In vitro leishmanicidal activity of novel N-arylspermidine derivatives

MARÍA C. MOLLO; LEONARDO G. FERREIRA; NATALIA B. KILIMCILER; JUAN A. BISCEGLIA; ADRIANO D. ANDRICOPULO; LILIANA R. ORELLI

CABA

Congreso; Drug Discovery for Neglected Diseases International Congress 2018; 2018

DDNDI

In vitro leishmanicidal activity of novel N-arylspermidine derivatives Mollo MC1, Ferreira LG2, Kilimciler NB1, Bisceglia JA, Andricopulo AD, Orelli LR1. 1Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Orgánica, Argentina 2Universidad de São Paulo, Laboratorio de Química Medicinal y Computacional, Departamento de Física, Brasilmcmollo@ffyb.uba.arVisceral leishmaniasis (VL) is the second-largest parasitic killer disease in the world, responsible for near one million infections each year. Polyamines are ubiquitous organic molecules that play key roles in kinetoplastids metabolism. This makes them attractive for antiparasitic drug development, and several natural polyamine analogs have been synthesized and evaluated [1]. Most of the efforts were directed to symmetrically N1, N8-disubstituted spermidines, while N-aryl derivatives have been scarcely investigated. We present here an in vitro anti Leishmania infantum 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) were determined by the resazurin-based fluorescence assay. IC50 values for intracellular amastigotes were determined by Giemsa staining and microscopic counting. Miltefosine was used as a positive 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 anti-leishmanial 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). 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.