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

Tien L. Huang, Cyrus J. Bacchi, Nageswara R. Kode, Qiang Zhang, Guangdi Wang, Nigel Yartlet, Donna Rattendi, Indira Londono, Lakshman Mazumder, Jean Jacques Vanden Eynde, Annie Mayence, Isaac Donkor

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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.

Original languageEnglish (US)
Pages (from-to)555-561
Number of pages7
JournalInternational Journal of Antimicrobial Agents
Volume30
Issue number6
DOIs
StatePublished - Dec 1 2007

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Prodrugs
Inhibitory Concentration 50
Nitrogen
Trypanosoma brucei rhodesiense
Pentamidine
Trypanosoma brucei brucei
Pharmaceutical Preparations
piperazine
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

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

In: International Journal of Antimicrobial Agents, Vol. 30, No. 6, 01.12.2007, p. 555-561.

Research output: Contribution to journalArticle

Huang, TL, Bacchi, CJ, Kode, NR, Zhang, Q, Wang, G, Yartlet, N, Rattendi, D, Londono, I, Mazumder, L, Vanden Eynde, JJ, Mayence, A & Donkor, I 2007, 'Trypanocidal activity of piperazine-linked bisbenzamidines and bisbenzamidoxime, an orally active prodrug', International Journal of Antimicrobial Agents, vol. 30, no. 6, pp. 555-561. https://doi.org/10.1016/j.ijantimicag.2007.07.021
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. / Trypanocidal activity of piperazine-linked bisbenzamidines and bisbenzamidoxime, an orally active prodrug. In: International Journal of Antimicrobial Agents. 2007 ; Vol. 30, No. 6. pp. 555-561.
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