| Full text | |
| Author(s): |
da Costa-Silva, Thais A.
[1]
;
Silva, Matheus L.
[1]
;
Antar, Guilherme M.
[2]
;
Tempone, Andre G.
[3]
;
Lago, Joao Henrique G.
[1]
Total Authors: 5
|
| Affiliation: | [1] Univ Fed ABC, Ctr Ciencias Nat & Humanas, BR-09210180 Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Biosci, Dept Bot, BR-05508090 Sao Paulo - Brazil
[3] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246902 Sao Paulo - Brazil
Total Affiliations: 3
|
| Document type: | Journal article |
| Source: | Phytomedicine; v. 93, DEC 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
Background: In the present work the bioactivity-guided fractionation of n-hexane extract from aerial parts of Baccharis sphenophylla (Asteraceae) against trypomastigote forms of Trypanosoma cruzi was performed. Purpose: To evaluate the antitrypanosomal potential of diterpenes ent-kaurenoic (1), grandifloric (2). and 15 beta-tiglinoyloxy-ent-kaurenoic (3) acids, isolated from n-hexane extract from aerial parts of B. sphenophylla, and elucidate their mechanism of action against T. cruzi. Methods/Study Design: n-Hexane and MeOH extracts from aerial parts of B. sphenophylla were prepared and caused, respectively, 100% and 50% of death of trypomastigote forms of T. cruzi. Based on these results, the n-hexane extract was subjected to bioactivity-guided fractionation procedures to afford three related ent-kaurane diterpenoids (1-3). Based on spectrofluorometric assays and flow cytometry analysis, the mechanism of action of compounds 1 and 3 was investigated. Results: Compounds 1 and 3, isolated from n-hexane extract from aerial parts of B. sphenophylla, showed potent activity against parasites with EC50 values of 10.6 mu M (SI > 18.8) and 2.4 mu M (SI = 34.8), respectively. On the other hand, compound 2 was inactive against trypomastigotes. In mechanism of action studies using the fluorescent probe SYTOX Green, the plasma membrane permeability was unaltered after treatment with compounds 1 and 3, but compound 1 induced a depolarization of the plasma membrane electric potential (Delta psi p). No substantial alterations were observed in the mitochondria after treatment with compound 3, but a transient hyperpolarization of the mitochondrial membrane potential (Delta psi m) by compound 1. Despite the increased ATP levels induced by compounds 1 and 3, no alterations of ROS and Ca2+ levels were registered. However, both compounds promoted a time-dependent alkalinization of the acidocalcisomes, probably contributing to an osmotic imbalance of the cell. In silico physicochemical studies of compounds 1-3 suggested that lipophilicity and molecular complexity may play an important role in the antitrypanosomal activity. Moreover, no pan-assay interference compounds (PAINS) alerts were detected for compounds 1-3. Conclusion: Obtained data indicated that the isolated ent-kaurane diterpenes from n-hexane extract from aerial parts of B. sphenophylla, especially compound 3, could be considered interesting prototypes for further modifications aiming the discovery of new hits against T. cruzi. (AU) | |
| FAPESP's process: | 21/04464-8 - Microbial and plant prototypes as drug candidates for protozoan neglected diseases and multidrug-resistant bacteria |
| Grantee: | André Gustavo Tempone Cardoso |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 21/02789-7 - Search for bioactive metabolites with antiparasitic action in plant species from Atlantic Forest and Cerrado regions - a chemical, phenotypical, and metabolomic approach |
| Grantee: | João Henrique Ghilardi Lago |
| Support Opportunities: | BIOTA-FAPESP Program - Regular Research Grants |