Banca de DEFESA: WELINGTON DA SILVA PAULA DO NASCIMENTO

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : WELINGTON DA SILVA PAULA DO NASCIMENTO
DATE: 20/10/2023
TIME: 13:00
LOCAL: Sala Virtual Remota https://bit.ly/DefMSc_WelingtonNascimento_PGBIOEXP
TITLE:

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KEY WORDS:

bi-triazole, antimalarial, ookinete, ex vivo.

PAGES: 73
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

Malaria is a febrile disease caused by the protozoan Plasmodium spp., responsible for high rates of morbidity and mortality worldwide. The development of new antimalarial compounds is crucial to address the growing challenge of drug resistance. Based on this premise, triazole compounds, which feature two linked nitrogen-containing heterocyclic rings, known as bi-triazoles, are molecules with rapid production and various described activities in the literature. Recent antimalarial studies have demonstrated the significant potential of this chemical class. In this context, this study aimed to assess the antimalarial activity of the bi-triazole compound (4-(phenoxy methyl)-1-(5-trifluoromethyl)-4H-1,2,4-triazol-3-yl)1H-), in both asexual and sexual forms of circulating Plasmodium falciparum W2 and Plasmodium vivax. The tests began with the W2 strain of P. falciparum, assessing its toxicity in HepG2 and VERO cell lines and its toxicity to human erythrocytes. Additionally, the inhibitory potential in circulating isolates of P. falciparum and P. vivax was evaluated, the molecule's selectivity index (SI) in relation to the tested cells was determined, and the molecule's inhibitory potential in inhibiting P. vivax ookinete formation was assessed. The inhibitory concentration of 8RJ on W2 P. falciparum parasites was determined by the SYBR Green method, and cell cytotoxicity was observed through the MTT method. Ex vivo assays with Plasmodium spp. isolates obtained from patients were monitored by optical microscopy for up to 60 hours of incubation. SI results were calculated from the ratio of CC50 (50% cytotoxic concentration) and IC50 (50% inhibitory concentration). Ookinete formation inhibition was revealed by optical microscopy after 24 hours of incubation with ookinete medium. In silico analysis of the compound was performed using Molinspiration and Osiris software. The obtained results showed that the compound 8RJ had an IC50 value of 5.2 μM ± 2.5 considering the asexual forms of the W2 strain, without displaying toxicity for the tested hepatic and renal cells (CC50 ≥ 500 μM) in vitro. Furthermore, 8RJ showed no hemolytic effect. The compound proved to be selective against the protozoan (SI ≥ 10). The compound's action velocity data indicated its ability to inhibit protozoan growth within the first 8 hours. Inhibition results of circulating strains of P. vivax and P. falciparum showed a median IC50 of 5.2 μM and 6.35 μM, respectively, corroborating with those obtained in the W2 strain. However, it was not able to inhibit the growth of sexual forms of the parasite, inhibiting only 15.7% of parasites at 10 μM. In summary, the preliminary results of this study provided promising evidence of the antimalarial potential of the bi-triazole compound 8RJ. The compound exhibited activity against the asexual forms of the parasite in in vitro assays without cytotoxicity for the tested cells. Additionally, it showed inhibitory activity in the early hours of the parasitic cycle and was effective against circulating isolates. However, it did not demonstrate inhibitory activity against P. vivax ookinetes. In silico analysis indicated that the compound possibly lacks toxicity and will have good bioavailability. The obtained results are important for demonstrating the antimalarial potential of the bi-triazole group, enriching this study's target with new information.

COMMITTEE MEMBERS:
Presidente - ***.429.088-** - CAROLINA BIONI GARCIA TELES - FIOCRUZ
Externo à Instituição - PAULO RENATO RIVAS TOTINO
Externa à Instituição - SARAH EL CHAMY MALUF - USP