O estudo químico das raízes de Tephrosia toxicaria levou ao isolamento de três flavonoides: a flavanona obovatina e os rotenoides deguelina e 12a-hidroxi-α- toxicarol. O estudo químico das folhas de Stemodia maritima Linn., conduziu à obtenção de quatro diterpenos, sendo dois destes glicosilados: estemodina, estemodinol, estemodina-α-L-arabinopiranosídeo e estemodina-α-L-arabinofuranosídeo. O composto estemodinol foi obtido pela primeira como produto natural.
Os compostos isolados foram condizentes com relatos da literatura para ambos os gêneros Tephrosia e Stemodia, cujo perfil quimiotaxonômico indica a presença de flavonoides e diterpenos estemodanos, respectivamente.
O extrato das raízes de T. toxicaria e os flavonoides isolados demostraram ação anti-inflamatória e antinociceptiva em modelo experimental de indução de inflamação por zymosan. TTRE (0,2; 2,0; 20,0 mg/Kg), obovatina (1,0; 10,0 mg/Kg), deguelina (1,0 mg/Kg) e 12a-hidroxi-α-toxicarol (10,0 mg/Kg) aumentaram o limiar nociceptivo, semelhante ao grupo controle positivo, tratado com Indometacina. O tratamento com o extrato e os flavonoides reduziu significativamente a contagem de leucócitos, parâmetro diretamente ligado ao processo inflamatório. O tratamento com T. toxicaria foi tão eficaz quanto ao grupo tratado com Indometacina.
Também foram observados efeitos anti-inflamatórios e antinociceptivos no extrato das folhas de S. maritima (0,01 mg/Kg) e estemodina (0,01 mg/Kg). Estas dosagens reduziram de forma significativa a resposta nociceptiva induzida por formalina, em modelo experimental de inflamação na ATM.
O extrato das raízes de T. toxicaria e os flavonoides isolados foram submetidos a testes de atividade antibacteriana. Verificando-se que as amostras apresentaram atividade inibitória para linhagens gram-positivas e gram-negativas, com os melhores resultados encontrados para deguelina, com concentração inibitória mínima de 64 μ/mL frente a P. aeruginosa e 12a-hidroxi-α-toxicarol (256 μ/mL) frente a S. aureus.
Com o extrato das folhas de S. maritima, foram realizados diferentes modelos in vivo para testes de atividades ansiolítica e antidepressiva, revelando que
S. maritima apresenta atividade no sistema nervoso central, exibindo atividade antidepressiva similar ao antidepressivo imipramina.
O composto estemodina, encontrado como o diterpeno majoritário na espécie, foi submetido a reações de biotransformação com fungos endofíticos do gênero Lasiodiplodia. Foi possível avaliar o potencial biocatalítico de quartorze culturas, onde todas estas, mostraram-se capazes de bioconverter o substrato em derivados mais polares. A biotransformação de estemodina foi realizada em escala preparativa com o fungo Lasiodiplodia pontae, uma vez que não foram encontrados relatos na literatura de estudos com este fungo. A incubação de estemodina levou, portanto, a obtenção de dois derivados hidroxilados, 7β-hidroxiestemodina e 18-hidroxiestemodina. A utilização de L. pontae como biocatalisador é relatada pela primeira vez nesse trabalho.
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Tephrosia toxicaria TTRE (TT-1) Obovatina Testes de atividades anti-inflamatória, antinociceptiva e antibacteriana (TT-2) Deguelina Testes de atividades anti-inflamatória, antinociceptiva e antibacteriana (TT-3) 12a-hidroxi-α-toxicarol Testes de atividades anti-inflamatória, antinociceptiva e antibacteriana Testes de atividades anti-inflamatória, antinociceptiva e antibacteriana
Stemodia maritima SMFE (SM-1) Estemodina Estemodinol(SM-2) (SM-3) Estemodina-α-L- arabinopiranosídeo Testes de atividades anti-inflamatória antinociceptiva, ansiolítica e antidepressiva (SM-4) Estemodina-α-L- arabinofuranosídeo (BS-1) 7β-hidroxiestemodina (BS-2) 18-hidroxiestemodina Biotransformação com Lasiodiplodia pontae Testes de atividades anti-inflamatória e antinociceptiva
CHEMISTRY”, RESULTADOS FORAM APRESENTADOS NO ITEM 6.3, P. 145
Chemical Compounds and Antibacterial Activity of Tephrosia toxicaria
Pers.
ANGELA MARTHA CAMPOS ARRIAGA1*, FRANCISCA RENATA LOPES DA SILVA1, MARIA VALDELINE SOUSA TEXEIRA1, ITALO GOMES PEREIRA1, MARCOS
REINALDO DA SILVA1, JAIR MAFEZOLI1, GILVANDETE MARIA PEREIRA SANTIAGO1, JACKSON NUNES E VASCONCELOS2, RAIMUNDO BRAZ-FILHO3, JOSÉ GALBERTO MARTINS DA COSTA4 and FABIOLA FERNANDES GALVÃO RODRIGUES4
1 Departamento de Química Orgânica e Inorgânica, Centro de Ciências, Universidade Federal
do Ceará, CP 12.200, 60021-940, Fortaleza-CE, Brazil.
