RESUMO
Leishmaniasis is a parasitic disease caused by Leishmania protozoa, which presents a large spectrum of clinical manifestations. In the present study, a quinoline derivative salt named N-(2-((7-chloroquinolin-4-yl)amino)ethyl)-N-(prop-2-yn-1-yl)prop-2-yn-1-aminium chloride or QDS3 was in vitro and in vivo tested against L. infantum by means of its incorporation in Poloxamer 407-based polymeric micelles (QDS3/M). The in vitro antileishmanial activity of QDS3 and QDS3/M was investigated in L. infantum promastigotes, axenic amastigotes and infected macrophages. BALB/c mice were infected with L. infantum, and parasitological parameters were evaluated 1 and 15 days post-treatment by determining the parasite load by a limiting dilution assay, besides a quantitative PCR (qPCR) method. Immunological response was assessed based on production of cellular cytokines, as well as by quantification of nitrite levels and specific antibodies. In vitro results showed that QDS3 free or in micelles presented effective antileishmanial action against both parasite stages, being more effective in amastigotes. In vivo data showed that treatment using QDS3 or QDS3/M reduced the parasite load in the livers, spleens, draining lymph nodes (dLN) and bone marrows of the treated animals, 1 and 15 days after treatment, when compared to values found in the control groups. Additionally, treated mice developed a polarized Th1-type immune response, with higher levels of IL-12, IFN-γ, GM-CSF and nitrite, besides high production of specific IgG2a antibodies, when compared to the controls. Parasitological and immunological data obtained using the micellar composition were better than the others. In conclusion, QDS3, mainly when applied in a delivery adjuvant system, could be considered for future studies as therapeutic candidate against VL.
Assuntos
Antiprotozoários , Leishmania infantum , Leishmaniose Visceral , Leishmaniose , Quinolinas , Animais , Antiprotozoários/uso terapêutico , Leishmaniose/parasitologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Nitritos/uso terapêutico , Polímeros/uso terapêutico , Quinolinas/uso terapêuticoRESUMO
Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, being fatal if untreated. In search of a more effective treatment for VL, one of the main strategies is the development and screening of new antileishmanial compounds. Here, we reported the synthesis of seven new acetyl functionalized 1,2,3-triazolium salts, together with four 1,2,3-triazole precursors, and investigated their effect against different strains of L. infantum from dogs and humans. The 1,2,3-triazolium salts exhibited better activity than the 1,2,3-triazole derivatives with IC50 range from 0.12 to 8.66 µM and, among them, compound 5 showed significant activity against promastigotes (IC50 from 4.55 to 5.28 µM) and intracellular amastigotes (IC50 from 5.36 to 7.92 µM), with the best selective index (SI ~ 6-9) and reduced toxicity. Our findings, using biochemical and ultrastructural approaches, demonstrated that compound 5 targets the mitochondrion of L. infantum promastigotes, leading to the formation of reactive oxygen species (ROS), increase of the mitochondrial membrane potential, and mitochondrial alteration. Moreover, quantitative transmission electron microscopy (TEM) revealed that compound 5 induces the reduction of promastigote size and cytoplasmic vacuolization. Interestingly, the effect of compound 5 was not associated with apoptosis or necrosis of the parasites but, instead, seems to be mediated through a pathway involving autophagy, with a clear detection of autophagic vacuoles in the cytoplasm by using both a fluorescent marker and TEM. As for the in vivo studies, compound 5 showed activity in a mouse model of VL at 20 mg/kg, reducing the parasite load in both spleen and liver (59.80% and 26.88%, respectively). Finally, this compound did not induce hepatoxicity or nephrotoxicity and was able to normalize the altered biochemical parameters in the infected mice. Thus, our findings support the use of 1,2,3-triazolium salts as potential agents against visceral leishmaniasis.
