Banca de DEFESA: LEANDRO DO NASCIMENTO MARTINEZ

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : LEANDRO DO NASCIMENTO MARTINEZ
DATE: 17/06/2025
TIME: 08:00
LOCAL: Sala Virtual Remota https://bit.ly/DefDoc_LeandroMartinez_PGBIOEXP
TITLE:

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KEY WORDS:

bi-triazoles, antimalarial, Plasmodium falciparum, Plasmodium vivax.

PAGES: 128
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

Despite advances in the field of malaria chemotherapy, this disease continues to claim the lives of thousands of people every year. Given this issue, the search for new antimalarial compounds becomes essential, as reports of resistance threaten and jeopardize the current therapeutic arsenal available for treating this condition. From this perspective, the bi-triazole compounds 7RJ and 10RJ (the focus of this study) are diversified chemical classes that, in previous studies, have already shown promising results in inhibiting the asexual and sexual forms of Plasmodium falciparum, and may support the development of a new antimalarial compound. Therefore, the objective of this study is to evaluate the in vitro, ex vivo, and in vivo antimalarial activity of two bi-triazole compounds against the asexual and sexual forms of malaria parasite. Initially, the bi-triazole was analyzed using computational software -OSIRIS, Molinspiration, and ADMETlab - for the determination of physicochemical, toxicological, pharmacokinetic, and pharmacodynamic properties, respectively. Subsequently, a combination assay of the bi-triazole with a reference drug was conducted to evaluate the potential synergistic, additive, or antagonistic effect. In parallel, the antimalarial activity of bi-triazoles 7RJ and 10RJ was confirmed against circulating strains of P. falciparum and P. vivax through ex vivo schizont maturation assays using patient samples. Then, an ookinete inhibition assay was performed on samples from patients infected with P. vivax. Finally, the most active and selective compound, 10RJ, was tested in vivo murine models using Plasmodium berghei. From the results, in silico predictions of physicochemical properties revealed that all compounds met Lipinski's and Veber's rules and may have great potential in the development of a future orally bioavailable drug. The following values were obtained for compounds 7RJ and 10RJ, respectively: LogP (0.46 - -0.015), LogS (1.54 - 1.69), polar surface area (98.60 - 98.60), hydrogen bond acceptors (7 for both), hydrogen bond donors (1 for both), number of violations (0), number of rotatable bonds (5), and volume (201.81 - 201.81). Among the pharmacokinetic predictions, in most parameters, both compounds showed satisfactory results. The values were as follows, respectively: Caco-2 cell permeability (low), volume of distribution (low), elimination clearance (low), acute oral toxicity (204.33 mg/kg - 187.58 mg/kg), half-life (low), plasma protein binding (low), blood-brain barrier permeability (all values were positive), Pgp inhibitor (positive and negative), Pgp substrate (all values were negative), drug-induced liver injury (all values were positive), and maximum recommended daily dose (all values were positive). Regarding the pharmacodynamic prediction results, only compound 10RJ was active in enzyme inhibition, which may guide future studies on its potential protein target. For the in vitro drug combination results, analysis of the fractional inhibitory concentration values allowed for an additive classification of compound 10RJ. As for compound sensitivity against circulating strains, values were within the variation range, close to IC50 values (P. falciparum: 7RJ - 6.85 μM; 10RJ - 7.65 μM; P. vivax: 7RJ - 1.85 μM; 10RJ - 2.45 μM) obtained for the W2 strain of P. falciparum for both compounds. Finally, the P. vivax ookinete inhibition results showed inactivity for compound 7RJ in these forms and a promising activity ≥ 66% for compound 10RJ at the highest tested concentration of 10 μM. The in vivo evaluation results of compound 10RJ against P. berghei in murine models demonstrated that the compound was not active at the maximum tested concentration of 20 mg/kg after 4 days of treatment. Based on the results presented, it is possible to infer that compound 10RJ was the most promising regarding the development of a potential antimalarial, with action against both asexual and sexual forms of Plasmodium spp. However, it is worth noting that specific modifications to the molecule’s chemical structure may be necessary to increase its bioavailability, always respecting its toxicity threshold.

COMMITTEE MEMBERS:
Externo à Instituição - ROBERTO RUDGE DE MORAES BARROS - UNIFESP
Presidente - ***.429.088-** - CAROLINA BIONI GARCIA TELES - FIOCRUZ
Externa à Instituição - GEISA PAULINO CAPRINI EVARISTO - FIOCRUZ
Externo à Instituição - PAULO RENATO RIVAS TOTINO
Externa à Instituição - SARAH EL CHAMY MALUF - USP