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

Abstract

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 comprisingalkylation with ω-halonitriles followed by reduction. The cyclic N-arylamidine directs the alkylation to theunsubstituted nitrogen and also provides the N-benzyl group present in the triamine after simultaneous reductionof the resulting quaternary salt 2 and the cyano group. The N-aryl spermidines were tested in Leishmania infantumpromastigotes and also in the more challenging form intracellular amastigotes. The compounds toxicity was alsoassessed in two cell lines, THP-1 and HepG2. In silico physicochemical and ADME predictions were also carriedout. 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 suitablepredicted physicochemical ADME properties. The antileishmanial activity of the compounds would rely on the Narylspermidine moiety, as assessed by evaluation of related substructures which were inactive. This first series ofcompounds, among which two derivatives (3b,h) displayed EC50 values comparable to Miltefosine, represent agood starting point for further studies and multiparametric optimization to obtain more potent and selectivecandidates for the treatment of this neglected tropical disease.