RESUMO
For the first time, compounds developed from the 1,2,3-triazole scaffold were evaluated as novel drugs to treat triple-negative breast cancer (TNBC). Four organic salts were idealized as nonclassical bioisosteres of miltefosine, which is used in the topical treatment for skin metastasizing breast carcinoma. Among them, derivative dhmtAc displayed better solubility and higher cytotoxicity against the human breast adenocarcinoma cell line and mouse 4T1 cell lines, which are representatives of TNBC. In vitro assays revealed that dhmtAc interferes with cell integrity, confirmed by lactate dehydogenase leakage. Due to its human peripheral blood mononuclear cell (PBMC) toxicity, dhmtAc in vivo studies were carried out with the drug incorporated in a long-circulating and pH-sensitive liposome (SpHL-dhmtAc), and the acute toxicity in BALB/c mice was determined. Free dhmtAc displayed cardiac and pulmonary toxicity after the systemic administration of 5 mg/kg doses. On the other hand, SpHL-dhmtAc displayed no toxicity at 20 mg/kg. The in vivo antitumor effect of SpHL-dhmtAc was investigated using the 4T1 heterotopic murine model. Intravenous administration of SpHL-dhmtAc reduced the tumor volume and weight, without interfering with the body weight, compared with the control group and the dhmtAc free form. The incorporation of the triazole compound in the liposome allowed the demonstration of its anticancer potential. These findings evidenced 1,3,4-trisubstituted-1,2,3-triazole as a promising scaffold for the development of novel drugs with applicability for the treatment of patients with TNBC.
Assuntos
Lipossomos , Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , Humanos , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade , Triazóis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
In this work, we combined molecular modeling, computational docking and in vitro analysis to explore the antileishmanial effect of some resveratrol analogs (ResAn), focusing on their pro-oxidant effect. The molecular target was the trypanothione reductase of Leishmania braziliensis (LbTryR), an essential component of the antioxidant defenses in trypanosomatid parasites. Three-dimensional structures of LbTryR were modeled and molecular docking studies of ResAn1-5 compounds showed the following affinity: ResAn1 > ResAn2 > ResAn4 > ResAn5 > ResAn3. Positive correlation was observed between these compounds' affinity to the LbTryR and the IC50 values against Leishmania sp (ResAn1 < ResAn2 < ResAn4), which allows for TryR being considered an important target for them. As the compound ResAn1 showed the best antileishmanial activity, and docking studies showed its high affinity for NADP binding site (NS) of TryR, plus having been able to induce ROS production in L. braziliensis promastigotes treated, ResAn1 probably occupies NS interfering in the electron transfer processes responsible for the catalytic reaction. The in silico prediction of ADMET properties suggests that ResAn1 may be a promising drug candidate with properties to cross biological membranes and high gastrointestinal absorption, not violating Lipinski's rules. Ultimately, the antileishmanial effect of ResAn can be associated with a pro-oxidant effect which, in turn, can be exploited as an antimicrobial agent. Communicated by Ramaswamy H. Sarma.
Assuntos
Antiprotozoários/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Leishmania braziliensis/efeitos dos fármacos , Leishmania braziliensis/enzimologia , Leishmaniose/tratamento farmacológico , NADH NADPH Oxirredutases/metabolismo , Resveratrol/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Antiprotozoários/química , Sítios de Ligação , Leishmaniose/parasitologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , NADH NADPH Oxirredutases/química , Conformação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/farmacologia , Relação Estrutura-AtividadeRESUMO
Ionic liquids (ILs) have been extensively studied and are considered green solvents capable of replacing traditional organic solvents. In this study, seven 1,2,3-triazolium derivative ILs have been synthesized. In order to study the effect of the cation nature on the ILs cytotoxicity, their structures were first identified by 1H, 13C NMR 1D, and 2D spectroscopy. DFT calculations have also been performed in a way to help to provide an insightful structural analysis from 13C NMR spectroscopy. The comparison made with the NMR experimental shifts was quite important to show that the 1,2,3-triazolium derivatives have the expected structure shown here. The in vitro cytotoxicity of ILs toward macrophages showed that among the compounds tested, five did not exhibit expressive cytotoxicity on mammalian cells. Besides the well-established relationship between the carbonic chain size of the cation and the cytotoxicity, the log P of the compounds predicts that the toxicity increases with the size of the carbon chain, demonstrating that the most cytotoxic compound is also the most lipophilic one. The low cytotoxicity effect of ILs on mammalian cells points to their potential application in large-scale by industry. Graphical abstract Seven triazolium ILs were synthesized and their in vitro cytotoxicity on murine macrophages showed a relationship with the carbonic chain size.
