Synthesis, DNA affinity, and Antiprotozoal activity of fused ring dicationic compounds and their prodrugs
Arafa, RK; Brun, R; Wenzler, T; Tanious, FA; Wilson, WD; Stephens, CE; Boykin, DW
| HERO ID | 2243359 |
|---|---|
| In Press | No |
| Year | 2005 |
| Title | Synthesis, DNA affinity, and Antiprotozoal activity of fused ring dicationic compounds and their prodrugs |
| Authors | Arafa, RK; Brun, R; Wenzler, T; Tanious, FA; Wilson, WD; Stephens, CE; Boykin, DW |
| Journal | Journal of Medicinal Chemistry |
| Volume | 48 |
| Issue | 17 |
| Page Numbers | 5480-5488 |
| Abstract | Dicationic guanidine, N-alkylguanidine, and reversed amidine derivatives of fused ring systems 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, giving 4/4 cures of the treated animals in the STIB900 animal model for African trypanosomiasis. The N-methyl analogue 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 were not effective as prodrugs. In contrast, a number of the carbamates showed promising activity. The value of the carbamate prodrugs was clearly demonstrated by the results, which gave 4/4 cures on oral administration in the STIB900 mouse model. |
| Doi | 10.1021/jm058190h |
| Pmid | 16107146 |
| Wosid | WOS:000231459600011 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Scopus URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-23944453324&doi=10.1021%2fjm058190h&partnerID=40&md5=6d52258d3554b87b002075e767030ff2 |
| Is Public | Yes |
| Language Text | English |
| Keyword | 2,7 bis(n' ethoxycarbonyl n'' isopropyl)guanidino 9h fluorene; 2,7 bis(n' ethoxycarbonyl)guanidino 9h fluorene; 2,7 bis(n' ethoxycarbonyl)guanidinofluoren 9 one; 2,7 bis(n' ethyl)guanidino 9h fluorene; 2,7 bis(n' isopropyl)guanidino 9h fluorene; 2,7 bis(n' methyl)guanidino 9h fluorene; 2,7 bis[4 (iminobenzylamino)] 9h fluorene; 2,7 bis[4 [imino (2 pyridylmethyl)]amino] 9h fluorene; 2,7 bisguanidino 9h fluorene; 2,7 bisguanidinoanthraquinone; 2,7 bisguanidinofluoren 9 one; 2,7 nis(n ethoxycarbonyl n'' methyl)guanidino 9h fluorene; 3,6 bisguanidinoacridine; amidine; guanidine derivative; prodrug; unclassified drug; African trypanosomiasis; animal experiment; animal model; antiprotozoal activity; article; controlled study; drug binding; drug bioavailability; drug DNA binding; drug efficacy; drug structure; drug synthesis; in vitro study; in vivo study; mouse; nonhuman; Plasmodium falciparum; structure activity relation; Trypanosoma rhodesiense; Animals; Antiprotozoal Agents; Carbamates; Cations; Circular Dichroism; DNA; Fluorenes; Guanidines; Mice; Plasmodium falciparum; Poly dA-dT; Prodrugs; Structure-Activity Relationship; Trypanosoma brucei rhodesiense; Trypanosomiasis, African |