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1.
Phytother Res ; 31(4): 624-630, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28111828

ABSTRACT

Pilocarpus microphyllus Stapf ex Wardlew (Rutaceae), popularly known as jaborandi, is a plant native to the northern and northeastern macroregions of Brazil. Several alkaloids from this species have been isolated. There are few reports of antibacterial and anthelmintic activities for these compounds. In this work, we report the antibacterial and anthelmintic activity of five alkaloids found in P. microphyllus leaves, namely, pilosine, epiisopilosine, isopilosine, epiisopiloturine and macaubine. Of these, only anthelmintic activity of one of the compounds has been previously reported. Nuclear magnetic resonance, HPLC and mass spectrometry were combined and used to identify and confirm the structure of the five compounds. As regards the anthelmintic activity, the alkaloids were studied using in vitro assays to evaluate survival time and damaged teguments for Schistosoma mansoni adult worms. We found epiisopilosine to have anthelmintic activity at very low concentrations (3.125 µg mL-1 ); at this concentration, it prevented mating, oviposition, reducing motor activity and altered the tegument of these worms. In contrast, none of the alkaloids showed antibacterial activity. Additionally, alkaloids displayed no cytotoxic effect on vero cells. The potent anthelmintic activity of epiisopilosine indicates the potential of this natural compound as an antiparasitic agent. Copyright © 2017 John Wiley & Sons, Ltd.


Subject(s)
Alkaloids/chemistry , Anthelmintics/chemistry , Anti-Bacterial Agents/chemistry , Imidazoles/chemistry , Pilocarpus/chemistry , Plant Extracts/chemistry , Plant Leaves/chemistry , 4-Butyrolactone/analogs & derivatives , Animals , Imidazoles/pharmacology , Vero Cells
2.
Biomed Pharmacother ; 87: 188-195, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28056423

ABSTRACT

OBJECTIVE: This study aimed to investigate the protective effect of epiisopiloturine hydrochloride (EPI), an imidazole alkaloid, on NAP-induced gastrointestinal damage in rats. METHODS: Initially, rats were pretreated with 0.5% carboxymethylcellulose (vehicle) or EPI (3, 10 and 30mg/kg, p.o. or i.p., groups 3-5, respectively) twice daily, for 2days. After 1h, NAP (80mg/kg, p.o.) was given. The control group received only vehicle (group 1) or vehicle+naproxen (group 2). Rats were euthanized on 2nd day, 4h after NAP treatment. Stomachs lesions were measured. Samples were collected for histological evaluation and glutathione (GSH), malonyldialdehyde (MDA), myeloperoxidase (MPO), and cytokines levels. Moreover, gastric mucosal blood flow (GMBF) was evaluated. RESULTS: EPI pretreatment prevented NAP-induced macro and microscopic gastric damage with a maximal effect at 10mg/kg. Histological analysis revealed that EPI decreased scores of damage caused by NAP. EPI reduced MPO (3.4±0.3U/mg of gastric tissue) and inhibited changes in MDA (70.4±8.3mg/g of gastric tissue) and GSH (246.2±26.4mg/g of gastric tissue). NAP increased TNF-α levels, and this effect was reduced by EPI pretreatment. Furthermore, EPI increased GMBF by 15% compared with the control group. CONCLUSION: Our data show that EPI protects against NAP-induced gastric and intestinal damage by reducing pro-inflammatory cytokines, reducing oxidative stress, and increasing GMBF.


Subject(s)
4-Butyrolactone/analogs & derivatives , Alkaloids/therapeutic use , Gastrointestinal Diseases/prevention & control , Imidazoles/therapeutic use , Naproxen/toxicity , Pilocarpus , Plant Extracts/pharmacology , 4-Butyrolactone/isolation & purification , 4-Butyrolactone/pharmacology , 4-Butyrolactone/therapeutic use , Alkaloids/isolation & purification , Alkaloids/pharmacology , Animals , Dose-Response Relationship, Drug , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/pathology , Imidazoles/isolation & purification , Imidazoles/pharmacology , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Male , Plant Extracts/isolation & purification , Plant Leaves , Protective Agents/isolation & purification , Protective Agents/pharmacology , Rats , Rats, Wistar
3.
PLoS Negl Trop Dis ; 9(3): e0003656, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25816129

ABSTRACT

Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported.


Subject(s)
4-Butyrolactone/analogs & derivatives , Imidazoles/pharmacology , Schistosoma mansoni/drug effects , Schistosomiasis mansoni/drug therapy , Schistosomicides/pharmacology , 4-Butyrolactone/pharmacology , Animals , Dose-Response Relationship, Drug , Feces/parasitology , Granuloma/pathology , Liver/drug effects , Liver/parasitology , Mice , Microscopy, Electron, Scanning , Schistosoma mansoni/ultrastructure
4.
PLoS One ; 8(6): e66702, 2013.
Article in English | MEDLINE | ID: mdl-23840522

