plasmodium falciparum within human erythrocytes in vitro at its lifecycle stage 'trophozoite' specifically. It is known that artemisinin compounds, which are currently used for curing malaria, have other stage-specificities. Therefore, it is likely that the antimalarial mechanism of N-89 and N-251 differs from those of artemisinin compounds. As malaria parasites resistant to artemisinin-based combination therapy are currently emerging in some tropical regions, N-89 and N-251 are candidates for overcoming these new problems.

Topics: Animals; Antimalarials; Artemisinins; Drug Resistance, Multiple; Erythrocytes; Heterocyclic Compounds, 2-Ring; Humans; Malaria; Parasitic Sensitivity Tests; Plasmodium falciparum; Spiro Compounds; Tetraoxanes; Trophozoites

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