期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 143, 期 -, 页码 1590-1596出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.10.056
关键词
Diamidines; Stille coupling; Pinner reaction; DNA minor groove binders; Trypanocidal; Antimalarial; African sleeping sickness; Malaria
资金
- Bill and Melinda Gates Foundation through the Consortium for Parasitic Drug Development [38920]
- National Institutes of Health [GM111749]
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 (LiNESi(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 x 5 mg/kg i.p. and hence 7c is more potent in vivo than pentamidine. Published by Elsevier Masson SAS.
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