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Phytochemical study of Aristolochia cordigera and synthesis of lignans with antimalarial potential

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Author(s):
Marcos Donizete Peliçon Pereira
Total Authors: 1
Document type: Doctoral Thesis
Press: Araraquara. 2017-04-07.
Institution: Universidade Estadual Paulista (Unesp). Instituto de Química. Araraquara
Defense date:
Advisor: Lucia Maria Xavier Lopes
Abstract

This work describes a comparative study on the intraspecific chemical variability of Aristolochia cordigera species, collected in two different regions of Brazil, Biome Cerrado (semi-arid) and Biome Amazônia (coastal). The used of GC-MS and statistical methods led to identification of 56 compounds. Higher concentrations of palmitone and germacrene-D in the hexanes extracts of the leaves of plants from these respective biomes characterized the plant provenance. Moreover, phytochemical studies on the extracts led to the isolation and identification of 19 known compounds, including lignans, neolignans, aristolochic acids, indole-β-carboline and indole alkaloids. In addition, two new indole alkaloids, 3,4-dihydro-hyrtiosulawesine and 6-O-(β-glucopyranosyl)hyrtiosulawesine were isolated and cis-eupomatenoid-7, a new neolignan, was obtained in a mixture with its known isomer eupomatenoid-7. Their structures were determined by spectroscopic methods, mainly by 1D- and 2D-NMR and HRESIMS. The occurrence of indole alkaloids is being described for the first time in the Aristolochiaceae family. Moreover, the in vitro susceptibility of intracellular amastigotes and promastigotes forms of Leishmania amazonensis to the alkaloids and eupomatenoid-7 was evaluated. This neolignan exhibited low activity against promastigotes (IC50 = 46 µM) and toxicity against amastigotes at concentrations of 50 and 100 µM, while the alkaloids did not show inhibitory activity at the same experimental conditions. Several of the isolated alkaloids were also evaluated in vitro against Plasmodium falciparum. The alkaloid 6-O-(β-glucopyranosyl)hyrtiosulawesine exhibited activity, with IC50 value of 5 µM and selectivity index (SI) higher than 50. The lignan 8’-epi-aristoligone and its 36 analogous, with different substituents on the A and C rings, were obtained by synthesis. The lignan was also transformed into aryltetralols and aryltetralenes. The antiplasmodial activity of these derivatives were evaluated. The most active derivatives were 4’-bromo-4,5-dimethoxy-2,7’-cyclolignan-7-one and 3’,4’-dimethoxy-4,5-dimethyl-2,7’-cyclolignan-7-one, with IC50 = 1.3 ±0.8 µM and IC50 = 2.6 ±0.8 µM, respectively. Thus, the in vitro inhibitory activity evaluation against L. amazonensis and P. falciparum suggests that the isolated compounds from A. cordigera as well as the synthetic derivatives obtained may be investigated as novel molecular scaffolds for antiparasitic drug development. (AU)

FAPESP's process: 12/25405-0 - Phytochemistry studies of Aristolochia cordigera and syntheses of lignans with potential antimalarial activity
Grantee:Marcos Donizete Peliçon Pereira
Support type: Scholarships in Brazil - Doctorate