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

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Martins, Ligia F. ; Mesquita, Juliana T. ; Pinto, Erika G. ; Costa-Silva, Thais A. ; Borborema, Samanta E. T. ; Galisteo Junior, Andres J. ; Neves, Bruno J. ; Andrade, Carolina H. ; Al Shuhaib, Zainab ; Bennett, Elliot L. ; Black, Gregory P. ; Harper, Philip M. ; Evans, Daniel M. ; Fituri, Hisham S. ; Leyland, John P. ; Martin, Claire ; Roberts, Terence D. ; Thornhill, Andrew J. ; Vale, Stephen A. ; Howard-Jones, Andrew ; Thomas, Dafydd A. ; Williams, Harri L. ; Overman, Larry E. ; Berlinck, Roberto G. S. ; Murphy, Patrick J. ; Tempone, Andre G.

• Document type: Journal article
• Source: Journal of Natural Products; v. 79, n. 9, p. 2202-2210, SEP 2016.
• Web of Science Citations: 15

Abstract

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-gamma. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism. (AU)

• FAPESP's process: 11/23703-1 - Study of the therapeutic potential of drugs and synthetic compounds, free or loaded into nanoliposomes: in vitro and experimental approach
• Grantee: Érika Gracielle Pinto
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/07275-5 - In vitro study of cellular immune response against synthetic drugs with antileishmanial activities
• Grantee: Thaís Alves da Costa Silva
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/50228-8 - Biodiversity components, and its metabolic characters, of Brazilian Islands
• Grantee: Roberto Gomes de Souza Berlinck
• Support type: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 12/18756-1 - Evaluation of novel alternative therapies with synthetic drugs using in vitro and experimental models of Leishmania (L.) infantum chagasi
• Grantee: André Gustavo Tempone Cardoso
• Support type: Regular Research Grants