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

• Published in: Bioorganic & medicinal chemistry letters 2009-10, Vol.19 (20), p.5884-5886
• Main Authors: Huang, Tien L., Eynde, Jean Jacques Vanden, Mayence, Annie, Collins, Margaret S., Cushion, Melanie T., Rattendi, Donna, Londono, Indira, Mazumder, Lakshman, Bacchi, Cyrus J., Yarlett, Nigel
• Format: Article
• Language: English
• Subjects: Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; Anilides - chemical synthesis; Anilides - chemistry; Anilides - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - toxicity; Benzamidine; Benzamidines - chemical synthesis; Benzamidines - chemistry; Benzamidines - toxicity; Biological and medical sciences; Cell Line, Tumor; Diamide - chemistry; DNA binding; Human African Trypanosomiasis; Humans; Medical sciences; Pentamidine; Pharmacology. Drug treatments; Pneumocystis - drug effects; Pneumocystis carinii; Structure-Activity Relationship; Trypanosoma brucei; Trypanosoma brucei brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei rhodesiense; Trypanosoma brucei rhodesiense - drug effects
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.08.073

The synthesis and SAR of a series of alkanediamide-linked bisbenzamidines as potent inhibitors of Trypanosomal brucei and Pneumocystis carinii are described. 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 (IC 50 = 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.