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Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose
[Image: see text] We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544003/ https://www.ncbi.nlm.nih.gov/pubmed/37722077 http://dx.doi.org/10.1021/acs.jmedchem.3c01051 |
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author | Racané, Livio Ptiček, Lucija Kostrun, Sanja Raić-Malić, Silvana Taylor, Martin Craig Delves, Michael Alsford, Sam Olmo, Francisco Francisco, Amanda Fortes Kelly, John M. |
author_facet | Racané, Livio Ptiček, Lucija Kostrun, Sanja Raić-Malić, Silvana Taylor, Martin Craig Delves, Michael Alsford, Sam Olmo, Francisco Francisco, Amanda Fortes Kelly, John M. |
author_sort | Racané, Livio |
collection | PubMed |
description | [Image: see text] We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg(–1) were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential. |
format | Online Article Text |
id | pubmed-10544003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-105440032023-10-03 Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose Racané, Livio Ptiček, Lucija Kostrun, Sanja Raić-Malić, Silvana Taylor, Martin Craig Delves, Michael Alsford, Sam Olmo, Francisco Francisco, Amanda Fortes Kelly, John M. J Med Chem [Image: see text] We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome Trypanosoma brucei. Of these, a dicationic benzothiazole compound (9a) exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity. In all cases, mice treated with a single dose of 20 mg kg(–1) were cured of stage 1 trypanosomiasis. The compound displayed a favorable in vitro ADME profile, with the exception of low membrane permeability. However, we found evidence that uptake by T. brucei is mediated by endocytosis, a process that results in lysosomal sequestration. The compound was also active in low nanomolar concentrations against cultured asexual forms of the malaria parasite Plasmodium falciparum. Therefore, 9a has exquisite cross-species efficacy and represents a lead compound with considerable therapeutic potential. American Chemical Society 2023-09-18 /pmc/articles/PMC10544003/ /pubmed/37722077 http://dx.doi.org/10.1021/acs.jmedchem.3c01051 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Racané, Livio Ptiček, Lucija Kostrun, Sanja Raić-Malić, Silvana Taylor, Martin Craig Delves, Michael Alsford, Sam Olmo, Francisco Francisco, Amanda Fortes Kelly, John M. Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose |
title | Bis-6-amidino-benzothiazole
Derivative that Cures
Experimental Stage 1 African Trypanosomiasis with a Single Dose |
title_full | Bis-6-amidino-benzothiazole
Derivative that Cures
Experimental Stage 1 African Trypanosomiasis with a Single Dose |
title_fullStr | Bis-6-amidino-benzothiazole
Derivative that Cures
Experimental Stage 1 African Trypanosomiasis with a Single Dose |
title_full_unstemmed | Bis-6-amidino-benzothiazole
Derivative that Cures
Experimental Stage 1 African Trypanosomiasis with a Single Dose |
title_short | Bis-6-amidino-benzothiazole
Derivative that Cures
Experimental Stage 1 African Trypanosomiasis with a Single Dose |
title_sort | bis-6-amidino-benzothiazole
derivative that cures
experimental stage 1 african trypanosomiasis with a single dose |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544003/ https://www.ncbi.nlm.nih.gov/pubmed/37722077 http://dx.doi.org/10.1021/acs.jmedchem.3c01051 |
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