2'-Hydroxyflavanone activity in vitro and in vivo against wild-type and antimony-resistant Leishmania amazonensis

Abstract

Background

To overcome the current problems in leishmaniasis chemotherapy, natural products have become an interesting alternative over the past few decades. Flavonoids have been studied as promising family of compounds for leishmaniasis treatment. 2’-Hydroxyflavanone (2HF) is a flavanone, a class of flavonoid that has shown promising results in cancer studies. In this study, we demonstrated the effects of 2HF in vitro and in vivo against wild-type and antimony-resistant Leishmania amazonensis promastigotes.

Methodology/Principal findings

2HF was effective against promastigotes and the intracellular amastigote form, decreasing the infection index in macrophages infected with wild-type and antimony-resistant promastigotes, but it was not toxic to macrophages. In silico analysis indicated 2HF as a good oral candidate for leishmaniasis treatment. In vivo, 2HF was able to reduce the lesion size and parasite load in a murine model of cutaneous leishmaniasis using wild-type and antimony-resistant promastigotes, demonstrating no cross-resistance with antimonials.

Conclusions/Significance

Taken together, these results suggest 2HF as a potential candidate for leishmaniasis chemotherapy for cutaneous leishmaniasis caused by both wild-type and antimony-resistant Leishmania species by oral administration. Furthermore, studies should be conducted to determine the ideal dose and therapeutic regimen.

Author summary

Leishmaniasis is a parasitic disease endemic to 98 countries, affecting more than 12 million people globally, and there are more than 350 million people in risk areas. Although there are many drugs available as alternatives for leishmaniasis treatment, they remain mostly ineffective, expensive and longstanding, in addition to generating side effects and resistance. Antimonial resistance is currently one of the biggest obstacles in leishmaniasis chemotherapy. Due to the poor chemotherapy scenario and the need for a drug able to overcome resistance problems and therapeutic failures, natural products have become an important alternative for leishmaniasis treatment. Here, we evaluated the antileishmanicidal activity of 2HF in vitro and in vivo against wild-type and antimony-resistant L. amazonensis cells. 2HF inhibited the cellular proliferation of promastigotes and the intracellular amastigote form in a dose-dependent manner in both wild-type and antimony-resistant cells. Furthermore, 2HF reduced the lesion size and parasitic load in a murine model of cutaneous leishmaniasis using wild-type and antimony-resistant promastigotes without altering hematological parameters and serological toxicology markers. This is the first time that the activity of a flavonoid on the antimony-resistant L. amazonensis has been demonstrated in vitro and in vivo by the oral route.