Investigation of antimalarial activity, cytotoxicity and action mechanism of piperazine derivatives of betulinic acid.
Trop Med Int Health
; 20(1): 29-39, 2015 Jan.
Article
en En
| MEDLINE
| ID: mdl-25308185
ABSTRACT
OBJECTIVES:
To semisynthesise piperazine derivatives of betulinic acid to evaluate antimalarial activity, cytotoxicity and action mechanism.METHODS:
The new derivatives were evaluated against the CQ-sensitive Plasmodium falciparum 3D7 strain by flow cytometry (FC) using YOYO-1 as stain. Cytotoxicity of 4a and 4b was performed with HEK293T cells for 24 and 48 h by MTT assay. The capability of compound 4a to modulate Ca(2+) in the trophozoite stage was investigated. The trophozoites were stained with Fluo4-AM and analysed by spectrofluorimetry. Effect on mitochondrial membrane potential (ΔΨm) was tested for 4a by FC with DiOC6 (3) as stain. For ß-haematin assay, 4a was incubated for 24 h with reagents such as haemin, and the fluorescence was measured by FlexStation at an absorbance of 405 nm.RESULTS:
Antimalarial activity of 4a and 4b was IC50 = 1 and 4 µm, respectively. Compound 4a displayed cytotoxicity with IC50 = 69 and 29 µm for 24 and 48 h, respectively, and 4b was not cytotoxic at the tested concentrations. Addition of 4a leads to an increase in cytosolic Ca(2+) . We have measured ΔΨm after treating parasites with the compound. Data on Figure 4a show that mitochondria were not affected. The action mechanism for 4a, inhibition of ß-haematin formation (17%), was lower than CQ treatment (83%; IC50 = 3 mm).CONCLUSION:
Compound 4a showed excellent antimalarial activity, and its action mechanism is involved in Ca(2+) pathway(s).Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Plasmodium falciparum
/
Triterpenos
/
Antimaláricos
Límite:
Humans
Idioma:
En
Revista:
Trop Med Int Health
Asunto de la revista:
MEDICINA TROPICAL
/
SAUDE PUBLICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Brasil