Assuntos
Líquidos Iônicos/química , Espectroscopia de Ressonância Magnética , Triazóis/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
Nitrogenated heterocyclic compounds are present in both natural and synthetic drugs, and hexahydropyrimidine derivatives may prove to be efficient in treating dermatomycosis causing fungi. This study evaluated the antifungal activity of four hexahydropyrimidine derivatives against the dermatomycosis causing fungi. These derivatives were synthesized, characterized, and assessed in terms of their activity against Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, Trichophyton rubrum, Fusarium oxysporum, and Epidermophyton floccosum between concentrations 7.8 and 1,000 µg mL-1. Scanning electron micrographs were assessed for the active derivatives and reference drugs, and these micrographs revealed that new agents cause morphological changes in fungi. The derivatives HHP1, HHP3, and HHP4 revealed poor activity against the four fungal strains (MICs range 500-1000 µg mL-1). Compound HHP3 was found to be the best potential antifungal agent among those tested and was the most effective among all the active derivatives that caused morphological changes in the susceptible strains.
Assuntos
Antifúngicos/farmacologia , Dermatomicoses/microbiologia , Fungos/efeitos dos fármacos , Pirimidinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Dermatomicoses/tratamento farmacológico , Fungos/ultraestrutura , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/químicaRESUMO
In our previous work, we demonstrated the promising in vitro effect of VOSalophen, a vanadium complex with a stilbene derivative, against Leishmania amazonensis. Its antileishmanial activity has been associated with oxidative stress in L. amazonensis promastigotes and L. amazonensis-infected macrophages. In the present study, the mechanism involved in the death of parasites after treatment with VOSalophen, as well as in vivo effect in the murine model cutaneous leishmaniasis, has been investigated. Promastigotes of L. amazonensis treated with VOSalophen presented apoptotic cells features, such as cell volume decrease, phosphatidylserine externalization, and DNA fragmentation. An increase in autophagic vacuoles formation in treated promastigotes was also observed, showing that autophagy also may be involved in the death of these parasites. In intracellular amastigotes, DNA fragmentation was observed after treatment with VOSalophen, but this effect was not observed in host cells, highlighting the selective effect of this vanadium complex. In addition, VOSalophen showed activity in the murine model of cutaneous leishmaniasis, without hepatic and renal damages. The outcome described here points out that VOSalophen had promising antileishmanial properties and these data also contribute to the understanding of the mechanisms involved in the death of protozoa induced by metal complexes.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Estilbenos/química , Vanádio/química , Animais , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Leishmaniose Cutânea/genética , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organometálicos/uso terapêuticoRESUMO
Here, we report the effect of new non-classical bioisosteres of miltefosine on Leishmania amazonensis. Fifteen compounds were synthesized and the compound dhmtAc, containing an acetate anion, a side chain of 10 carbon atoms linked to N-1 and a methyl group linked to N-3, showed high and selective biological activity against L. amazonensis. On the intracellular amastigotes, stages of the parasite related to human disease, the IC50 values were near or similar to the 1.0µM (0.9, 0.8 and 1.0µM on L. amazonensis-WT, and two transgenic L. amazonensis expressing GFP and RFP, respectively), being more active than miltefosine. Furthermore, dhmtAc did not show toxic effects on human erythrocytes and macrophages (CC50=115.9µM) being more destructive to the intracellular parasites (selectivity index>115). Promastigotes and intramacrophage amastigotes treated with dhmtAc showed low capacity for reversion of the effect of the compound. A study of the mechanism of action of this compound showed some features of metazoan apoptosis, including cell volume decreases, loss of mitochondrial membrane potential, ROS production, an increase in the intracellular lipid bodies, in situ labeling of DNA fragments by TUNEL labeling and phosphatidylserine exposure to the outerleaflet of the plasma membrane. In addition, the plasma membrane disruption, revealed by PI labeling, suggests cell death by necrosis. No increase in autophagic vacuoles formation in treated promastigotes was observed. Taken together, the data indicate that the bioisostere of miltefosine, dhmtAc, has promising antileishmanial activity that is mediated via apoptosis and necrosis.