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

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.