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.