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Bis(2-aminoimidazolines) and Bisguanidines: Synthetic Approaches, Antiparasitic Activity and DNA Binding Properties

[ Vol. 24 , Issue. 33 ]

Author(s):

Christophe Dardonville * and Jorge J.N. Martinez   Pages 3606 - 3632 ( 27 )

Abstract:


Background: Parasitic diseases caused by protozoan parasites of the genus Trypanosoma and Plasmodium cause some of the deadliest and disabling human infections in tropical and subtropical areas. Diphenyl-based bis(2-phenylimino)imidazolidines and bisguanidines are extremely potent antiparasitic agents against Trypanosoma brucei (etiological agent of African trypanosomiasis) and Plasmodium falciparum (etiological agent of severe malaria). Many of these compounds are also curative in mouse models of stage 1 African trypanosomiasis representing promising leads for the development of antitrypanosomal drugs. In addition, different classes of bis(2-iminoimidazolidines) and bisguanidines have been shown to have antimicrobial activity against other pathogens (e.g. bacteria, fungi, parasitic worms). Due to their structural and physicochemical properties, these dibasic compounds, which are dications at physiological pH, are prone to bind to the minor groove of DNA at AT-rich sites. In several cases, such interaction is thought to be responsible for their antimicrobial activity.

Results: In this review, we give a comprehensive view of the synthetic methods used to introduce the 2-aminoimidazoline scaffold in a molecule. Synthetic routes that give access to these cyclic guanidines (i.e. unsubstituted, 1-, 4-, and 5-substituted 2-aminoimidazolines) are detailed. The in vitro and in vivo antiprotozoal activity of bis(2-aminoimidazolines) and bisguanidines against kinetoplastid parasites (T. brucei, T. cruzi, Leishmania), Plasmodium spp. and other pathogens (e.g. ESKAPE bacteria, Candida spp., M. tuberculosis, E. multilocularia) is also reviewed. Finally, the targets that are involved in the antimicrobial activity (e.g. DNA) or other biological activities (e.g. α-adrenergic receptors, imidazoline binding sites, kinases) of this class of dicationic compounds are discussed.

Keywords:

Dication, 2-(phenylimino)imidazolidine, synthesis of 2-aminoimidazoline, synthesis of cyclic guanidine, DNA minor groove binder, Trypanosoma brucei, T. congolense, Plasmodium falciparum, sleeping sickness.

Affiliation:

Instituto de Quimica Medica, IQM-CSIC, Juan de la Cierva 3, E–28006 Madrid, Departamento de ingenieria, Pontificia Universidad Catolica del Peru-PUCP, Av. Universitaria 1801, Lima 32



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