Trypanocidal activity of piperazine-linked bisbenzamidines and bisbenzamidoxime, an orally active prodrug

• Published in: International journal of antimicrobial agents 2007-12, Vol.30 (6), p.555-561
• Main Authors: Huang, Tien L, Bacchi, Cyrus J, Kode, Nageswara R, Zhang, Qiang, Wang, Guangdi, Yartlet, Nigel, Rattendi, Donna, Londono, Indira, Mazumder, Lakshman, Vanden Eynde, Jean Jacques, Mayence, Annie, Donkor, Isaac O
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Benzamidines - chemical synthesis; Benzamidines - chemistry; Benzamidines - pharmacology; Benzamidines - therapeutic use; Biological and medical sciences; Diamidine; Diamidoxime; Drug Resistance; Human African trypanosomiasis; Human protozoal diseases; Humans; Infectious Disease; Infectious diseases; Medical sciences; Mice; Parasitic diseases; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Piperazines - therapeutic use; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; Protozoal diseases; Rats; Trypanocidal agents; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanocidal Agents - therapeutic use; Trypanosoma brucei; Trypanosoma brucei brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei rhodesiense; Trypanosoma brucei rhodesiense - drug effects; Trypanosomiasis; Trypanosomiasis, African - drug therapy; Trypanosomiasis, African - mortality; Trypanosomiasis, African - parasitology
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2007.07.021

Abstract A series of 32 piperazine-linked bisbenzamidines (and related analogues) were analysed for their in vitro and in vivo trypanocidal activity against a drug-sensitive strain of Trypanosoma brucei brucei and a drug-resistant strain of Trypanosoma brucei rhodesiense . The compounds showed similar potencies against both strains. The most potent compounds were bisbenzamidines substituted at the amidinium nitrogens with a linear pentyl group ( 8 , inhibitory concentration for 50% (IC50 ) = 1.7–3.0 nM) or cyclic octyl group ( 17 , IC50 = 2.3–4.6 nM). Replacement of the diamidine groups with diamidoxime groups resulted in a prodrug ( 22 ) that was effective orally against T. b. brucei -infected mice. Three compounds ( 7 , 11 and 15 ) provided 100% cure when administered parenterally. The results indicate that the nature of the substituents at the amidinium nitrogens of bisbenzamidines strongly influence their trypanocidal activity.