In Vitro Susceptibility of Kinetoplastids to Celastroloids from Maytenus chiapensis

Abstract

Leishmaniasis and Chagas are among the most significant neglected tropical diseases. Due to several drawbacks with the current chemotherapy, developing new antikinetoplastid drugs has become an urgent issue. In the present work, a bioassay-guided investigation of the root bark of Maytenus chiapensis on Leishmania amazonensis and Trypanosoma cruzi led to the identification of two D:A-friedo-nor-oleanane triterpenoids (celastroloids), 20β-hydroxy-tingenone (celastroloid 5) and 3-O-methyl-6-oxo-tingenol (celastroloid 8), as promising antikinetoplastid leads. They displayed higher potency on L. amazonensis promastigotes (50% inhibitory concentrations [IC₅₀s], 0.44 and 1.12 μM, respectively), intracellular amastigotes (IC₅₀s, 0.83 and 1.91 μM, respectively), and T. cruzi epimastigote stage (IC₅₀s, 2.61 and 3.41 μM, respectively) than reference drugs miltefosine and benznidazole. This potency was coupled with an excellent selectivity index on murine macrophages. Mechanism of action studies, including mitochondrial membrane potential (Δψm) and ATP-level analysis, revealed that celastroloids could induce apoptotic cell death in L. amazonensis triggered by the mitochondria. In addition, the structure-activity relationship is discussed. These findings strongly underline the potential of celastroloids as lead compounds to develop novel antikinetoplastid drugs.

Keywords: Chagas disease; bioactive natural products; leishmaniasis.

FIG 1

Flowchart of antikinetoplastid-bioguided fractionation of Maytenus chiapensis root bark.

FIG 2

Chemical structures of celastroloids 1 to 10 isolated from M. chiapensis roots through bioguided fractionation.

FIG 3

(A) Changes in the mitochondrial membrane potential (ΔΨm) of Leishmania amazonensis promastigotes after 24 h of incubation with the IC₉₀ of the celastroloids. (B) ATP levels in relative luminescence units (RLU) of promastigotes after 24 h of incubation with the IC₉₀ of the celastroloids. Error bars represent the standard deviations (SD). C−, negative control.