RESUMO
BACKGROUND: Dimeric acylphloroglucinols occurring in species from sections Brathys and Trigynobrathys of the genus Hypericum exhibit acylfilicinic acid and acylphloroglucinol moieties linked by a methylene bridge. However, this chemical feature differs from hyperforin, from H. perforatum (Hypericum section). Some dimeric acylphloroglucinols, such as uliginosin B, display similar pharmacological activities, namely antidepressant and antinociceptive. However, there is no knowledge about the pharmacokinetic profile and no toxicity studies of these compounds in intact mammals. OBJECTIVE: To perform an in silico evaluation of the similarity, pharmacokinetics and toxicity (ADMET) properties of dimeric acylphloroglucinols from species native to Central and South America. METHODS: ADMET prediction of eleven elected phloroglucinols followed by the chemical space evaluation of thirty-five dimeric acylphloroglucinols derivatives labeled according to their prenylation/ geranylation pattern through principal component analysis (PCA). The similarity analysis was performed using the Tanimoto similarity index. ADMET properties were predicted with the opensource software SwissADME and pkCSM-pharmacokinetics. RESULTS: Several compounds showed good human intestinal absorption. However, they may present difficulties in crossing the blood-brain barrier, probably due to the high tPSA values. The predicted toxicity parameters indicated that most compounds have low toxicity. Most non-prenylated phloroglucinols were disposed into Lipinski's rule limits. Uliginosin B, isouliginosin B and japonicin A seem to be druglike compounds. The PCA model explained 77.49% of the total variance, and molecular similarity analyses revealed some expected similarities between isomers and different compounds. CONCLUSION: Dimeric acylphloroglucinols may be promising drug candidates and deserve further pharmacological and medicinal chemistry studies.
RESUMO
Bioactive molecules isolated from plants are promising sources for the development of new therapies against leishmaniasis. We investigated the leishmanicidal activity of cariphenone A (1), isouliginosin B (2) and uliginosin B (3) isolated from Hypericum species. Promastigotes and amastigotes of Leishmania amazonensis were incubated with compounds 1-3 at concentrations 1-100 µm for 48 h. The anti-promastigote effect of compounds was also tested in combinations. The cytotoxicity against macrophages and human erythrocytes were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method and hemolysis assay, respectively. The compounds 1-3 showed high leishmanicidal activity against promastigotes, IC50 values of 10.5, 17.5 and 11.3 µm, respectively. Synergistic interactions were found to the associations of compounds 1 and 2 [Σ fractional inhibitory concentration (FIC) = 0.41], and 2 and 3 (ΣFIC = 0.28) on promastigotes. All Hypericum compounds induced mitochondrial hyperpolarization and reactive oxygen species production in promastigotes. The compounds showed low cytotoxicity toward mammalian cells, high selectivity index and killed intracellular amastigotes probably mediated by oxidative stress. These results indicate that these compounds are promising candidates for the development of drugs against leishmaniasis.
Assuntos
Antiprotozoários/farmacologia , Hypericum/química , Leishmania/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Floroglucinol/farmacologia , Extratos Vegetais/farmacologia , Células Cultivadas , Eritrócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estágios do Ciclo de Vida/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Mitocôndrias/patologia , Estresse Oxidativo , Floroglucinol/análogos & derivados , Espécies Reativas de Oxigênio/metabolismoRESUMO
ABSTRACT Uliginosin B, a phloroglucinol isolated from Hypericum polyanthemum Klotzsch ex Reichardt, Hypericaceae, has antidepressant-like effect in the forced swimming test in rodents and inhibits monoamines neuronal reuptake without binding to their neuronal carriers. Studies showed the involvement of Na+,K+-ATPase brain activity in depressive disorders, as well as the dependence of neuronal monoamine transport from Na+ gradient generated by Na+,K+-ATPase. This study aimed at evaluating the effect of uliginosin B on Na+,K+-ATPase activity in mice cerebral cortex and hippocampus (1 and 3 h after the last administration) as well as the influence of veratrine, a Na+ channel opener, on the antidepressant-like effect of uliginosin B. Mice were treated (p.o.) with uliginosin B single (10 mg/kg) or repeated doses (10 mg/kg/day, 3 days). Acute administration reduced the immobility in the forced swimming test and tail suspension test and increased Na+,K+-ATPase activity in cerebral cortex 1 h after treating, whereas the repeated treatment induced the antidepressant-like effect and increased the Na+,K+-ATPase activity at both times evaluated. None treatment affected the hippocampus enzyme activity. Veratrine pretreatment prevented uliginosin B antidepressant-like effect in the forced swimming test, suggesting the involvement of Na+ balance regulation on this effect. Altogether, these data indicate that uliginosin B reduces the monoamine uptake by altering Na+ gradient.
