Antimalarial activity of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) and its carboxylic acid derivatives

• Published in: Parasitology international 2011-12, Vol.60 (4), p.488-492
• Main Authors: Sato, Akira, Kawai, Satoru, Hiramoto, Akiko, Morita, Masayuki, Tanigawa, Natsuki, Nakase, Yukari, Komichi, Yuka, Matsumoto, Masahiro, Hiraoka, Osamu, Hiramoto, Kazuyuki, Tokuhara, Hidekazu, Masuyama, Araki, Nojima, Masatomo, Higaki, Kazutaka, Hayatsu, Hikoya, Wataya, Yusuke, Kim, Hye-Sook
• Format: Article
• Language: English
• Subjects: 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol; Animals; Antimalarial activity; antimalarials; Antimalarials - administration & dosage; Antimalarials - chemical synthesis; Antimalarials - therapeutic use; antiparasitic properties; carbon; Carbon - chemistry; Carbon - metabolism; Carbon radical; Carboxylic Acids - chemistry; Drug Evaluation, Preclinical; Ferrous Compounds - metabolism; Free Radicals - chemistry; Free Radicals - metabolism; Gastroenterology and Hepatology; Hexanols - administration & dosage; Hexanols - chemical synthesis; Hexanols - therapeutic use; Humans; Infectious Disease; Inhibitory Concentration 50; iron; malaria; Malaria - drug therapy; Malaria - parasitology; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Mice; Mice, Inbred ICR; N-251; Oxidation-Reduction; parasites; parasitology; peroxides; Peroxides - chemistry; Peroxides - metabolism; Plasmodium berghei; Plasmodium berghei - drug effects; Plasmodium berghei - growth & development; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - growth & development; Spiro Compounds - administration & dosage; Spiro Compounds - chemical synthesis; Spiro Compounds - therapeutic use; Structure-Activity Relationship; water solubility
• ISSN: 1383-5769; 1873-0329
• DOI: 10.1016/j.parint.2011.08.017

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.