In vitro leishmanicidal activity of novel N-arylspermidine derivatives

Abstract

Visceral leishmaniasis (VL) is the second-largest parasitic killer disease in the world, responsiblefor near one million infections each year. Polyamines are ubiquitous organic molecules that play key roles in kinetoplastids metabolism. This makes them attractive for antiparasitic drugdevelopment, and several natural polyamine analogs have been synthesized and evaluated [1].Most of the efforts were directed to symmetrically N1, N8-disubstituted spermidines, while Naryl derivatives have been scarcely investigated. We present here an in vitro anti Leishmaniainfantum study of a series of novel N-arylspermidines 1 and discuss their ADME properties.Chemistry: Compounds 1 were synthesized by alkylation and reduction of cyclic amidines.In vitro assays: IC50 values for L. infantum promastigote (MHOM/MA/67/ITMAP-263) weredetermined by the resazurin-based fluorescence assay. IC50 values for intracellular amastigoteswere determined by Giemsa staining and microscopic counting. Miltefosine was used as apositive control. Cytotoxicity on human HepG2 hepatocytes was measured by MTS assay.Computational methods: physicochemical parameters were calculated using Star Drop.The initial screening on L. infantum promastigotes showed antileishmanial activity for some derivatives in the low micromolar range (IC50= 3-13 µM). They were also active against the clinically relevant intramacrophage amastigotes (IC50=2-13 µM). These results meet the hit and lead criteria for VL (IC50<10 µM) [2].Compounds displayed moderate cytotoxicity on HepG2 (CC50> 10 µM). Bioactivity was not affected by polyamine chain length and, for spermidines 1, N-aryl substitution would play a key role. Calculated pharmacokinetic parameters complied with Lipinski?s rule of five (Log P, MW, H-bond donors/acceptors) and displayed high oral absorption and blood:brain barrier permeability.Conclusion: We present a series of novel N-arylspermidines with antileishmanial activity against L. infantum promastigotes and intramacrophage amastigotes. Their ADME properties in silico suggest the suitability of the compounds for further drug development.