Compostos fenólicos como abordagem terapêutica para leishmanioses tegumentar e visceral.

Abstract

Treatment of leishmaniasis presents high toxicity and cost, in addition to the emergence of parasite resistant strains and therapeutic failure. Therefore, the identification of new antileishmanial compounds is necessary, with natural products and their synthetic derivatives being a promising alternative. In the present study, antileishmanial activity of three phenolic compounds was evaluated for the first time. The initial molecule, CMt (5, 7, 3’, 4’- tetrahydroxy-6,8-diprenylisoflavone), obtained from Maclura tinctoria extracts was evaluated in vitro against promastigote and amastigote stages of Leishmania infantum and L. amazonensis. Results showed that this compound was more effective against parasites than murine macrophages and red blood cells, with significantly higher selectivity index than amphotericin B. Moreover, CMt was effective in treating infected macrophages and inhibiting infection using parasites pre-incubated with the molecule. The mechanism of action in L. infantum revealed disturbances in the parasite's mitochondria. Two additional molecules, synthetic derivatives from vanillin: [4-(2-hydroxy-3-(4-octyl-1H-1,2,3-triazol-1-yl)propoxy)- 3-methoxybenzaldehyde] or 3s and [4-(3-(4-decyl-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)- 3-methoxybenzaldehyde] or 3t, alongside CMt, were evaluated in BALB/c mice infected with L. infantum or L. amazonensis, either in pure form or incorporated into polymeric micelles. Micellar compositions induced a more significant reduction in parasite load in the distinct organs (L. infantum and L. amazonensis) and infected tissue (L. amazonensis) of treated animals. In addition, it triggered the development of a Th1-type cellular and humoral immune response, with higher levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite, and IgG2a antibodies. These phenolic compounds showed low renal and hepatic toxicity, and in L. amazonensis infection, they also decreased the average diameter of lesions in treated animals. The micellar compositions exhibited a better therapeutic response compared to free molecules and the drugs used as controls, including miltefosine in CMt assays, and amphotericin B and AmBisome® for 3s and 3t. Parasitological and immunological evaluations were conducted at one, 15, and/or 30 days post-treatment, with results indicating protection against reinfection. Therefore, results suggest CMt, 3s and 3t, especially incorporated into polymeric micelles, could be considered for future studies as therapeutic candidates against cutaneous and visceral leishmaniasis.