Pentamidine Congeners. 2. 2-Butene-Bridged Aromatic Diamidines and Diimidazolines as Potential Anti-Pneumocystis carinii Pneumonia Agents

Isaac Donkor, Richard R. Tidwell, Susan K. Jones

Research output: Contribution to journalComment/debate

25 Citations (Scopus)

Abstract

We have synthesized cis and trans geometric isomers 1–8 as semirigid congeners of pentamidine. Compounds 1–4 were more potent than pentamidine in treating Pneumocystis carinii pneumonia in immunosuppressed rats. These compounds also demonstrated no clinical toxicity or histopathologic abnormalities. Introduction of methoxy substituents meta to the amidine or imidazoline groups of the phenyl rings as in compounds 5–8 generally resulted in compounds with decreased anti-P. carinii activity and increased toxicity to the host. Compounds 1–4 were evaluated as DNA binders. These compounds showed greater affinity for poly(dA)·poly(dT) than for calf thymus DNA. The cis isomers, 1 and 2, demonstrated greater affinity for DNA than their trans counterparts 3 and 4. This difference in DNA binding affinity, however, did not reflect in a corresponding difference in the anti-P. carinii activity of these compounds.

Original languageEnglish (US)
Pages (from-to)4554-4557
Number of pages4
JournalJournal of Medicinal Chemistry
Volume37
Issue number26
DOIs
StatePublished - Dec 1 1994

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Pentamidine
Pneumocystis Pneumonia
Pneumocystis carinii
DNA
Amidines
Imidazolines
2-butene

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Pentamidine Congeners. 2. 2-Butene-Bridged Aromatic Diamidines and Diimidazolines as Potential Anti-Pneumocystis carinii Pneumonia Agents. / Donkor, Isaac; Tidwell, Richard R.; Jones, Susan K.

In: Journal of Medicinal Chemistry, Vol. 37, No. 26, 01.12.1994, p. 4554-4557.

Research output: Contribution to journalComment/debate

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abstract = "We have synthesized cis and trans geometric isomers 1–8 as semirigid congeners of pentamidine. Compounds 1–4 were more potent than pentamidine in treating Pneumocystis carinii pneumonia in immunosuppressed rats. These compounds also demonstrated no clinical toxicity or histopathologic abnormalities. Introduction of methoxy substituents meta to the amidine or imidazoline groups of the phenyl rings as in compounds 5–8 generally resulted in compounds with decreased anti-P. carinii activity and increased toxicity to the host. Compounds 1–4 were evaluated as DNA binders. These compounds showed greater affinity for poly(dA)·poly(dT) than for calf thymus DNA. The cis isomers, 1 and 2, demonstrated greater affinity for DNA than their trans counterparts 3 and 4. This difference in DNA binding affinity, however, did not reflect in a corresponding difference in the anti-P. carinii activity of these compounds.",
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N2 - We have synthesized cis and trans geometric isomers 1–8 as semirigid congeners of pentamidine. Compounds 1–4 were more potent than pentamidine in treating Pneumocystis carinii pneumonia in immunosuppressed rats. These compounds also demonstrated no clinical toxicity or histopathologic abnormalities. Introduction of methoxy substituents meta to the amidine or imidazoline groups of the phenyl rings as in compounds 5–8 generally resulted in compounds with decreased anti-P. carinii activity and increased toxicity to the host. Compounds 1–4 were evaluated as DNA binders. These compounds showed greater affinity for poly(dA)·poly(dT) than for calf thymus DNA. The cis isomers, 1 and 2, demonstrated greater affinity for DNA than their trans counterparts 3 and 4. This difference in DNA binding affinity, however, did not reflect in a corresponding difference in the anti-P. carinii activity of these compounds.

AB - We have synthesized cis and trans geometric isomers 1–8 as semirigid congeners of pentamidine. Compounds 1–4 were more potent than pentamidine in treating Pneumocystis carinii pneumonia in immunosuppressed rats. These compounds also demonstrated no clinical toxicity or histopathologic abnormalities. Introduction of methoxy substituents meta to the amidine or imidazoline groups of the phenyl rings as in compounds 5–8 generally resulted in compounds with decreased anti-P. carinii activity and increased toxicity to the host. Compounds 1–4 were evaluated as DNA binders. These compounds showed greater affinity for poly(dA)·poly(dT) than for calf thymus DNA. The cis isomers, 1 and 2, demonstrated greater affinity for DNA than their trans counterparts 3 and 4. This difference in DNA binding affinity, however, did not reflect in a corresponding difference in the anti-P. carinii activity of these compounds.

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