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania mexicana/efeitos dos fármacos , Fosforilcolina/análogos & derivados , Triazóis/química , Triazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Eritrócitos/parasitologia , Humanos , Leishmania mexicana/citologia , Leishmania mexicana/fisiologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Macrófagos/parasitologia , Camundongos , Fosforilcolina/química , Fosforilcolina/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The leishmanicidal activity of a series of 4-aminoquinoline (AMQ) derivatives was assayed against Leishmania amazonensis. This activity against the intracellular parasite was found stronger than for L. amazonensis promastigotes. Neither compound was cytotoxic against macrophages. The compound AMQ-j, which exhibited a strong activity against promastigotes and amastigotes of L. amazonensis (IC50 values of 5.9 and 2.4 µg/mL, respectively) and similar leishmanicidal activity to reference drugs, was chosen for studies regarding its possible mechanism of action toward parasite death. The results showed that the compound AMQ-j induced depolarization of the mitochondrial membrane potential in promastigotes and in L. amazonensis-infected macrophages, but not in uninfected macrophages. Furthermore, the depolarization of the mitochondrial membrane potential was dose dependent in infected macrophages. We have established that promastigotes and L. amazonensis-infected macrophages treated with AMQ-j were submitted to oxidative stress. This is in line with the increase in the level of reactive oxygen species (ROS). Leishmania amazonensis-infected macrophages treated with AMQ-j did not show a significant increase in the production of nitric oxide. Our results indicate the effective and selective action of AMQ-j against L. amazonensis, and its mechanism of action appears to be mediated by mitochondrial dysfunction associated with ROS production.
Assuntos
Aminoquinolinas/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania mexicana/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Leishmania mexicana/citologia , Leishmania mexicana/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C/parasitologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
The title compound, C14H11NO4, exists in the solid phase in the zwitterionic form, 2-{[(4-carboxy-3-hydroxyphenyl)iminiumyl]methyl}phenolate, with the H atom from the phenol group on the 2-hydroxybenzylidene ring transferred to the imine N atom, resulting in a strong intramolecular N-HâââO hydrogen bond between the iminium H atom and the phenolate O atom, forming a six-membered hydrogen-bonded ring. In addition, there is an intramolecular O-HâââO hydrogen bond between the carboxylic acid group and the adjacent hydroxy group of the other ring, and an intermolecular C-HâââO contact involving the phenol group and the C-H group adjacent to the imine bond, connecting the molecules into a two-dimensional network in the (103) plane. π-π stacking interactions result in a three-dimensional network. This study is important because it provides crystallographic evidence, supported by IR data, for the iminium zwitterionic form of Schiff bases.
RESUMO
Resveratrol has been extensively researched for its powerful antioxidant capacity and other biological effects. The number of patents involving this compound has been growing in recent years. However, the biggest problem associated with this molecule, a limited bioavailability due to its fast metabolism in the liver, has led to obtaining its analogues or derivatives. In this work, we selected patents which describe the application of the antioxidant activity of resveratrol and its analogues as food for the human segment.