Synthesis and anti-Pneumocystis carinii activity of conformationally restricted analogues of pentamidine

Bin Tao, Tien L. Huang, Qian Zhang, Latasha Jackson, Sherry F. Queener, Isaac O. Donkor

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A series of conformationally restricted analogues of pentamidine in which the flexible central bridge has been replaced by trans-cyclopropyl, phenyl, pyridinyl, piperazinyl or homopiperazinyl groups as conformationally restricted linkers have been synthesized. The anti-Pneumocystis carinii activity of these compounds was evaluated in a cell culture model and the DNA binding affinity was determined by thermal denaturation measurements. At 1 μM, compounds 2, 3, 5, 7, 9 and pentamidine were highly effective and caused total inhibition of P. carinii growth in culture. At 0.1 μM, compounds 2, 5, 7 and 10 were more active than pentamidine with N, N'- bis(4amidinophenyl)piperazine 7 being approximately 15-fold more effective than pentamidine. The most active compounds, 7 and 10, showed strong binding affinities for calf thymus DNA and poly(dA-dT); however, a clear correlation between DNA binding affinity and the in vitro anti-P, carinii activity of these compounds was not observed. The results suggest that the nature of the central linker influences the biological actions of these compounds.

Original languageEnglish (US)
Pages (from-to)531-538
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Issue number6
StatePublished - Jun 1999



  • Conformationally restricted
  • DNA
  • Pentamidine analogues
  • Pneumocystis carinii pneumonia
  • Poly(dA-dT)

ASJC Scopus subject areas

  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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