Trypanocidal activity of conformationally restricted pentamidine congeners

Isaac Donkor, Tien L. Huang, Bin Tao, Donna Rattendi, Schennella Lane, Marc Vargas, Burt Goldberg, Cyrus Bacchi

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

A series of conformationally restricted congeners of pentamidine in which the flexible pentyl bridge of pentamidine was replaced by trans-1,2-bismethylenecyclopropyl, phenyl, pyridinyl, piperazinyl, homopiperazinyl, and piperidinyl groups were synthesized. The compounds were evaluated for trypanocidal activity in vitro and in vivo against one drug-sensitive and three drug-resistant trypanosome isolates. The DNA binding affinity of the compounds was also studied using calf thymus DNA and poly(dA-dT). The nature of the linker influenced the DNA binding affinity as well as the trypanocidal activity of the compounds, trans-1,2-Bis (4-amidinophenoxymethylene)cyclopropane (1) was over 25-fold more potent than pentamidine against the drug-resistant isolate KETRI 243As-10-3, albeit with comparable DNA binding affinity. N,N′-Bis(4-amidinophenyl)homopiperazine (8) was the most potent trypanocide in vitro against all four trypanosome isolates studied, but N,N′-bis(4-amidinophenyl)piperazine (6) was the most effective agent in vivo against both drug-sensitive and drug-resistant trypanosomes.

Original languageEnglish (US)
Pages (from-to)1041-1048
Number of pages8
JournalJournal of Medicinal Chemistry
Volume46
Issue number6
DOIs
StatePublished - Mar 13 2003

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Pentamidine
Trypanosomiasis
Pharmaceutical Preparations
DNA
Trypanocidal Agents
Poly dA-dT

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Donkor, I., Huang, T. L., Tao, B., Rattendi, D., Lane, S., Vargas, M., ... Bacchi, C. (2003). Trypanocidal activity of conformationally restricted pentamidine congeners. Journal of Medicinal Chemistry, 46(6), 1041-1048. https://doi.org/10.1021/jm020375q

Trypanocidal activity of conformationally restricted pentamidine congeners. / Donkor, Isaac; Huang, Tien L.; Tao, Bin; Rattendi, Donna; Lane, Schennella; Vargas, Marc; Goldberg, Burt; Bacchi, Cyrus.

In: Journal of Medicinal Chemistry, Vol. 46, No. 6, 13.03.2003, p. 1041-1048.

Research output: Contribution to journalArticle

Donkor, I, Huang, TL, Tao, B, Rattendi, D, Lane, S, Vargas, M, Goldberg, B & Bacchi, C 2003, 'Trypanocidal activity of conformationally restricted pentamidine congeners', Journal of Medicinal Chemistry, vol. 46, no. 6, pp. 1041-1048. https://doi.org/10.1021/jm020375q
Donkor, Isaac ; Huang, Tien L. ; Tao, Bin ; Rattendi, Donna ; Lane, Schennella ; Vargas, Marc ; Goldberg, Burt ; Bacchi, Cyrus. / Trypanocidal activity of conformationally restricted pentamidine congeners. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 6. pp. 1041-1048.
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