In Vivo Biological Evaluation of a Synthetic Royleanone Derivative as a Promising Fast-Acting Trypanocidal Agent by Inducing Mitochondrial-Dependent Necrosis
| Autor: | Juan J. Guardia, Manuel Sánchez-Moreno, Rubén Martín-Escolano, Javier Martín-Escolano, Antonio Fernandez, Clotilde Marín, Rachid Chahboun, Nuria Cirauqui, Enrique Alvarez-Manzaneda, María José Rosales |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Drug
Chagas disease media_common.quotation_subject Pharmaceutical Science Pharmacology Biology Analytical Chemistry chemistry.chemical_compound Mice Necrosis In vivo Drug Discovery medicine Animals Humans Trypanosoma cruzi media_common Abietane Trypanocidal agent Organic Chemistry biology.organism_classification medicine.disease Trypanocidal Agents Mitochondria Complementary and alternative medicine chemistry Benznidazole Abietanes Neglected tropical diseases Molecular Medicine medicine.drug |
| Zdroj: | Journal of natural products. 83(12) |
| ISSN: | 1520-6025 |
| Popis: | The life-long and life-threatening Chagas disease is one of the most neglected tropical diseases caused by the protozoan parasite Trypanosoma cruzi. It is a major public health problem in Latin America, as six to seven million people are infected, being the principal cause of mortality in many endemic regions. Moreover, Chagas disease has become widespread due to migrant populations. Additionally, there are no vaccines nor effective treatments to fight the disease because of its long-term nature and complex pathology. Therefore, these facts emphasize how crucial the international effort for the development of new treatments against Chagas disease is. Here, we present the in vitro and in vivo trypanocidal activity of some oxygenated abietane diterpenoids and related compounds. The 1,4-benzoquinone 15, not yet reported, was identified as a fast-acting trypanocidal drug with efficacy against different strains in vitro and higher activity and lower toxicity than benznidazole in both phases of murine Chagas disease. The mode of action was also evaluated, suggesting that quinone 15 kills T. cruzi by inducing mitochondrion-dependent necrosis through a bioenergetics collapse caused by a mitochondrial membrane depolarization and iron-containing superoxide dismutase inhibition. Therefore, the abietane 1,4-benzoquinone 15 can be considered as a new candidate molecule for the development of an appropriate and commercially accessible anti-Chagas drug. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|