Antiprotozoal activity of novel diaryliminophenazines

Recently, we synthesized a set of novel iminofenazines bearing a bicyclic basic head linked through an alkyl chain to the imino nitrogen in position 3 on the phenazine nucleus (Fig.1).
Most of these compounds inhibited the growth of different species of Leishmania promastigotes as well as of chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of P. falciparum with IC50 in the submicromolar range. Unfortunately, these compounds exhibited also a significant toxicity against the human endothelial cell line HMEC-1 with IC50 in the low micromolar range and with a consequent low selectivity index.



Figure1.Structures of the previously synthesized compounds.

To continue the studies on the antiprotozoal potentialities of this class of compounds and with the aim to improve their activity and selectivity on protozoa, we have now synthesized novel compounds characterized by the replacement of the aniline moiety in pos. 2 of the phenazine nucleus with an aminopyridine, and/or by a quaternarization of the basic nitrogen in the side chain with a methyl group (Fig.2).



Figure 2. Structures of the new compounds synthesized.

The in vitro activity of the new compounds on Leishmania promastigotes and on CQ-S and CQ-R strains of P. falciparum, as well as on the HMEC-1 cell line will be presented and discussed.


References
[1] A. Barteselli, M. Gavazzi, N. Basilico, S. Parapini, D. Taramelli, A. Sparatore. Clofazimine analogs with antileishmanial and antimalarial activities. XXII National Meeting on Medicinal Chemistry, Roma 2013.