RT info:eu-repo/semantics/article
T1 Triazole-functionalized jatrophone derivatives as antiprotozoal agents against Trypanosoma cruzi : synthesis, biological evaluation and structure—activity relationships
A1 Pertino, Mariano Walter
A1 Carreño González, Patricio
A1 Venegas González, Camila
A1 Schmeda Hirschmann, Guillermo
A1 Vega Gómez, María Celeste
A1 Rolón, Miriam Soledad
A1 Rojas de Arias, Gladys Antonieta
AB Background/Objectives: Jatrophone is a bioactive diterpenoid with reported antitrypanosomal activity; however, its development as a lead compound is limited by pronounced cytotoxicity toward mammalian cells. This study aimed to explore the structural modification of jatrophone through triazole functionalization to modulate its antiparasitic activity and improve selectivity against Trypanosoma cruzi. Methods: A series of mono- and bis-triazole jatrophone derivatives was semi-synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) from a stereoselectively prepared diazido intermediate. Jatrophone, its azido precursor, and the synthesized triazole derivatives were evaluated in vitro against T. cruzi epimastigotes and intracellular amastigotes. Cytotoxicity toward mammalian host cells was assessed in parallel to determine selectivity indices. Results: Jatrophone exhibited potent activity against epimastigotes but showed poor selectivity due to significant mammalian cell toxicity. Introduction of azide and triazole functionalities altered the biological profile of the parent scaffold, leading to derivatives with reduced cytotoxicity and improved selectivity in extracellular assays. Among the evaluated compounds, a mono-triazole derivative bearing a methylene-linked cycloalkyl substituent retained antiparasitic activity while displaying markedly lower toxicity toward mammalian cells. However, in the intracellular amastigote model, most derivatives demonstrated a substantial reduction in selectivity, indicating limited translation of extracellular activity to the intracellular parasite stage. Conclusions: Triazole functionalization of the jatrophone scaffold represents a viable strategy to modulate its biological properties and reduce host-cell toxicity. Nevertheless, the reduced efficacy observed in intracellular assays underscores the limitations of epimastigote-based screening and highlights the challenges in developing selective intracellular antitrypanosomal agents from the jatrophone scaffold.
PB Multidisciplinary Digital Publishing Institute
YR 2026
FD 2026-05-21
LK http://hdl.handle.net/20.500.14066/4793
UL http://hdl.handle.net/20.500.14066/4793
LA eng
NO Pertino, M. W., Carreño Gonzalez, P., Venegas González, C., Schmeda-Hirschmann, G., Vega Gómez, C., Rolón, M., & Rojas de Arias, A. (2026). Triazole-Functionalized Jatrophone Derivatives as Antiprotozoal Agents Against Trypanosoma cruzi: Synthesis, Biological Evaluation and Structure—Activity Relationships. Pharmaceuticals, 19(5), 801. https://doi.org/10.3390/ph19050801
NO Correspondence: mwalter@utalca.cl; Tel.: +56-71-2418866.
NO This article belongs to the Section Medicinal Chemistry.
NO Consejo Nacional de Ciencia y Tecnología
DS MINDS@UW
RD 04-sep-2026