Antileishmanial activity of Riparin structural analogs of Aniba riparia: Biological evaluation, in silico Adme-Tox, and molecular docking.

We performed a biological evaluation of antileishmanial activity, in silico ADME-Tox profile, and molecular docking of riparins A-F. The antileishmanial activity was evaluated in Leishmania major promastigotes, whereas the cytotoxic activity was tested on murine macrophages. Computational parameters were predicted by in silico analysis. Molecular docking was performed with 18 L. major molecular targets. Riparins, especially RipC and RipE, showed cytotoxic activity in vitro toward L. major promastigotes and a high selectivity index. Riparins showed small differences in their physicochemical properties, such as polarity and aqueous solubility. LogP was an important parameter for the differences in the antileishmanial activity between the molecules. In molecular docking, the ligands displayed Ki < 1 µM for LmNMT and LmLEI. Significant molecular interactions were observed with residues from the active site and adjacent regions of such enzymes. Thus, riparins have the potential for application in antileishmanial therapy.

In vitro antileishmanial and immunomodulatory activities of the synthetic analogue riparin E.

Leishmaniases are infectious diseases caused by protozoa of the genus Leishmania, that may have different clinical manifestations. First line drugs used in the treatment of leishmaniosis are high costly, and are very aggressive requiring medical monitoring. Thus new therapeutic alternatives are needed and, in this context, natural products have been considered as a source of new antileishmania agents. Riparins are alkamides found in the unripe fruits of Aniba riparia. Several biological activities are described for this group of compounds, such as antimicrobial and antiparasitic potential. The objective of this work was to evaluate the anti-leishmania activity riparin E (Rip-E) in vitro, against promastigotes and internalized amastigotes of Leishmania amazonensis. Rip-E was able to inhibit promastigote cell growth (IC50 4.7 µg/ml) and to reduce the percentage of macrophages infected with amastigotes, reducing its infectivity (survival index) (IC50 1.3 µg/ml). The cytotoxicity against BALB/c murine macrophages was also assessed (CC50 50.6 µg/ml) and the selectivity index was 38.9. Rip-E also demonstrated immunomodulatory activity, evidenced by the increase of the phagocytic capacity and lysosomal activity. However, Rip-E did not affect directly the production of nitric oxide. These results suggest that Rip-E has antileishmania potential, by both its direct inhibitory effect and its ability to activate macrophages.

Psychopharmacological effects of riparin III from Aniba riparia (Nees) Mez. (Lauraceae) supported by metabolic approach and multivariate data analysis.

BACKGROUND: Currently there is a high prevalence of humor disorders such as anxiety and depression throughout the world, especially concerning advanced age patients. Aniba riparia (Nees) Mez. (Lauraceae), popular known as "louro", can be found from the Amazon through Guianas until the Andes. Previous studies have already reported the isolation of alkamide-type alkaloids such as riparin III (O-methyl-N-2,6-dyhydroxy-benzoyl tyramine) which has demonstrated anxiolytic and antidepressant-like effects in high doses by intraperitoneal administration. METHODS: Experimental protocol was conducted in order to analyze the anxiolytic-like effect of riparin III at lower doses by intravenous administration to Wistar rats (Rattus norvegicus) (n = 5). The experimental approach was designed to last 15 days, divided in 3 distinct periods of five days: control, anxiogenic and treatment periods. The anxiolytic-like effect was evaluated by experimental behavior tests such as open field and elevated plus-maze test, combined with urine metabolic footprint analysis. The urine was collected daily and analyzed by 1H NMR. Generated data were statistically treated by Principal Component Analysis in order to detect patterns among the distinct periods evaluated as well as biomarkers responsible for its distinction. RESULTS: It was observed on treatment group that cortisol, biomarker related to physiological stress was reduced, indicating anxiolytic-like effect of riparin III, probably through activation of 5-HT2A receptors, which was corroborated by behavioral tests. CONCLUSION: 1H NMR urine metabolic footprint combined with multivariate data analysis have demonstrated to be an important diagnostic tool to prove the anxiolytic-like effect of riparin III in a more efficient and pragmatic way.

Riparin II ameliorates corticosterone-induced depressive-like behavior in mice: Role of antioxidant and neurotrophic mechanisms.

Riparin II (RIP II) is an alkamide isolated from Aniba riparia that has presented antidepressant and anxiolytic effects in acute stress behavioral models. This study aimed to investigate the activity of RIP II in a corticosterone-induced depression mice model. Corticosterone (20 mg/kg, s.c.) was administered once a day for 21 days. RIP II (50 mg/kg, p.o.) or fluvoxamine (FLU, 50 mg/kg, standard antidepressant, p.o.) was administered after corticosterone (CORT) injection, for the last 7 days of CORT treatment. Mice were exposed to the following behavioral tests: forced swimming, tail suspension, open field, sucrose preference, elevated plus maze and ymaze. After behavioral evaluation, brain areas (prefrontal cortex, hippocampus and striatum) were dissected for neurochemical evaluation: oxidative stress parameters (MDA, nitrite and GSH) and BDNF dosage. Repeated CORT administration caused depressive-like behavior in mice as indicated by increased despair effects in forced swimming and tail suspension tests and anhedonia in sucrose preference test. In addition, CORT decreased BDNF levels in the mice hippocampus and induced oxidative load in the brain with significative increase in pro-oxidant markers (lipid peroxidation and nitrite levels) and a decline in anti-oxidant defense system (reduced glutathione levels), indicating a direct effect of stress hormones in the induction of the brain oxidative stress. On the other hand, RIP II treatment reversed CORT-induced depressive-like behavior. Furthermore, this treatment reversed the impairment in BDNF levels and oxidative brain insults caused by CORT. This may demonstrate the mechanisms involved in antidepressant-like effect of RIP II. These findings further support that RIP II may be implicated as pharmacological intervention targeting depression associated with HPA-axis dysregulation.

