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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

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 a...

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Autores principales: Kwofie, Kofi Dadzie, Sato, Kai, Sanjoba, Chizu, Hino, Akina, Shimogawara, Rieko, Amoa-Bosompem, Michael, Ayi, Irene, Boakye, Daniel A., Anang, Abraham K., Chang, Kyung-Soo, Ohashi, Mitsuko, Kim, Hye-Sook, Ohta, Nobuo, Matsumoto, Yoshitsugu, Iwanaga, Shiroh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433226/
https://www.ncbi.nlm.nih.gov/pubmed/30908481
http://dx.doi.org/10.1371/journal.pntd.0007235
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author Kwofie, Kofi Dadzie
Sato, Kai
Sanjoba, Chizu
Hino, Akina
Shimogawara, Rieko
Amoa-Bosompem, Michael
Ayi, Irene
Boakye, Daniel A.
Anang, Abraham K.
Chang, Kyung-Soo
Ohashi, Mitsuko
Kim, Hye-Sook
Ohta, Nobuo
Matsumoto, Yoshitsugu
Iwanaga, Shiroh
author_facet Kwofie, Kofi Dadzie
Sato, Kai
Sanjoba, Chizu
Hino, Akina
Shimogawara, Rieko
Amoa-Bosompem, Michael
Ayi, Irene
Boakye, Daniel A.
Anang, Abraham K.
Chang, Kyung-Soo
Ohashi, Mitsuko
Kim, Hye-Sook
Ohta, Nobuo
Matsumoto, Yoshitsugu
Iwanaga, Shiroh
author_sort Kwofie, Kofi Dadzie
collection PubMed
description 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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spelling pubmed-64332262019-04-08 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 Kwofie, Kofi Dadzie Sato, Kai Sanjoba, Chizu Hino, Akina Shimogawara, Rieko Amoa-Bosompem, Michael Ayi, Irene Boakye, Daniel A. Anang, Abraham K. Chang, Kyung-Soo Ohashi, Mitsuko Kim, Hye-Sook Ohta, Nobuo Matsumoto, Yoshitsugu Iwanaga, Shiroh PLoS Negl Trop Dis Research Article 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. Public Library of Science 2019-03-25 /pmc/articles/PMC6433226/ /pubmed/30908481 http://dx.doi.org/10.1371/journal.pntd.0007235 Text en © 2019 Kwofie et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kwofie, Kofi Dadzie
Sato, Kai
Sanjoba, Chizu
Hino, Akina
Shimogawara, Rieko
Amoa-Bosompem, Michael
Ayi, Irene
Boakye, Daniel A.
Anang, Abraham K.
Chang, Kyung-Soo
Ohashi, Mitsuko
Kim, Hye-Sook
Ohta, Nobuo
Matsumoto, Yoshitsugu
Iwanaga, Shiroh
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433226/
https://www.ncbi.nlm.nih.gov/pubmed/30908481
http://dx.doi.org/10.1371/journal.pntd.0007235
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