Bisguanidine, bis(2-aminoimidazoline), and polyamine derivatives as potent and selective chemotherapeutic agents against Trypanosoma brucei rhodesiense. Synthesis and in vitro evaluation.

The in vitro screening for trypanocidal activity against Trypanosoma brucei rhodesiense of an in-house library of 62 compounds [i.e. alkane, diphenyl, and azaalkane bisguanidines and bis(2-aminoimidazolines)], which were chosen for their structural similarity to the trypanocidal agents synthalin (1,10-decanediguanidine) and 4,4'-diguanidinodiphenylmethane and the polyamine N(1)-(3-amino-propyl)propane-1,3-diamine, respectively, is reported. The original synthetic procedure for the preparation of 21 of these compounds is also reported. Most compounds displayed low micromolar antitrypanosomal activity, with five of them presenting a nanomolar inhibitory action on the parasite: 1,9-nonanediguanidine (1c), 1,12-dodecanediguanidine (1d), 4,4'-bis[1,3-bis(tert-butoxycarbonyl)-2-imidazolidinylimino]diphenylamine (28a), 4,4'-bis(4,5-dihydro-1H-2-imidazolylamino)diphenylamine (28b), and 4,4'-diguanidinodiphenylamine (32b). Those molecules that showed an excellent in vitro activity as well as high selectivity for the parasite [e.g. 1c (IC(50) = 49 nM; SI > 5294), 28b (IC(50) = 69 nM; SI = 3072), 32b (IC(50) = 22 nM; SI = 29.5), 41b (IC(50) = 118 nM; SI = 881)] represent new antitrypanosomal lead compounds.