TY - JOUR
T1 - Oral activity of the antimalarial endoperoxide 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Leishmania donovani complex
AU - Kwofie, Kofi Dadzie
AU - Sato, Kai
AU - Sanjoba, Chizu
AU - Hino, Akina
AU - Shimogawara, Rieko
AU - Amoa-Bosompem, Michael
AU - Ayi, Irene
AU - Boakye, Daniel A.
AU - Anang, Abraham K.
AU - Chang, Kyung Soo
AU - Ohashi, Mitsuko
AU - Kim, Hye Sook
AU - Ohta, Nobuo
AU - Matsumoto, Yoshitsugu
AU - Iwanaga, Shiroh
N1 - Funding Information:
This work was supported by grant from the Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (AMED)(https://www.amed.go.jp/program/list/01/06/001.html), awarded to S. I. (15650501) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors are grateful to the members of the Section of Environmental Parasitology at the Tokyo Medical Dental University (TMDU), as well as members of the Laboratory of Molecular Immunology at the Department of Animal Resource Sciences, University of Tokyo. The authors would also like to thank the staff of the Research Center for Medical Dental Sciences, TMDU, for technical advice.
Publisher Copyright:
© 2019 Kwofie et al.
PY - 2018/3
Y1 - 2018/3
N2 - Visceral leishmaniasis (VL) is a major problem worldwide and causes significant morbidity and mortality. Existing drugs against VL have limitations, including their invasive means of administration long duration of treatment regimens. There are also concerns regarding increasing treatment relapses as well as the identification of resistant clinical strains with the use of miltefosine, the sole oral drug for VL. There is, therefore, an urgent need for new alternative oral drugs for VL. In the present study, we show the leishmanicidal effect of a novel, oral antimalarial endoperoxide N-251. In our In vitro studies, N-251 selectively and specifically killed Leishmania donovani D10 amastigotes with no accompanying toxicity toward the host cells. In addition, N-251 exhibited comparable activities against promastigotes of L. donovani D10, as well as other L. donovani complex parasites, suggesting a wide spectrum of activity. Furthermore, even after a progressive infection was established in mice, N-251 significantly eliminated amastigotes when administered orally. Finally, N-251 suppressed granuloma formation in mice liver through parasite death. These findings indicate the therapeutic effect of N-251 as an oral drug, hence suggest N-251 to be a promising lead compound for the development of a new oral chemotherapy against VL.
AB - Visceral leishmaniasis (VL) is a major problem worldwide and causes significant morbidity and mortality. Existing drugs against VL have limitations, including their invasive means of administration long duration of treatment regimens. There are also concerns regarding increasing treatment relapses as well as the identification of resistant clinical strains with the use of miltefosine, the sole oral drug for VL. There is, therefore, an urgent need for new alternative oral drugs for VL. In the present study, we show the leishmanicidal effect of a novel, oral antimalarial endoperoxide N-251. In our In vitro studies, N-251 selectively and specifically killed Leishmania donovani D10 amastigotes with no accompanying toxicity toward the host cells. In addition, N-251 exhibited comparable activities against promastigotes of L. donovani D10, as well as other L. donovani complex parasites, suggesting a wide spectrum of activity. Furthermore, even after a progressive infection was established in mice, N-251 significantly eliminated amastigotes when administered orally. Finally, N-251 suppressed granuloma formation in mice liver through parasite death. These findings indicate the therapeutic effect of N-251 as an oral drug, hence suggest N-251 to be a promising lead compound for the development of a new oral chemotherapy against VL.
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U2 - 10.1371/journal.pntd.0007235
DO - 10.1371/journal.pntd.0007235
M3 - Article
C2 - 30908481
AN - SCOPUS:85063712038
VL - 13
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
SN - 1935-2727
IS - 3
M1 - e0007235
ER -