Synthesis, DNA affinity, and antiprotozoal activity of fused ring dicationic compounds and their prodrugs

Reem K. Arafa, Reto Brun, Tanja Wenzler, Farial A. Tanious, W. David Wilson, Chad E. Stephens, David W. Boykin

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Dicationic guanidine, N-alkylguanidine, and reversed amidine derivatives of fused ring systems (9a-d, 12a-c, 13a, and 13b) have been synthesized from their corresponding bis-amines. DNA binding studies suggest that the diguanidines and the N-alkyl diguanidines fluorenes bind in the minor groove in a manner similar to that of the previously reported dicationic carbazole derivatives. The diguanidines and the N-alkyl diguanidines showed promising in vitro activity against both Trypanosoma brucei rhodesiense and Plasmodium falciparum. Promising in vivo biological results were obtained for the dicationic N-isopropylguanidino-9H-fluorene (12c), giving 4/4 cures of the treated animals in the STIB900 animal model for African trypanosomiasis. The N-methyl analogue (12a) showed high activity as well. In addition, with the goal of enhancing the oral bioavailability, two novel classes of potential guanidine prodrugs were prepared. The N-alkoxyguanidine derivatives (12d) and (12e) were not effective as prodrugs. In contrast, a number of the carbamates (11a,c-e) showed promising activity. The value of the carbamate prodrugs was clearly demonstrated by the results for (11c), which gave 4/4 cures on oral administration in the STIB900 mouse model.

Original languageEnglish (US)
Pages (from-to)5480-5488
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number17
DOIs
StatePublished - Aug 25 2005
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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