Assuntos
Antiprotozoários , Leishmania infantum , Leishmaniose Visceral , Animais , Antiprotozoários/uso terapêutico , Cães , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Sais/farmacologia , Sais/uso terapêutico , Triazóis/farmacologia , Triazóis/uso terapêuticoRESUMO
The determination of the kinetics of inclusion processes is significant for the application of inclusion complexes as carriers for bioactive molecules. We determined the kinetic parameters of inclusion between modified ß-cyclodextrin (ß-CD-NH2) and the polyphenols resveratrol (RES) and its structural analog (RESAn1), using the real-time analysis of surface plasmon resonance. The association and dissociation rate constants (ka and kd) showed that RESAn1 inclusion and its dissociation from ß-CD-NH2 were faster than a similar process for RES ( [Formula: see text] = 3.10â104 ± 0.14 M-1s-1, [Formula: see text] =1.87â103 ± 0.11 M-1s-1; [Formula: see text] =0.39 ± 0.02 s-1, [Formula: see text] =0.30 ± 0.02 s-1, at 25 °C). The activated complex formation was also affected by the structural differences between the polyphenols, as showed by the activation energies of the association step ( [Formula: see text] 14.81 ± 0.64 kJâmol-1, [Formula: see text] -15.01 ± 0.75 to 82.35 ± 4.47 kJâmol-1). These effects of polyphenol structural differences are due to the desolvation process of interacting molecules. These results elucidate the role of small group to the dynamics of the molecular inclusion of ß-CD.
Assuntos
Ciclodextrinas , Cinética , Polifenóis , Resveratrol , Ressonância de Plasmônio de SuperfícieRESUMO
Quinoline and 1,2,3-triazoles are well-known nitrogen-based heterocycles presenting diverse pharmacological properties, although their antileishmanial activity is still poorly exploited. As an effort to contribute with studies involving these interesting chemical groups, in the present study, a series of compounds derived from 4-aminoquinoline and 1,2,3-triazole were synthetized and biological studies using L. amazonensis species were performed. The results pointed that the derivative 4, a hybrid of 4-aminoquinoline/1,2,3-triazole exhibited the best antileishmanial action, with inhibitory concentration (IC50) values of ~1 µM against intramacrophage amastigotes of L. amazonensis , and being 16-fold more active to parasites than to the host cell. The mechanism of action of derivative 4 suggest a multi-target action on Leishmania parasites, since the treatment of L. amazonensis promastigotes caused mitochondrial membrane depolarization, accumulation of ROS products, plasma membrane permeabilization, increase in neutral lipids, exposure of phosphatidylserine to the cell surface, changes in the cell cycle and DNA fragmentation. The results suggest that the antileishmanial effect of this compound is primarily altering critical biochemical processes for the correct functioning of organelles and macromolecules of parasites, with consequent cell death by processes related to apoptosis-like and necrosis. No up-regulation of reactive oxygen and nitrogen intermediates was promoted by derivative 4 on L. amazonensis -infected macrophages, suggesting a mechanism of action independent from the activation of the host cell. In conclusion, data suggest that derivative 4 presents selective antileishmanial effect, which is associated with multi-target action, and can be considered for future studies for the treatment against disease.
Assuntos
Aminoquinolinas/farmacologia , Antiprotozoários/farmacologia , Leishmania mexicana/efeitos dos fármacos , Triazóis/farmacologia , Aminoquinolinas/síntese química , Animais , Antiprotozoários/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Membrana Celular/química , Membrana Celular/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Organelas/efeitos dos fármacos , Fosfatidilserinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Triazóis/síntese químicaRESUMO
Inflammaging is known as an imbalance between pro-inflammatory and anti-inflammatory immune mechanisms, being related to the onset of neurological disorders, such as major depression and Alzheimer's disease. Considering the known disadvantages regarding the FDA approved drug to manage such illnesses, resveratrol emerges as a natural drug candidate, despite its low bioavailability. In this study, resveratrol analogues were evaluated for their capacity of inhibiting acetylcholinesterase in silico, in vitro, and in vivo. Molecular docking simulations pointed out RSVA1 and RSVA6 as potent inhibitors, even more than resveratrol. Ellman's assay demonstrated RSVA6 as capable of inhibiting 92.4% of the enzyme activity. Further, male Swiss mice were pretreated with RSVA6 (100 mg kg-1) 60 min before receiving scopolamine (1 mg kg-1). The Novel Recognition Object (NOR), Object Location (OLT), and Buried Pellet tests (BPL) demonstrated an RSVA6 neuroprotective effect. In the second round of tests, mice received a single intraperitoneal injection of lipopolysaccharide (0.5 mg kg-1) 24 h before treatment with RSVA6 (1, 10, and 100 mg kg-1). The Open Field (OFT), Tail Suspension (TST), and Splash tests (ST) were evaluated. LPS had no significant effect on the crossing and rearing number, indicating an association between the immobility time and anhedonia observed in the TST and ST, respectively, with depressive-like behavior. RSVA6 significantly reduced the depressive-like behavior triggered by LPS in the TST and ST. Altogether, our data suggest RSVA6 as a potential drug candidate for the treatment of neuroinflammatory conditions.
Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Resveratrol/uso terapêutico , Animais , Simulação por Computador , Técnicas In Vitro , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Simulação de Acoplamento Molecular , Doenças do Sistema Nervoso/induzido quimicamente , Resveratrol/análogos & derivados , Escopolamina/administração & dosagemRESUMO
The thermodynamics and kinetics of binding between human serum albumin (HSA) and resveratrol (RES) or its analog (RESAn1) were investigated by surface plasmon resonance (SPR). The binding constant and the kinetic constants of association and dissociation indicated that RESAn1 has higher affinity toward HSA than does RES. The formation of these complexes was entropically driven ( [Formula: see text] , [Formula: see text] â¯KJâ¯mol-1). However, for both polyphenols, the activation energy (Eact) of association (a) of free molecules was higher than that for dissociation (d) of the stable complex ( [Formula: see text] â¯KJâ¯mol-1), and the rate of association was faster than that of dissociation since the activation Gibbs free energy (ΔG) was lower for the former (ΔGaHSA-RESâ 54.73,ΔGdHSA-RESâ 73.83,ΔGaHSA-RESAn1â 54.14,ΔGdHSA-RESAn1â 73.97â¯KJâ¯mol-1). This study showed that small differences in the structure of polyphenols such as RES and RESAn1 influenced the thermodynamics and kinetics of the complex formation with HSA.
Assuntos
Fenóis/química , Resveratrol/metabolismo , Albumina Sérica Humana/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Cinética , Ligação Proteica , Resveratrol/química , Albumina Sérica Humana/química , Ressonância de Plasmônio de Superfície , Temperatura , TermodinâmicaRESUMO
1,2,3-triazolium salts are poorly understood regarding their antileishmanial activity. Hence, as an effort to identify novel chemical scaffolds as antileishmanial agents, a series of 1,2,3-triazolium salts (TS) and corresponding 1,2,3-triazole (T) precursors including new epoxide derivatives were synthesized and assayed against Leishmania amazonensis promastigote and intracellular amastigote forms. Among them, the compound TS-6 exhibited promising activity on promastigotes (IC50â¯=â¯3.61⯵M) and intracellular amastigotes (IC50â¯=â¯7.61⯵M) of L. amazonensis, superior to miltefosine (IC50â¯>â¯10.0⯵M), used as reference drug. In addition, TS-6 showed negligible cytotoxicity on murine peritoneal macrophages with a SI of about 10. Studies on the mode of action of TS-6 indicate mitochondrial dysfunction through an increase in 'total' and mitochondrial-ROS as well as depolarization of mitochondrial membrane potential of L. amazonensis promastigotes. In silico physicochemical studies indicate that the TS-6 could potentially be used as an oral drug.
Assuntos
Antiprotozoários/farmacologia , Leishmania mexicana/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Triazóis/farmacologia , Animais , Leishmania mexicana/metabolismo , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologiaRESUMO
OBJECTIVES: The in vitro antileishmanial effect of analogues of resveratrol (AR) present in the N-aryl imines and N-aryl hydrazones series was investigated. In addition, possible parasite targets were evaluated. METHODS: Antipromastigote activity of Leishmania amazonensis, L. braziliensis and L. infantum, as well as the cytotoxicity on macrophages was determined by MTT assay and L. braziliensis-infected macrophages effect by Giemsa stain. After staining, effects on the parasite targets were analysed by flow cytometry or by fluorescence microscopy. KEY-FINDINGS: Among the tested compounds, the derivative AR26 showed the best effect against promastigotes of all Leishmania species (IC50 < 3.0 µg/ml), being more active than miltefosine, the control drug. AR26 was also effective against amastigotes of L. braziliensis (IC50 = 15.9 µg/ml), with low toxicity to mammalian cells. The evaluation of mechanism of action of AR26 on L. braziliensis promastigotes indicates mitochondrial potential depolarization, plasma membrane permeabilization, interference in the progression of the cell cycle and accumulation of autophagic vacuoles. In addition, any increase of the reactive oxygen species levels was detected in the treated L. braziliensis-macrophages. CONCLUSIONS: Data indicate that the antileishmanial activity of AR26 is related to multitarget action, and the resveratrol analogues could be used in future studies as antileishmanial agent.
Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Resveratrol/farmacologia , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Modelos Animais de Doenças , Feminino , Hidrazonas/administração & dosagem , Hidrazonas/química , Hidrazonas/farmacologia , Iminas/administração & dosagem , Iminas/química , Iminas/farmacologia , Concentração Inibidora 50 , Leishmaniose/parasitologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/administração & dosagem , Resveratrol/análogos & derivadosRESUMO
Currently, available treatment options for leishmaniasis are limited and unsatisfactory. In a previous study, a quinoline derivative (AMQ-j), exhibited a strong effect against Leishmania amazonensis and its antileishmanial activity was preliminarily associated with mitochondrial dysfunction. The present study further explores the antileishmanial effect of this compound against L. amazonensis, as well as determines the main cellular processes involved in the death of the parasite. Moreover, this study evaluated the in vivo effect of the AMQ-j in BALB/c mice experimentally infected by L. amazonensis. The results showed that the compound AMQ-j induces a set of morphological and biochemical features that could correlate with both autophagy-related and apoptosis-like processes, indicating intense mitochondrial swelling, a collapse of the mitochondrial membrane potential, an abnormal chromatin condensation, an externalization of phosphatidylserine, an accumulation of lipid bodies, a disorganization of cell cycle, a formation of autophagic vacuoles, and an increase of acidic compartments. Treatment with AMQ-j through an intralesional route was effective in reducing the parasite burden and size of the lesion. No significant increase in the serum levels of hepatic or renal damage toxicity markers was observed. These findings contribute to the understanding of the mode of action of quinoline derivatives involved in the death of Leishmania parasites and encourage new studies in other experimental models of Leishmania infection.
Assuntos
Aminoquinolinas/farmacologia , Antiprotozoários/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Aminoquinolinas/toxicidade , Animais , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Ciclo Celular/efeitos dos fármacos , Chlorocebus aethiops , Creatinina/metabolismo , Orelha Externa/parasitologia , Orelha Externa/patologia , Feminino , Concentração Inibidora 50 , Rim/efeitos dos fármacos , Leishmania mexicana/citologia , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/ultraestrutura , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Células VeroRESUMO
Resveratrol is a natural polyphenol found mainly on red grapes and in red wine, pointed as an important anti-inflammatory/immunomodulatory molecule. However, its bioavailability problems have limited its use encouraging the search for new alternatives agents. Thus, in this study, we synthetize 12 resveratrol analogues (6 imines, 1 thioimine and 5 hydrazones) and investigated its cytotoxicity, antioxidant activity and in vitro anti-inflammatory/immunomodulatory properties. The most promising compounds were also evaluated in vivo. The results showed that imines presented less cytotoxicity, were more effective than resveratrol on DPPH scavenger and exhibited an anti-inflammatory profile. Among them, the imines with a radical in the para position, on the ring B, not engaged in an intramolecular hydrogen-interaction, showed more prominent anti-inflammatory activity modulating, in vivo, the edema formation, the inflammatory infiltration and cytokine levels. An immunomodulatory activity also was observed in these molecules. Thus, our results suggest that imines with these characteristics presents potential to control inflammatory disorders.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Iminas/química , Resveratrol/análogos & derivados , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios/farmacocinética , Antioxidantes/farmacologia , Disponibilidade Biológica , Compostos de Bifenilo/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Regulação para Baixo/efeitos dos fármacos , Inflamação/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Complexo Principal de Histocompatibilidade/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/biossíntese , Picratos/metabolismo , Células RAW 264.7RESUMO
The search for new drugs for the treatment of leishmaniasis is an important strategy for improving the current therapeutic arsenal for the disease. There are several limitations to the available drugs including high toxicity, low efficacy, prolonged parenteral administration, and high costs. Steroids are a diverse group of compounds with various applications in pharmacology. However, the antileishmanial activity of this class of molecules has not yet been explored. Therefore, in the present study, we investigated the antileishmanial activity and cytotoxicity of novel steroids against murine macrophages with a focus on the derivatives of cholesterol (CD), cholic acid (CA), and deoxycholic acid (DA). Furthermore, the mechanism of action of the best compound was assessed, and in silico studies to evaluate the physicochemical and pharmacokinetic properties were also conducted. Among the sixteen derivatives, schiffbase2, CD2 and deoxycholic acid derivatives (DOCADs) were effective against promastigotes of Leishmania species. Despite their low toxicity to macrophages, the majority of DOCADs were active against intracellular amastigotes of L. amazonensis, and DOCAD5 exhibited the best biological effect against these parasitic stages (IC50 = 15.34 µM). Neither the CA derivatives (CAD) nor DA alone inhibited the intracellular parasites. Thus, the absence of hydroxyl in the C-7 position of the steroid nucleus, as well as the modification of the acid group in DOCADs were considered important for antileishmanial activity. The treatment of L. amazonensis promastigote forms with DOCAD5 induced biochemical changes such as depolarization of the mitochondrial membrane potential, increased ROS production and cell cycle arrest. No alterations in parasite plasma membrane integrity were observed. In silico physicochemical and pharmacokinetic studies suggest that DOCAD5 could be a good candidate for an oral drug. The data demonstrate the potential antileishmanial effect of certain steroid derivatives and encourage new in vivo studies.
