Synthesis and SAR of alkanediamide-linked bisbenzamidines with anti-trypanosomal and anti-pneumocystis activity

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Huang, Tien L.¹  Eynde, Jean Jacques Vanden¹  Mayence, Annie¹  Collins, Margaret S.²  Cushion, Melanie T.²  Rattendi, Donna³  Londono, Indira³  Mazumder, Lakshman³  Bacchi, Cyrus J.^3,4  Yarlett, Nigel^3,5 

[1] Xavier Univ Louisiana, Coll Pharm, New Orleans, LA 70125 USA

[2] Univ Cincinnati, Dept Internal Med, Div Infect Dis, Cincinnati, OH 45267 USA

[3] Pace Univ, Haskins Labs, New York, NY 10038 USA

[4] Dept Biol & Hlth Sci, New York, NY 10038 USA

[5] Dept Chem & Phys Sci, New York, NY 10038 USA

关键词: Benzamidine;    Pentamidine;    DNA binding;    Human African Trypanosomiasis;    Trypanosoma brucei;    Pneumocystis carinii;   

DOI  :  10.1016/j.bmcl.2009.08.073

来源: Elsevier

【 摘 要 】

A series of alkanediamide-linked bisbenzamidines was synthesized and tested in vitro against a drug-sensitive strain of Trypanosoma brucei brucei, a drug-resistant strain of Trypanosoma brucei rhodesiense and Pneumocystis carinii. Bisbenzamidines linked with longer alkanediamide chains were potent inhibitors of both strains of T. brucei. However, bisbenzamidines linked with shorter alkanediamide chains were the most potent compounds against P. carinii. N,N'-Bis[4-(aminoiminomethyl)phenyl]hexanediamide, 4 displayed potent inhibition (IC50 = 2-3 nM) against T. brucei and P. carinii, and was non-cytotoxic in the A549 human lung carcinoma cell line. The inhibitory bioactivity was significantly reduced when the amidine groups in 4 were moved from the para to the meta positions or replaced with amides. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

Free