Marine guanidine derivatives affect the redox biology of Leishmania infantum and downregulate cytokines of macrophages

Marine guanidine compounds have been shown promising antimicrobial and antiparasitic activities [1,2]. Considering the need for novel drugs for neglected protozoan diseases as Visceral Leishmaniasis, we evaluated the in vitro antileishmanial activity of a series of fifteen synthetic guanidines and investigated the lethal action and the immunomodulatory potential of two most selective compounds. Six synthetic guanidines displayed selective antiparasitic activity against Leishmania (L.) infantum intracellular amastigotes, with IC₅₀ values in the range between 2.2 µM and 18.8 µM. The mammalian cytotoxicity demonstrated CC₅₀ values in the range between 42.2 µM and > 150 µM. The lethal action studies demonstrated that two synthetic guanidines induced alteration of reactive oxygen species (ROS) levels in Leishmania parasites, resulting in the depolarization of mitochondrial membrane potential. The immunomodulatory assays using flow cytometry, suggested a NO-independent effect on macrophages. An anti-inflammatory effect was observed in Leishmania-infected macrophages co-cultived with lymphocytes, reducing the production of the cytokines MCP-1 and INF-_γ without modulation of TNF, IL-6 and IL-10. By affecting the redox balance of Leishmania and attenuating the cellular immune response of macrophages, the two synthetic guanidines selectively eliminated parasites and may be explored as hit compounds for VL.

Acknowledgement: FAPESP 2013/50228 – 8

References:

[1] Hua HM, Peng J, Fronczek FR, Kelly M, Hamann MT. Crystallographic and NMR studies of antiinfective tricyclic guanidine alkaloids from the sponge Monanchora unguifera. Bioorg Med Chem 2004; 12: 6461 – 6464

[2] Ebada SS, Proksch P. Chemical and pharmacological significance of natural guanidines from marine invertebrates. Mini Rev Med Chem 2011; 11: 225 – 246