RESUMO
AbstractPrevious studies by us demonstrated the antidepressant-like and antinociceptive effects of lipophilic extracts and dimeric acyl-phloroglucinols from species of the genus Hypericum native to Southern Brazil. Uliginosin B and HC1 (an enriched phloroglucinol fraction from Hypericum caprifoliatum) are able to inhibit monoamine synaptosomal uptake without binding to the monoaminergic sites on neuronal transporters, unlike classical antidepressants. The current study aimed at investigating the action of H. caprifoliatum Cham. & Schltdl. and Hypericum polyanthemum Klotzsch ex Reichardt, Hypericaceae, cyclohexane extracts and their main component, HC1 and uliginosin B, on G protein coupled receptors by using the [35S]-guanosine-5′-O-(3-thio)triphosphate ([35S]-GTPγS) binding assay, which reveals the G protein activity. The antidepressant-like effect of acute (one or three treatments within 24 h) and repeated (five days with and without a three day wash-out) treatments with the cyclohexane extracts was evaluated using the rat forced swimming test. The [35S]-GTPγS binding to monoamines and opioid receptors stimulated by agonists was performed ex vivo in brain membranes of rats acutely or repeatedly treated with the cyclohexane extracts. The effect of HC1 and Uliginosin B on [35S]-GTPγS binding assay was performed by direct incubation with brain membranes in the absence of agonists. Their antidepressant-like effect was evaluated through the mice forced swimming test. The extracts, HC1 and Uliginosin B showed antidepressant-like effect in the forced swimming test. The acute treatments with extracts increased the [35S]-GTPγS binding stimulated by the monoamines, while after five days of treatment the [35S]-GTPγS binding was reduced even after three day wash-out. These effects are not due to HC1 or Uliginosin B interaction with the receptors, since direct incubation with these phloroglucinols did not affect [35S]-GTPγS binding to membranes. Our findings indicate that H. caprifoliatum and H. polyanthemumextracts bring about adaptive changes in monoamine receptors, which reinforces their antidepressant-like profile.
RESUMO
Uliginosin B is a natural phloroglucinol derivative, obtained from Hypericum species native to South America. Previous studies have shown that uliginosin B presents antidepressant-like and antinociceptive effects. Although its mechanism of action is still not completely elucidated, it is known that it involves the activation of monoaminergic neurotransmission. The aim of the current study was to further investigate the antinociceptive mechanism of action of uliginosin B by combining it with different drugs used for treating pain in clinical practice. The intraperitoneal administration of uliginosin B, morphine, amitriptyline and clonidine, alone or in mixture, produced a dose-dependent antinociceptive effect in the hot-plate assay in mice. The effect of the mixtures of drugs was studied using an adapted isobologram analysis at the effect level of 50% of the maximal effect observed. The analysis showed that the interactions between uliginosin B and morphine was synergistic, while the interactions between uliginosin B and amitriptyline or clonidine were additive. These findings point to uliginosin B as a potential adjuvant for pain pharmacotherapy, especially for opioid analgesia.