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Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity

A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing African sleeping sickness and malaria. The dicyanoindoles needed to synthesize the target diamidines were obtained through Stille...

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Detalles Bibliográficos
Autores principales: Farahat, Abdelbasset A., Ismail, Mohamed A., Kumar, Arvind, Wenzler, Tanja, Brun, Reto, Paul, Ananya, Wilson, W. David, Boykin, David W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Editions Scientifiques Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744864/
https://www.ncbi.nlm.nih.gov/pubmed/29126729
http://dx.doi.org/10.1016/j.ejmech.2017.10.056
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author Farahat, Abdelbasset A.
Ismail, Mohamed A.
Kumar, Arvind
Wenzler, Tanja
Brun, Reto
Paul, Ananya
Wilson, W. David
Boykin, David W.
author_facet Farahat, Abdelbasset A.
Ismail, Mohamed A.
Kumar, Arvind
Wenzler, Tanja
Brun, Reto
Paul, Ananya
Wilson, W. David
Boykin, David W.
author_sort Farahat, Abdelbasset A.
collection PubMed
description A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing African sleeping sickness and malaria. The dicyanoindoles needed to synthesize the target diamidines were obtained through Stille coupling reactions while the bis-cyanobenzimidazoles intermediates were made via condensation/cyclization reactions of different aldehydes with 4-cyano-1,2-diaminobenzene. Different amidine synthesis methodologies namely, lithium bis-trimethylsilylamide (LiN[Si(CH3)(3)](2)) and Pinner methods were used to prepare the diamidines. Both types (indole and benzimidazole) derivatives of the new diamidines bind strongly with the DNA minor groove and generally show excellent in vitro antitrypanosomal activity. The diamidino-indole derivatives also showed excellent in vitro antimalarial activity while their benzimidazole counterparts were generally less active. Compound 7c was highly active in vivo and cured all mice infected with Trypanosoma brucei rhodesiense, a model that mimics the acute stage of African sleeping sickness, at a low dose of 4 × 5 mg/kg i.p. and hence 7c is more potent in vivo than pentamidine.
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spelling pubmed-57448642018-01-02 Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity Farahat, Abdelbasset A. Ismail, Mohamed A. Kumar, Arvind Wenzler, Tanja Brun, Reto Paul, Ananya Wilson, W. David Boykin, David W. Eur J Med Chem Article A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing African sleeping sickness and malaria. The dicyanoindoles needed to synthesize the target diamidines were obtained through Stille coupling reactions while the bis-cyanobenzimidazoles intermediates were made via condensation/cyclization reactions of different aldehydes with 4-cyano-1,2-diaminobenzene. Different amidine synthesis methodologies namely, lithium bis-trimethylsilylamide (LiN[Si(CH3)(3)](2)) and Pinner methods were used to prepare the diamidines. Both types (indole and benzimidazole) derivatives of the new diamidines bind strongly with the DNA minor groove and generally show excellent in vitro antitrypanosomal activity. The diamidino-indole derivatives also showed excellent in vitro antimalarial activity while their benzimidazole counterparts were generally less active. Compound 7c was highly active in vivo and cured all mice infected with Trypanosoma brucei rhodesiense, a model that mimics the acute stage of African sleeping sickness, at a low dose of 4 × 5 mg/kg i.p. and hence 7c is more potent in vivo than pentamidine. Editions Scientifiques Elsevier 2018-01-01 /pmc/articles/PMC5744864/ /pubmed/29126729 http://dx.doi.org/10.1016/j.ejmech.2017.10.056 Text en http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Farahat, Abdelbasset A.
Ismail, Mohamed A.
Kumar, Arvind
Wenzler, Tanja
Brun, Reto
Paul, Ananya
Wilson, W. David
Boykin, David W.
Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity
title Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity
title_full Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity
title_fullStr Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity
title_full_unstemmed Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity
title_short Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity
title_sort indole and benzimidazole bichalcophenes: synthesis, dna binding and antiparasitic activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744864/
https://www.ncbi.nlm.nih.gov/pubmed/29126729
http://dx.doi.org/10.1016/j.ejmech.2017.10.056
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