Bis(2-aminoimidazolinium)diphenyl Compounds as DNA Minor Groove Binders with in Vivo Antitrypanosomal and Antimalarial Activity: the cation is important

Abstract

Background: A pragmatic approach to the discovery of new drugs for neglected diseases is the “recycling” of available compounds. We have successfully applied this strategy during the last years with the (re)discovery of an attractive class of compounds (i.e., 2-aminoimidazolinium derivatives) showing excellent in vivo activity against T. brucei rhodesiense and P. falciparum, the ethiological agents of rhodesiense sleeping sickness and severe malaria, respectively. Methods: Based on their structural similarity with known antitrypanosomal and antimalarial agents, several series of dicationic compounds as well as their monocationic and neutral analogues were screened in vitro against T. b. rhodesiense, P. falciparum, and rat skeletal myoblast L6-cells as control for cytotoxicity. The compounds showing the highest activity and acceptable selectivity were assayed in vivo in models of acute and chronic T. brucei infections (STIB900 and GVR35 strains, respectively), and murine malaria (P. berghei). Their interaction with the DNA minor groove was also measured by thermal melting curves (Tm) and SPR experiments on AT sequence DNA polymers. Results: Several dicationic leads with nM in vitro activity and excellent selectivity against T. b. rhodesiense and P. falciparum were identified. A number of compounds cured 100% of the mice infected with T. b. rhodesiense and 4 compounds reduced the parasitemia in mice infected with P. berghei. A correlation between DNA binding affinity and trypanocidal activity was observed, indicating that DNA binding may be part of their mechanism of action. Most importantly, we found that the 2-aminoimidazoline cation afforded molecules with superior safety profile compared with its guanidine counterpart. Conclusion: 1) The rational screening of in-house libraries of compounds is a validated approach to find new drug leads for neglected diseases. 2) Bis(2-aminoimidazoline) derivatives represent a very promising class of DNA minor groove binding agents that have already demonstrated their antiprotozoal potential in vivo.