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dc.contributor.authorDardonville, Christophe-
dc.contributor.authorNieto, Lidia-
dc.contributor.authorRodríguez, Fernando-
dc.contributor.authorRozas, Isabel-
dc.contributor.authorKaiser, Marcel-
dc.contributor.authorBrun, Reto-
dc.contributor.authorNguyen, Binh-
dc.contributor.authorWilson, W. David-
dc.contributor.authorGarcía, Rory Nelson-
dc.description.abstractRecent findings by our group have shown that bisguanidine and especially bis(2-aminoimidazoline)diphenyl compounds displayed potent antitrypanosomal activity in vitro [1] and vivo [2] against T. b. rhodesiense, the causative agent of acute human African trypanosomiasis (HAT). These studies revealed that molecules bearing 2-aminoimidazoline cations had higher selectivity for the parasite and similar activities with respect to their guanidine counterparts. In addition, a correlation between antitrypanosomal activity and DNA binding affinity was observed, suggesting a possible mechanism of action for these compounds [2]. Last but not least, we showed that this kind of molecules entered into trypanosomes via different transporters in addition to P2, indicating that parasites that have lost the P2 transporter in selection of resistance to other drugs will not show cross-resistance to this class of molecules. Encouraged by these promising results, another series of 16 dicationic analogues were evaluated in vitro against T. b. rhodesiense (STIB900). Moreover, in order to extend our understanding of the SAR of this class of antiprotozoal agents, two new series of monocationic analogues, namely 2-aminoimidazolinium compounds and their guanidinium counterparts were assayed. Others have described excellent antiplasmodial activity of related aromatic dicationic structures such as pentamidine or DB289 [3] These findings prompted us to test the antiplasmodial potential of our dicationic diphenyl compounds. The capacity of the compounds to inhibit the formation of hemozoin, as a possible mechanism of action, was also evaluated in vitro with the ferriprotoporphyrin IX binding inhibition test (FBIT) [4]. References: [1] Dardonville, C.; Brun, R. J Med Chem 2004, 47, 2296. [2] Dardonville, C.; Barrett, M. P.; Brun, R.; Kaiser, M.; Tanious, F.; Wilson, W. D. J Med Chem 2006, 49, 3748. [3] Soeiro, M. N. C.; De Souza, E. M.; Stephens, C. E.; Boykin, D. W. Expert Opin Inv Drug 2005, 14, 957. [4] Deharo, E.; Garcia, R. N.; Oporto, P.; Gimenez, A.; Sauvain, M.; Jullian, V.; Ginsburg, H. Exp Parasitol 2002, 100, 252.en_US
dc.description.sponsorship- UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases - PIE grant from the CSIC (200680I121) - Ministerio de Educación y Ciencia “Programa Nacional de Biomedicina” (SAF2006-04698) - Cycle III HEA PRTLI grant by means of the CSCB in Ireland - Consejeria de Educacion Cultura y Deporte de la Comunidad Autonoma de La Rioja, Spain.en_US
dc.format.extent404992 bytes-
dc.titleAntitrypanosomal and antiplasmodial activity of bis(2-aminoimidazoline) and bisguanidine derivativesen_US
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