Abstract
Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.
Highlights
1.3 million people contract the disease annually; 300,000 cases correspond to visceral leishmaniasis (VL) and 1,000,000 to tegumentary leishmaniasis (TL)
We evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis [L. (L.) amazonensis], isolated from patients with therapeutic failure
Due to their efficacy and selectivity against intracellular parasites and the mechanisms underlying their leishmanicidal effect, some of these compounds could be used as tools for designing new chemotherapies against leishmaniasis
Summary
Leishmaniasis is endemic in 98 countries, in which 14 million people remain infected and more than 350 million are at risk [1,2]. 1.3 million people contract the disease annually; 300,000 cases correspond to visceral leishmaniasis (VL) and 1,000,000 to tegumentary leishmaniasis (TL). The estimated number of deaths from VL ranges between. 20,000 and 50,000 each year [3]. These numbers reflect the tip of the iceberg, since only 40 countries where the disease is endemic regularly report their health statistics to the
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