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BIBTEX RIS

Analogues of Marine Guanidine Alkaloids Are in Vitro Effective against Trypanosoma cruzi and Selectively Eliminate Leishmania ( L .) infantum Intracellular Amastigotes

2016; American Chemical Society; Volume: 79; Issue: 9 Linguagem: Inglês

10.1021/acs.jnatprod.6b00256

1520-6025

Ligia F. Martins, Juliana Tonini Mesquita, Érika G. Pinto, Thais A. Costa‐Silva, Samanta Etel Treiger Borborema, Andrés Jimenez Galisteo, Bruno J. Neves, Carolina Horta Andrade, Zainab Al Shuhaib, Elliot L. Bennett, Gregory P. Black, Philip M. Harper, Daniel M. Evans, Hisham S. Fituri, John P. Leyland, Claire Martin, Terence D. Roberts, Andrew J. Thornhill, Stephen A. Vale, Andrew Howard‐Jones, Dafydd A. Thomas, Harri Lloyd Williams, Larry E. Overman, Roberto G. S. Berlinck, P. J. Murphy, André G. Tempone,

Synthesis and Biological Evaluation

Synthetic analogues of marine sponge guanidine alkaloids showed in vitro antiparasitic activity against Leishmania (L.) infantum and Trypanosoma cruzi. Guanidines 10 and 11 presented the highest selectivity index when tested against Leishmania. The antiparasitic activity of 10 and 11 was investigated in host cells and in parasites. Both compounds induced depolarization of mitochondrial membrane potential, upregulation of reactive oxygen species levels, and increased plasma membrane permeability in Leishmania parasites. Immunomodulatory assays suggested an NO-independent effect of guanidines 10 and 11 on macrophages. The same compounds also promoted anti-inflammatory activity in L. (L.) infantum-infected macrophages cocultived with splenocytes, reducing the production of cytokines MCP-1 and IFN-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.