Banca de DEFESA: MINELLY AZEVEDO DA SILVA

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
DISCENTE : MINELLY AZEVEDO DA SILVA
DATA : 26/08/2021
HORA: 14:30
LOCAL: Programa de Pós-Graduação em Biologia Experimental
TÍTULO:

In silico investigations and in vitro activity of a natural amide and semisynthetic analogs against Leishmania (Viannia) braziliensis.

PALAVRAS-CHAVES:

Amides. Molecular docking. In vitro. In silico. Leishmania. Piperaceaes. Synthetic. Trypanothione reductase.

PÁGINAS: 90
GRANDE ÁREA: Ciências Biológicas
ÁREA: Parasitologia
RESUMO:

Leishmaniasis is considered a neglected disease, against which the therapeutic options are limited. The disease does not constitute an attractive market for the pharmaceutical industry. Thus, the efforts in the search for biologically active substances are hindered by this lack of interest. Within this context, the study aimed at assessing the cytotoxicity, the hemolytic, and the antileishmanial activity of the natural compound Piplartine (1a) and a series of five synthetic analogs (1b, 1g, 1k, 1m and 14f)  against Leishmania (V) braziliensis, a species that causes cutaneous leishmaniasis. The compounds with promising (ICA₅₀ ≤ 10 µM) antileishmanial activity were assessed for their action mechanism against promastigotes, as well as their enzyme-inhibition activity against Trypanothione reductase, responsible for the parasite’s redox balance. Among the evaluated compounds, Piplartine (1a) and 1m (synthetic derivative) were the most potente compounds against promastigote forms, with IC₅₀ values of 8.58 and 11.25 µM, respectively; for amastigotes, the ICA₅₀ values were 1.46 and 16.7 µM, respectively. The selectivity indexes (SI) estimated for 1a and 1m concerning the cytotoxicity data of THP-1 cells were 20.21 and 3.9, respectively. None of the compounds was hemolytic at the highest concentration (500 µM). 1b, 1g, and 1k were not found to present toxicity towards any of the cell lines here evaluated at the highest concentration (500 µM). On the other hand, 1m and 14f presented cytotoxicity for J774 (CC₅₀ = 89.5 and 18.5 µM, respectively) and THP-1 cell lines (THP-1 = CC₅₀ 65.2 and 251.6 µM, respectively). 1a was the less toxic compound against THP-1 cells. The structural modifications were observed to decrease both the cytotoxicity of the analogs (1b, 1g, 1k, 1m and 14f) and their antileishmanial activity. Results on the action mechanism investigations revealed that 1a increased reactive oxygen species (ROS) levels, and induced loss of cell membrane integrity and caused accumulation of lipid bodies after 24 h of incubation at its lowest inhibitory concentration (IC₅₀), which was not observed for 1m. Based on molecular docking and in vitro studies, we suggest that 1a (piplartine) may inhibit the Trypanothione reductase enzyme, decreasing the parasite’s defense against ROS, which would explain the activity of the compound against both the promastigote and amastigote forms.

MEMBROS DA BANCA:
Externo à Instituição - AMANDA FEITOSA CIDADE - IFRO
Presidente - 2148421 - CHRISTIAN COLLINS KUEHN
Interno - 457.646.382-91 - FERNANDO BERTON ZANCHI - UNIR
Externo à Instituição - GEISA PAULINO CAPRINI EVARISTO - FIOCRUZ
Externo à Instituição - IZALTINA SILVA JARDIM CAVALLI - USP