Assuntos
Colesterol/farmacologia , Ácido Desoxicólico/farmacologia , Descoberta de Drogas/métodos , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Macrófagos Peritoneais/efeitos dos fármacos , Tripanossomicidas/farmacologia , Administração Oral , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Colesterol/análogos & derivados , Colesterol/síntese química , Colesterol/farmacocinética , Ácido Cólico/síntese química , Ácido Cólico/farmacocinética , Ácido Cólico/farmacologia , Ácido Desoxicólico/análogos & derivados , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/farmacocinética , Relação Dose-Resposta a Droga , Leishmania/crescimento & desenvolvimento , Leishmania/metabolismo , Leishmaniose/parasitologia , Macrófagos Peritoneais/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacocinéticaRESUMO
Leishmaniases are infectious diseases, caused by protozoa of the Leishmania genus. These drugs present high toxicity, long-term administration, many adverse effects and are expensive, besides the identification of resistant parasites. In this work, the antileishmanial activity of quinoline derivative salts (QDS) was evaluated, as well as the toxicity on mammalian cells and the mechanism of action of the most promising compound. Among the compound tested, only the compound QDS3 showed activity against promastigotes and amastigotes of Leishmania spp., being more active against the intracellular amastigotes of L. amazonensis-GFP (IC50 of 5.48⯵M). This value is very close to the one observed for miltefosine (IC50 of 4.05⯵M), used as control drug. Furthermore, the compound QDS3 exhibited a selective effect, being 40.35 times more toxic to the amastigote form than to the host cell. Additionally, promastigotes of L. amazonensis treated with this compound exhibited characteristics of cells in the process of apoptosis such as mitochondrial membrane depolarization, mitochondrial swelling, increase of ROS production, phosphatidylserine externalization, reduced and rounded shape, and cell cycle alteration. The integrity of the plasma membrane remained unaltered, excluding necrosis in treated promastigotes. The compound QDS3 inhibited the formation of autophagic vacuoles, which may have contributed to parasite death by preventing autophagic mechanisms in the removal of damaged organelles, intensifying the damage caused by the treatment, highlighting the antileishmanial effect of this compound. In addition, treatment with QDS3 induced increased ROS levels in L. amazonensis-infected macrophages, but not in uninfected host cell. These data reinforce that the induction of oxidative stress is one of the main toxic effects caused by the treatment with the compound QDS3 in L. amazonensis, causing irreversible damage and triggering a selective death of intracellular parasites. Data shown here confirm the biological activity of quinoline derivatives and encourage future in vivo studies with this compound in the murine model.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Feminino , Leishmania/crescimento & desenvolvimento , Leishmania/metabolismo , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Leishmaniose/patologia , Leishmaniose/veterinária , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Quinolinas/química , Quinolinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sais/químicaRESUMO
In this study, we have investigated the antileishmanial activity of ten 7-chloro-4-quinolinylhydrazone derivatives. Among the compounds tested, compounds 2a and 2j presented activity against promastigotes (IC50 values of 52.5 and 21.1 µM, respectively) and compounds 2a and 2c were active against intracellular amastigotes (IC50 of 8.1 and 15.6 µM, respectively) of Leishmania amazonensis. The majority of compounds did not show toxicity against murine macrophages. Compound 2a exhibited low cytotoxicity to human erythrocytes and induced an oxidative imbalance in promastigote forms, reflected by an increase in the formation of reactive oxygen species (ROS) and a reduction of mitochondrial membrane potential. No alteration in the plasma membrane integrity of parasites was observed. Taken together, these results suggest that compound 2a is a selective antileishmanial agent, and preliminary observations suggest that its effects appear to be mediated by mitochondrial dysfunction.
