ABSTRACT
Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity.
Subject(s)
Antimalarials/administration & dosage , Hexanols/administration & dosage , Malaria, Falciparum/drug therapy , Malaria/drug therapy , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Spiro Compounds/administration & dosage , Animals , Antimalarials/chemical synthesis , Antimalarials/therapeutic use , Carbon/chemistry , Carbon/metabolism , Carboxylic Acids/chemistry , Drug Evaluation, Preclinical , Ferrous Compounds/metabolism , Free Radicals/chemistry , Free Radicals/metabolism , Hexanols/chemical synthesis , Hexanols/therapeutic use , Humans , Inhibitory Concentration 50 , Malaria/parasitology , Malaria, Falciparum/parasitology , Mice , Mice, Inbred ICR , Oxidation-Reduction , Peroxides/chemistry , Peroxides/metabolism , Plasmodium berghei/growth & development , Plasmodium falciparum/growth & development , Spiro Compounds/chemical synthesis , Spiro Compounds/therapeutic use , Structure-Activity RelationshipABSTRACT
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.
