Banca de QUALIFICAÇÃO: ANA CLAUDIA DE SOUZA PINTO

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : ANA CLAUDIA DE SOUZA PINTO
DATE: 15/02/2023
TIME: 09:00
LOCAL: Videoconferência
TITLE:

DETERMINATION OF ANTIPLASMODIAL ACTIVITY OF SYNTHETIC COMPOUNDS AND OF NATURAL ORIGIN

KEY WORDS:

Malaria; Resistance; N-acylhydrazones; Marine Sponges.

PAGES: 222
BIG AREA: Ciências da Saúde
AREA: Farmácia
SUMMARY:

Malaria is an infectious, non-contagious disease caused by protozoa belonging to the genus Plasmodium. Among the five species of Plasmodium responsible for human malaria, P. falciparum is the most prevalent species in Africa, being responsible for the most severe cases of the disease. The need for new drugs is urgent, given the spread of parasite resistance to currently available antimalarials. Although the search for new antimalarials is challenging, natural products and synthetic compounds still remain significant strategies in drug development. N-acylhydrazones are hydrazonic derivatives, defined as privileged structures, since they exhibit biological activities for different therapeutic targets. In this work, the evaluation of the in vitro antiplasmodial and cytotoxic activity of 7 synthetic compounds belonging to the class of N-acylhydrazones (AH1 – AH7) was carried out. According to the ideal parameters for the development of new antimalarials, compounds AH1, AH2, AH4 and AH5 were active against Plasmodium falciparum strain resistant to chloroquine (W2), and the IC50 determined by the traditional test ranged from 0.07 to 2.15 µM. All compounds showed low cytotoxicity against the fibroblast lineage (ATCC® CCL-95.1™) (IC50 > 100 µM). However, among the in vitro results, compounds AH1, AH4 and AH5 showed the best IC50 values, (0.19 ± 0.10 µM); (0.09 ± 0.05 µM); (0.07 ± 0.07 µM), respectively, and high selectivity index (SI) > 100. In order to understand the possible mechanism of
action, the compounds were subjected to a reverse virtual screening process, using the Brazilian Malaria Molecular Targets Bank (BraMMT). From the energy values generated by the AutoDock Vina program, it was possible to verify that the AH1 compound did not present the lowest binding energy among the tested compounds. Compound AH5 showed the lowest binding energy values among the compounds tested for 23 targets and among the targets, compound AH5 obtained lower energy than the crystallographic ligand in only 12 of them, showing low selectivity. Compound AH4 showed the lowest binding energy values among the compounds tested for 4 targets, however the compound exhibited the lowest binding energy -9.7 kcal/mol,
compared to -8.3 kcal/mol of the crystallographic ligand for the target Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) (PDB: 3PHC). Compounds AH4 and AH5 were evaluated for their physicochemical properties, both compounds did not violate any of the parameters analyzed, being compatible with the prediction of good availability by the oral route. The second aspect of the work consisted in the evaluation
of natural products. Living organisms are recognized sources of potentially bioactive molecules. The present study evaluated the in vitro antiplasmodial and cytotoxicity of 26 extracts from nine marine sponges collected in Salvador, Bahia, Brazil. All extracts tested were potently active against the chloroquine-resistant Plasmodium falciparum strain (W2) with IC50 values ranging from 0.28 to 22.34 μg/mL and did not demonstrate cytotoxicity against the fibroblast cell line (ATCC® CCL- 95.1™) (IC50 > 89 µg/mL). Thus, both alternatives showed potential candidates for the development of new antimalarials.

BANKING MEMBERS:
Externo à Instituição - BRUNO ANTÔNIO MARINHO SANCHEZ - UFMT
Externa à Instituição - KÉZIA KATIANI GORZA SCOPEL - UFJF
Presidente - 1084423 - RAFAEL GONCALVES TEIXEIRA NETO