ABSTRACT

This paper presents an industrial scale process for extraction, purification, and isolation of epiisopiloturine (EPI) (2(3H)-Furanone,dihydro-3-(hydroxyphenylmethyl)-4-[(1-methyl-1H-imidazol-4-yl)methyl]-, [3S-[3a(R*),4b]]), which is an alkaloid from jaborandi leaves (Pilocarpus microphyllus Stapf). Additionally for the first time a set of structural and spectroscopic techniques were used to characterize this alkaloid. EPI has shown schistomicidal activity against adults and young forms, as well as the reduction of the egg laying adult worms and low toxicity to mammalian cells (in vitro). At first, the extraction of EPI was done with toluene and methylene chloride to obtain a solution that was alkalinized with ammonium carbonate. The remaining solution was treated in sequence by acidification, filtration and alkalinization. These industrial procedures are necessary in order to remove impurities and subsequent application of the high performance liquid chromatography (HPLC). The HPLC was employed also to remove other alkaloids, to obtain EPI purity higher than 98%. The viability of the method was confirmed through HPLC and electrospray mass spectrometry, that yielded a pseudo molecular ion of m/z equal to 287.1 Da. EPI structure was characterized by single crystal X-ray diffraction (XRD), (1)H and (13)C nuclear magnetic resonance (NMR) in deuterated methanol/chloroform solution, vibrational spectroscopy and mass coupled thermal analyses. EPI molecule presents a parallel alignment of the benzene and the methyl imidazol ring separated by an interplanar spacing of 3.758 Å indicating a π-π bond interaction. The imidazole alkaloid melts at 225°C and decomposes above 230°C under air. EPI structure was used in theoretical Density Functional Theory calculations, considering the single crystal XRD data in order to simulate the NMR, infrared and Raman spectra of the molecule, and performs the signals attribution.


Subject(s)
4-Butyrolactone/analogs & derivatives , Imidazoles/isolation & purification , Pilocarpus/chemistry , Plant Leaves/chemistry , Schistosomicides/isolation & purification , 4-Butyrolactone/chemistry , 4-Butyrolactone/isolation & purification , Crystallography, X-Ray , Imidazoles/chemistry , Plant Extracts/chemistry
5.
J Nat Prod ; 76(6): 1071-7, 2013 Jun 28.
Article in English | MEDLINE | ID: mdl-23734744

ABSTRACT

The aim of this study was to investigate the antinociceptive and anti-inflammatory activities of epiisopiloturine (1), an imidazole alkaloid found in the leaves of Pilocarpus microphyllus. The anti-inflammatory activity of 1 was evaluated using several agents that induce paw edema and peritonitis in Swiss mice. Paw tissue and peritoneal fluid samples were obtained to determine myeloperoxidase (MPO) activity or tumor necrosis factor (TNF)-α and interleukin (IL)-1ß levels. The antinociceptive activity was evaluated by acetic acid-induced writhing, the hot plate test, and pain induction using formalin. Compared to vehicle treatment, pretreatment with 1 (0.1, 0.3, and 1 mg/kg, ip) of mice significantly reduced carrageenan-induced paw edema (p < 0.05). Furthermore, compound 1 at a dose of 1 mg/kg effectively inhibited edema induced by dextran sulfate, serotonin, and bradykinin, but had no effect on histamine-induced edema. The administration of 1 (1 mg/kg) following carrageenan-induced peritonitis reduced total and differential peritoneal leukocyte counts and also carrageenan-induced paw MPO activity and TNF-α and IL-1ß levels in the peritoneal cavity. Pretreatment with 1 also reduced acetic acid-induced writhing and inhibited the first and second phases of the formalin test, but did not alter response latency in the hot plate test. Pretreatment with naloxone reversed the antinociceptive effect of 1.


Subject(s)
4-Butyrolactone/analogs & derivatives , Alkaloids/pharmacology , Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Imidazoles/pharmacology , Pilocarpus/chemistry , 4-Butyrolactone/chemistry , 4-Butyrolactone/pharmacology , Alkaloids/blood , Alkaloids/chemistry , Analgesics/blood , Analgesics/chemistry , Animals , Anti-Inflammatory Agents/blood , Anti-Inflammatory Agents/chemistry , Brazil , Imidazoles/chemistry , Male , Mice , Molecular Structure , Neutrophils/drug effects , Pain Measurement , Peroxidase/blood , Peroxidase/metabolism
6.
Molecules ; 18(6): 7058-70, 2013 Jun 17.
Article in English | MEDLINE | ID: mdl-23774944

ABSTRACT

Antimicrobial peptides (AMPs) from the dermaseptin and phylloseptin families were isolated from the skin secretion of Phyllomedusa nordestina, a recently described amphibian species from Northeastern Brazil. One dermaseptin and three phylloseptins were chosen for solid phase peptide synthesis. The antiprotozoal and antimicrobial activities of the synthetic peptides were determined, as well as their cytotoxicity in mouse peritoneal cells. AMPs are being considered as frameworks for the development of novel drugs inspired by their mechanism of action.


Subject(s)
Antimicrobial Cationic Peptides/metabolism , Antimicrobial Cationic Peptides/pharmacology , Skin/metabolism , Amphibian Proteins/chemistry , Amphibian Proteins/metabolism , Amphibian Proteins/pharmacology , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antimicrobial Cationic Peptides/chemistry , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Anura , Macrophages/drug effects , Mice , Microbial Sensitivity Tests , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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