Leishmanicidal activity of betulin derivatives in leishmania amazonensis; effect on plasma and mitochondrial membrane potential, and macrophage nitric oxide and superoxide production

Wilmer Alcazar, Sami Alakurtti, Maritza Padrón-Nieves, Maija Liisa Tuononen, Noris Rodríguez, Jari Yli-Kauhaluoma (Corresponding Author), Alicia Ponte-Sucre (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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 com-pounds, 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.

Original languageEnglish
Article number320
Pages (from-to)1-18
Number of pages18
JournalMicroorganisms
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 2021
MoE publication typeA1 Journal article-refereed

Keywords

  • Betulin derivatives
  • Drug resistance
  • Leishmania
  • Mitochondrial membrane potential
  • Plasma membrane potential
  • Therapeutic failure

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