Synthesis and in vitro leishmanicidal activity of novel N-arylspermidine derivatives

This work describes the synthesis and biological evaluation of hitherto unknown N-arylspermidine derivatives 3. Compounds 3 were efficiently prepared from cyclic amidines through a novel synthetic approach comprising alkylation with ω-halonitriles followed by reduction. The cyclic N-arylamidine directs the alkylation to the unsubstituted nitrogen and also provides the N-benzyl group present in the triamine after simultaneous reduction of the resulting quaternary salt 2 and the cyano group. The N-aryl spermidines were tested in Leishmania infantum promastigotes and also in the more challenging form intracellular amastigotes. The compounds toxicity was also assessed in two cell lines, THP-1 and HepG2. In silico physicochemical and ADME predictions were also carried out. Eight out of ten compounds displayed EC₅₀ around 5 µM against L. infantum intracellular amastigotes. Among them, derivatives 3c, 3d, and 3h showed potency in the low micromolar range with SI > 5 and suitable predicted physicochemical ADME properties. The antileishmanial activity of the compounds would rely on the N-arylspermidine moiety, as assessed by evaluation of related substructures which were inactive. This first series of compounds, among which two derivatives (3b,h) displayed EC₅₀ values comparable to Miltefosine, represent a good starting point for further studies and multiparametric optimization to obtain more potent and selective candidates for the treatment of this neglected tropical disease.