2 Instituto Federal de Educação, Ciência e Tecnologia do Ceará, Campus Tiangua, Rodovia
CE 187 sn, Aeroporto, 62320-000, Tiangua-CE, Brazil.
3 Laboratório de Ciências Químicas, Universidade Estadual do Norte Fluminense Darcy
Ribeiro, 28013-602, Campos dos Goytacazes-RJ, Brazil.
4 Universidade Regional do Cariri, Laboratório de Pesquisas de Produtos Naturais, Rua Cel.
Antônio Luís 1161, 63105-000, Crato-CE, Brazil.
*Corresponding author E-mail: [email protected]
ABSTRACT
Eight known compounds were isolated from the shrub Tephrosia toxicaria. Among them, 6,7- dimethoxy-chromone (1), was described by the first time for this genus,
villosinol (2), which had been previously reported without its 13C-NMR data and sumatrol (3), which has its 13C-NMR data corrected. The antibacterial activity of Tephrosia toxicaria extract and obovatin (6), deguelin (7), 12a-hydroxy-α-toxicarol (8), 12a-hydroxy-rotenone (10), and tephrosin (11) is also described.
Tephrosia toxicaria Pers. (Fabaceae), also referred as T. sinapou (Buc´hoz), is a shrub popularly known as “timbó de caiena” in Ceará state (Northeast of Brazil) where it is used as pesticide and fishing poison1-2. The phytochemical studies of Tephrosia genus revealed compounds with anticinoceptive, larvicidal and antiinflammatory activities3,4. Previous investigations of T. toxicaria led to the identification of flavonoids, mainly rotenoids1-2,5-7. In this paper, we report the isolation of eight known compounds, including the chromone, 6,7- dimethoxy-chromone, 1 described for the first time for this genus, the flavonoid, villosinol, 2 which has been previously reported without its
13C-NMR data and sumatrol, 3 which has its 13C-NMR data corrected. In addition, as a
support of use of alternative source in the treatment of bacterial infections, we describe the antibacterial activity of ethanolic extract from its roots and of some its compounds.
MATERIAL AND METHODS Plant material
Pods and roots of T. toxicaria Pers. was collected during the flowering stage in Guaraciaba do Norte (Ceará state, Brazil). A voucher specimen (#32139) has been deposited at the
Herbarium Prisco Bezerra from the Universidade Federal do Ceará -Brazil. Methods
Melting points were determined using Microquímica apparatus, model MQAPF, a heating rate 3ºC/min. The 1H-NMR, 13C-NMR and 2D NMR of the compounds were run on Bruker NMR machine at 500 MHz and 125 MHz repectively. The solvent used were CDCl3 deuteriated.
A portion of the air-dried and powdered pods (180.0 g) were extracted with 95% EtOH at room temperature and provided the corresponding organic extract TTVE (26.0 g). An aliquot (8.7g) of TTVE was subjected to silica gel column chromatography (Merck 60-120 60 Mesh) using hexane, CH2Cl2 and EtOAc as solvents. The fraction eluted with CH2Cl2 (69.0 mg) was
further rechromatographed over a silica gel column chromatography and yielded 6.7 mg of 6a,12a-desydro-α-toxicarol8, 4. The fraction eluted with EtOAc (800.0 mg) was purified by
temperature. The solvent was removed by rotatory evaporation yielding TTRE (14.2 g). This extract was submitted to extraction with EtOAc and the organic fraction (1.5g) was
chromatographed over silica gel with gradient mixture of hexane/CH2Cl2. Fractions eluted
with hexane/CH2Cl2 (1:1) yielded 13.2 mg of obovatin10, 6, and the fractions eluted with
CH2Cl2 furnished 9.9 mg of deguelin8, 7. Another portion of roots (649.0 g) from T. toxicaria
was extracted in a Soxhlet system with water. After liophilization, the material (5.4 g) was extracted with ethyl acetate and yielded 2.1 g of organic fraction. This material was submitted to exclusion chromatography on Sephadex(TM) LH-20 (Amersham Biosciences, Sweden) by elution with a mixture of EtOAc:MeOH (1:1). The fractions obtained were combined
according to TLC to give four main fractions I-IV. Fraction II (819.5 mg) was submitted to HPLC on reversed-phase RP-18 (solvent MeOH/formic acid 0.1% 4:1) and provided pure compounds villosinol11 (2, 5.0 mg), 12a-hydroxy-α-toxicarol8 (8,
32.8 mg), sumatrol12 (3, 3.6 mg), α–toxicarol8 (9, 13.0 mg), 12a-hydroxyrotenone13 (10, 27.8 mg), tephrosin14 (11, 62.0 mg), and 6,7-dimethoxy-chromone15 (1, 2.0 mg).
Antibacterial activity Microorganisms
The following strains used in this study were provided by the Oswaldo Cruz Foundation – FIOCRUZ: K. pneumoniae ATCC 10031; P. aeruginosa ATCC 15442; S. mutans ATCC 0046; S. aureus ATCC 6538. Strains isolated from clinical material of Escherichia coli Ec 27 and Staphylococcus aureus Sa 358 were also used. The bacteria were activated in Brain Heart Infusion medium (BHI, Himedia laboratories PVT. LTD., Mumbai, INDIA) for 24 h at 35 °