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-γ. Guanidines 10 and 11 affect the bioenergetic metabolism of Leishmania, with selective elimination of parasites via a host-independent mechanism.
Subject(s)
Guanidines/chemical synthesis , Leishmania infantum/drug effects , Porifera/chemistry , Trypanosoma cruzi/drug effects , Alkaloids/pharmacology , Animals , Guanidines/chemistry , Guanidines/pharmacology , Marine Biology , Molecular Structure , Nitric Oxide/metabolismABSTRACT
Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC50=490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC50 = 8.5-59 microM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC50 = 9.2 microM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.
