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Optimization of neolignans as pharmaceutical prototypes for visceral leishmaniasis: mechanism of action and pharmacokinetic studies

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Author(s):
Maiara Amaral de Oliveira
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Faculdade de Medicina (FM/SBD)
Defense date:
Examining board members:
André Gustavo Tempone Cardoso; Nilmar Sílvio Moretti; Maria Carolina Quartim Barbosa Elias Sabbaga
Advisor: André Gustavo Tempone Cardoso
Abstract

Visceral leishmaniasis is a neglected protozoan disease with high mortality, whose available treatments has several limitations, triggering a serious public health challenge. Given this scenario and due to the high biodiversity and chemiodiversity available, natural products represent an attractive source of new pharmaceutical prototypes. In this context, the present work studied the anti-L. (L.) infantum potential of a new series of 55 synthetic and 2 semi-synthetic compounds derived from the neolignan dehydrodieugenol B, isolated from the Brazilian plant Nectandra leucanta. Among them, 19 exhibited activity against intracellular amastigotes with IC50 values ranging from 3 to 36.6 M. The neolignan PP480 was the most promising one, showing the highest selectivity (>20) and being selected for further studies. Through in silico predictions, it was demonstrated that this derivative present adequate physicochemical properties and druglikeness profile, without structural similarities to interference compounds (PAINS). The evaluation of toxicity in erythrocyte indicated that even at the maximum concentrations tested, this compound does not induce hemolytic activity. Furthermore, using different approaches of spectrofluorimetry and flow cytometry, it was possible to investigate PP480 mechanism of action in promastigotes of L. (L.) infantum. In short, an activity based on acidocalcisomes alkalinization and concomitant calcium leakage was proposed. Associated, these alterations possibly induce a mitochondrial breakdown, with successive collapse of the bioenergetic chain, reduction of ATP and reactive oxygen species (ROS) levels. It was also verified by the analysis of total proteins and mass spectrometry (MALDI-TOF/MS), that this derivative interferes with the parasites protein profile. Therefore, it is possible to suggest that PP480 promotes an autophagic cell death. Additionally, an immunomodulatory action was observed in the host cells, with a reduction of Th1 and Th2 cytokines response, characterizing an anti-inflammatory activity. A study of the pharmacokinetic profile in vivo showed promising parameters of the compound in the organism, including a mean plasma half-life (T1/2) of 21h, thus recommending more detailed analyzes to define an appropriate dosage regimen. Overall, these studied emphasize the promising potential of dehydrodieugenol B as a prototype for the synthesis of new anti-Leishmania drugs and provide a starting point for future preclinical efficacy studies in vivo (AU)

FAPESP's process: 18/25128-3 - Optimization of natural scaffolds as new therapeutic candidates for Visceral Leishmaniasis
Grantee:Maiara Amaral de Oliveira
Support Opportunities: Scholarships in Brazil - Doctorate