Subchronic administration of riparin III induces antidepressive-like effects and increases BDNF levels in the mouse hippocampus.

Riparin III (Rip III) is an alcamide isolated from Aniba riparia that has presented effects of antidepressant and anxiolytic activities in acute stress behavioral models. The trial's goal was to investigate the activity of Rip III in mice exposed to corticosterone-induced chronic depression model. Swiss female mice, 22-25 g, were distributed in following experimental groups: control group (vehicle1: saline containing 0.1% dimethyl sulfoxide and 0.1% Tween-80, SC+ vehicle 2: distilled water emulsified with 2% Tween-80, PO); stressed group (corticosterone, 20 mg/kg, SC, + vehicle 2, orally); Rip III group (50 mg/kg, orally); and fluvoxamine (Flu) group (50 mg/kg, orally). The mice were exposed to the behavioral tests, and posteriorly, Brain-derived neurotrophic factor protein levels were assessed in hippocampal samples. Statistical analysis of the data was performed by one-way anova, followed by Newman-Keuls test. Both administrations of Rip III and Flu significantly reduced the immobility time in tail suspension and forced swimming tests after 21 days without affecting locomotor function. There was also an increase in BDNF protein levels in the mice hippocampus. These findings further support the hypothesis that Rip III could be a new pharmacological target for the treatment of mood disorders.

Involvement of monoaminergic system in the antidepressant-like effect of riparin I from Aniba riparia (Nees) Mez (Lauraceae) in mice.

In past studies conducted by our group, riparin I (rip I) isolated from the green fruit of Aniba riparia presented antianxiety effects in mice, while its analogs rip II and III showed anxiolytic and antidepressant-like actions. This time around, we investigated a possible antidepressant activity of rip I using the forced swimming test (FST) and tail suspension test (TST) as predictive tests for antidepressant activity in rodents. In addition, the involvement of the monoaminergic system in this effect was also assessed. rip I was acutely administered by intraperitoneal (i.p.) and oral (p.o) routes to male mice at doses of 25 and 50 mg/kg. Results showed that rip I at both tested doses and administration routes produced a significant decrease in immobility time in FST and TST. The pretreatment of mice with prazosin (1 mg/kg, i.p., an α1 -adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α2 -adrenoceptor antagonist), SCH23390 (15 µg/kg, i.p., a dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), p-chlorophenylalanine (100 mg/kg, an inhibitor of serotonin synthesis) or ritanserin (4 mg/kg, a serotonin 5-HT2(A)/2(C) receptor antagonist) blocked the anti-immobility effects elicited by rip I (50 mg/kg, p.o.) in the FST. Taken together, results indicate that rip I produces significant antidepressant-like activity in the FST and TST, and this effect seems to be dependent on its interaction with noradrenergic, dopaminergic and serotonergic systems.

Avaliação da atividade antimicrobiana e efeitos biológicos de riparinas sobre eliminação de resistência a drogas em amostras de Staphylococcus aureus / Evaluation of the antimicrobial activity and biological effect by riparins about elimination the resistance of drugs in samples of Staphylococcus aureus

Linhagens de Staphylococcus aureus (319U e 122U) de origem bovina com padrões de resistência plasmidial a drogas previamente conhecidos foram submetidas ao tratametno com três riparinas constituintes de Aniba riparia (Ness), Mez (Lauraceae), planta típica da região amazônica com atividade antimicrobiana comprovada contra S. aureus. O objetivo foi avaliar o efeito dessas substâncias sobre a curva de morte bacteriana e sua influência sobre a eliminação de plamídeos de resistência a drogas. Os estudos foram realizados com éteres metilicos de N-benzoiltiramina (riparina I), N (2 hidroxibenzoil)-tiramina(riparina II) e N-(2,6 dihidroxibenzoil)-tiramina (riparina III), obtidos da A riparia. A riparina III apresentou atividade curagênica, eliminando marca de resistência para penicilina na linhagem 319U numa frequência de 61,7%. Nessa linhagem também foi evidenciada a perda da capacidade de expressar a enzima coagulase. A atividade antiplasmidial e a capacidade de modificar a expressão de fatores de virulência da riparina III mostram a importância desse estudo como contribuição para prevenção de linhagens de S, aureus multiresistentes, podendo aumentar a sensibilidade dessas linhagens a outros agentes antimicrobianos.