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

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 investigate...

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Published in:	Journal of natural products (Washington, D.C.) Vol. 79; no. 9; pp. 2202 - 2210
Main Authors:	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, Shuhaib, Zainab Al, 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
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society and American Society of Pharmacognosy 23-09-2016
Subjects:	Alkaloids - pharmacology Animals Guanidines - chemical synthesis Guanidines - chemistry Guanidines - pharmacology Leishmania infantum - drug effects Marine Biology Molecular Structure Nitric Oxide - metabolism Porifera - chemistry Trypanosoma cruzi - drug effects
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0163-3864 1520-6025
DOI:	10.1021/acs.jnatprod.6b00256