Aminoalkyl Derivatives of Guanidine Diaromatic Minor Groove Binders with Antiprotozoal Activity

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 (<b>12a</b>–<b>e</b>, <b>13a</b>–<b>e</b>, <b>14a</b>–<b>c</b>,<b>e</b>, <b>15a</b>–<b>e</b>, <b>16a</b>–<b>e</b>) 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 <i>Trypanosoma brucei rhodesiense</i> (8 compounds) and <i>Plasmodium falciparum</i> (18 compounds). The O-linked derivatives <b>13c</b> and <b>14c</b> showed 100 nM activities against <i>P. falciparum,</i> whereas for <i>T. b. rhodesiense</i> 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