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Aminoalkyl derivatives of guanidine diaromatic minor groove binders with antiprotozoal activity.

Journal of medicinal chemistry (2013-01-11)
Caitriona McKeever, Marcel Kaiser, Isabel Rozas
ABSTRACT

Considering the strong DNA minor groove binding observed for our previous series of diaromatic symmetric and asymmetric guanidinium and 2-aminoimidazolinium derivatives, we report now the synthesis of new aminoalkyl derivatives of diaromatic guanidines with potential as DNA minor groove binders and antiprotozoal activity. The preparation of these aminoalkyl derivatives (12a-e, 13a-e, 14a-c,e, 15a-e, 16a-e) is presented as well as their affinity for DNA which was evaluated by means of DNA thermal denaturation experiments. Finally, the antiprotozoal activity of most of these aminoalkyl minor groove binders was evaluated in vitro against Trypanosoma brucei rhodesiense (8 compounds) and Plasmodium falciparum (18 compounds). The O-linked derivatives 13c and 14c showed 100 nM activities against P. falciparum, whereas for T. b. rhodesiense all compounds tested showed micromolar activity. Some of the derivatives prepared seem to exert the antimalarial activity by binding to the DNA minor groove whereas other sets of compounds could exert this antimalarial activity by inhibiting the parasite dihydrofolate reductase, for example.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Guanidine hydrochloride, ≥99.5%
Sigma-Aldrich
Guanidine hydrochloride, BioUltra, for molecular biology, ≥99.5% (AT)
Sigma-Aldrich
Guanidine hydrochloride, ≥99.0% (AT)
Sigma-Aldrich
Guanidine hydrochloride, for molecular biology, ≥99%
Sigma-Aldrich
Guanidine hydrochloride, ≥99% (titration), organic base and chaeotropic agent
Sigma-Aldrich
Guanidine hydrochloride, BioXtra, ≥99.5% (titration)
Sigma-Aldrich
Guanidine hydrochloride, ≥98%
Sigma-Aldrich
Guanidine hydrochloride solution
Sigma-Aldrich
Guanidine hydrochloride solution, BioUltra, ~8 M in H2O