Banca de QUALIFICAÇÃO: LEANDRO DO NASCIMENTO MARTINEZ

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : LEANDRO DO NASCIMENTO MARTINEZ
DATE: 08/05/2024
TIME: 08:30
LOCAL: Sala Virtual Remota https://bit.ly/QualDoc_LeandroMartinez_PGBIOEXP
TITLE:

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KEY WORDS:

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

PAGES: 101
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

Despite advances in malaria chemotherapy, this disease continues to claim the lives of thousands of people every year. In the face of this issue, the search for new antimalarial compounds becomes essential as reports of resistance threaten and jeopardize the currently available therapeutic arsenal for treating this pathology. In this perspective, the bi-triazole compounds 7RJ and 10RJ (targets of this study) represent diverse chemical classes that have previously shown promising results in inhibiting both the asexual and sexual forms of Plasmodium falciparum and could lead to 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 both the asexual and sexual forms of the malaria parasite. Initially, the bi-triazole was analyzed using computational software including OSIRIS, Molinspiration, and ADMETlab to determine its physicochemical, toxicological, pharmacokinetic, and pharmacodynamic properties, respectively. Subsequently, a combination assay of the bi-triazole with a reference drug was conducted to evaluate potential synergistic, additive, or antagonistic effects. Concurrently, the antimalarial activity of bi-triazole 7RJ and 10RJ was confirmed in circulating strains of P. falciparum and P. vivax through ex vivo assays of schizont maturation in patient samples, followed by an assay of oocyst inhibition in patients affected by P. vivax. Regarding the results, in silico predictions for physicochemical properties revealed that all compounds met Lipinski and Veber rules and could have great potential in developing a potential orally bioavailable drug. The following values were obtained for compounds 7RJ and 10RJ, respectively: LogP (value: 0.46 – -0.015), LogS (value: 1.54 – 1.69), polar surface area (value: 98.60 – 98.60), hydrogen bond acceptors (value: 7 for both), hydrogen bond donors (value: 1 for both), number of violations (value: 0), number of rotatable bonds (value: 5), and volume (value: 201.81 – 201.81). Among pharmacokinetic predictions, almost all compounds showed satisfactory results for the evaluated parameters; the values were as follows, respectively: Caco-2 cell permeability (low), volume of distribution (low), elimination clearance (low), acute oral toxicity (value: 204.33 mg/kg - 187.58 mg/kg), half-life (low), plasma protein binding (low), blood-brain barrier (all values were positive), Pgp inhibitor (value: 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). For pharmacodynamic prediction results, only compound 10RJ showed activity in enzyme inhibition, which may guide future studies regarding its potential protein target. In the in vitro compound combination result analysis, it was possible to assign an additive value to compound 10RJ based on the fractional inhibitory concentration values. Concerning compound sensitivity to circulating strains, the values remained within the range, closely approaching the IC50 values obtained for the W2 strain of P. falciparum for both compounds in this study. Finally, the result for P. vivax oocyst inhibition evidenced the inactivity of compound 7RJ in these forms and a promising activity ≥ 66% for compound 10RJ at the highest tested concentration. It is expected that by the end of the study, the bioactivity data of bi-triazole 7RJ and 10RJ will confirm their viability as potential compounds with antiplasmodial activity at multiple parasite stages. Lastly, this study will conclude with the in vivo evaluation of the compound against P. berghei in murine models.

COMMITTEE MEMBERS:
Externo à Instituição - DANIEL YOUSSEF BARGIERI - USP
Presidente - 1786399 - DHELIO BATISTA PEREIRA
Externa à Instituição - GEISA PAULINO CAPRINI EVARISTO - FIOCRUZ