Assuntos
Aminoquinolinas/farmacologia , Eritrócitos/efeitos dos fármacos , Hidrazonas/farmacologia , Leishmania mexicana/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Aminoquinolinas/química , Aminoquinolinas/toxicidade , Animais , Eritrócitos/parasitologia , Humanos , Hidrazonas/química , Hidrazonas/toxicidade , Concentração Inibidora 50 , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Leishmaniasis is a group of disease caused by different species of the parasite Leishmania affecting millions of people worldwide. Conventional therapy relies on multiple parenteral injections with pentavalent antimonials which exhibit high toxicity and various side effects have been reported. Hence, the research for an effective and low toxic effect drug is necessary. In the present work, the synthesis, spectroscopic and analytical characterizations of stilbene derivative (H2Salophen) and its vanadium complex (VOSalophen) are reported. Besides the chemical ancillary information, investigation of the leishmanicidal effects of these compounds were provided. The biological assays against promastigote and amastigote forms of L. amazonensis have been shown that VOSalophen exhibited a strong antiparasitic activity (IC50 of 6.65 and 3.51 µM, respectively). Furthermore, the leishmanicidal activity was concentration and time-dependent. Regarding toxicity and selectivity on mammalian cells, VOSalophen have not caused significant damage to human erythrocytes in all concentrations tested and VOSalophen was almost seven times more destructive for the intracellular parasite than for macrophages. Furthermore, the leishmanicidal activity of VOSalophen in promastigote forms of L. amazonensis could be associated to mitochondrial dysfunction and increase of the reactive oxygen species (ROS) production. In L. amazonensis-infected macrophages, VOSalophen induces ROS production and a microbicidal action NO-dependent. Our biological results indicate the effective and selective action of VOSalophen against L. amazonensis and the leishmanicidal effect can be associated to parasite disorders and immumodulatory effects.
Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Salicilatos/farmacologia , Compostos de Vanádio/farmacologia , Animais , Eritrócitos/efeitos dos fármacos , Humanos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Espécies Reativas de OxigênioRESUMO
Synthesis, characterization, DFT studies and biological assays of new gold(I) and gold(III) complexes of benzimidazole are reported. Molecular and structural characterizations of the compounds were based on elemental (C, H and N) and thermal (TG-DTA) analyses, and FT-IR and UV-Visible spectroscopic measurements. The structures of complexes were proposed based DFT calculations. The benzimidazole compounds (Lig1 and Lig2) and the gold complexes were tested against three Leishmania species related to cutaneous manifestations of leishmaniasis. The free benzimidazole compounds showed no leishmanicidal activity. On the other hand, the gold(I and III) complexes have shown to possess significant activity against Leishmania in both stages of parasite, and the gold(III) complex with Lig2 exhibited expressive leishmanicidal activity with IC50 values below 5.7 µM. Also, the gold complexes showed high leishmania selectivity. The gold(I) complex with Lig1, for example, is almost 50 times more toxic for the parasite than for macrophages. Besides the leishmanicidal activity, all complexes exhibited toxic effect against SK-Mel 103 and Balb/c 3T3, cancer cells.
Assuntos
Antiprotozoários/farmacologia , Benzimidazóis/química , Leishmania/efeitos dos fármacos , Compostos Organoáuricos/síntese química , Compostos Organoáuricos/farmacologia , Células 3T3 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoáuricos/química , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
Currently, the research and development of sunscreens play an important role on the synthesis of actives that are stable in various kinds of formulations-in addition to their efficiency and broad spectrum of protection against ultraviolet radiation. Our objective here was to synthesize new sunscreening chemical agents using quinoline as a base molecule. Twelve quinoline derivatives were synthesized, four of them novel molecules, and their photoprotective activity was determined in vitro using diffuse transmittance spectrophotometry. We determined their SPF, UVAPF, UVA/UVB ratio, critical wavelength and Boots Star Rating. The quinolines derivatives presented a varied profile of photoprotection, their SPF ranging from 2 to 11 and their UVAPF from 2 to 7. In terms of the critical wavelength, all molecules were considered of broad-spectrum by different classifications. Regarding the Boots Star Rating, one compound received no rating, seven of them received a three stars rating, three received a four stars rating and three were given a five stars rating. The molecules showed in the present work have a wide range of possibilities for creating new sunscreen products, once they have good SPF or UVAPF for single molecules, and they also possess other different qualities that can act synergistically.
Assuntos
Quinolinas/síntese química , Protetores Solares/síntese química , Química Farmacêutica , Estrutura Molecular , Quinolinas/química , Espectrofotometria , Protetores Solares/químicaRESUMO
This research has been an effort to develop synthetic resveratrol analogs in order to improve the depigmenting potential of natural resveratrol. Six resveratrol analogs were synthesized and tested for tyrosinase inhibitory activity in vitro, by qualitative and quantitative steps. The results showed the analog C as being the most powerful tyrosinase inhibitor (IA50=65.67±0.60 µg/mL), followed by the analogs B, E, F, A, and D, respectively. The analog C presented a tyrosinase inhibition potential better than natural resveratrol (P<0.001). The best depigmenting activity was provided by the presence of hydroxyl in the orthoposition on the second phenolic ring.
Assuntos
Inibidores Enzimáticos/síntese química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Estilbenos/química , Agaricales/química , Agaricales/enzimologia , Antioxidantes/química , Inibidores Enzimáticos/química , Proteínas Fúngicas/química , Conformação Molecular , Fenóis/química , Pironas/química , Resveratrol , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Resveratrol is a promising agent for protecting human skin from UV radiation and to reduce the occurrence of cutaneous malignancies. We describe the photoprotective activity of six resveratrol analogues using the diffuse transmittance technique to determine the SPF and the protection against UVA radiation. The analogues presented a varied profile of photoprotection, the SPF ranging from 2 to 10 and the UVAPF from 0 to 9. Among the six compounds tested, the protection against UVB sunrays provided by compound B was more significant than the protection provided by resveratrol; compounds C, D, E and F show photoprotection similar to resveratrol.
Assuntos
Estilbenos/química , Protetores Solares/química , Humanos , Resveratrol , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Estilbenos/farmacologia , Relação Estrutura-Atividade , Fator de Proteção Solar , Protetores Solares/farmacologia , Raios UltravioletaRESUMO
Skin pigmentation disorders typically involve an overproduction or uneven distribution of melanin, which results in skin spots. Resveratrol can inhibit tyrosinase, the active enzyme in the synthesis of melanin, but it does not inhibit the synthesis of melanin to an extent that enables its use alone as a skin whitening agent in pharmaceutical formulations, so its use as a coadjuvant in treatment of hyperpigmentation is suggested. Six resveratrol analogs were tested for tyrosinase inhibitory activity in vitro. Among the analogs tested, compound D was the most powerful tyrosinase inhibitor (IC(50) = 28.66 µg/mL), two times more active than resveratrol (IC(50) = 57.05 µg/mL), followed by the analogs A, E, B, F and C, respectively. This demonstrated that the hydroxylation at C4' on the phenolic ring was the molecular modification with most importance for the observed activity.
Assuntos
Agaricales/enzimologia , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Estilbenos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Monofenol Mono-Oxigenase/metabolismo , Resveratrol , Estilbenos/químicaRESUMO
The high incidence of malaria and drug-resistant strains of Plasmodium have turned this disease into a problem of major health importance. One of the approaches used to control it is to search for new antimalarial agents, such as quinoline derivates. This class of compounds composes a broad group of antimalarial agents, which are largely employed, and inhibits the formation of ß-haematin (malaria pigment), which is lethal to the parasite. More specifically, 4-aminoquinoline derivates represent potential sources of antimalarials, as the example of chloroquine, the most used antimalarial worldwide. In order to assess antimalarial activity, 12 4-aminoquinoline derived drugs were obtained and some of these derivatives were used to obtain platinum complexes platinum (II). These compounds were tested in vivo in a murine model and revealed remarkable inhibition of parasite multiplication values, whose majority ranged from 50 to 80%. In addition they were not cytotoxic. Thus, they may be object of further research for new antimalarial agents.