RESUMO
In this work, several ribavirin analogues were synthesized and incorporated into a multivalent arrangement. Both were subsequently modified by the addition of polyhydroxylated residues. Their antiviral activity was tested against Junín virus, etiological agent responsible of Argentine hemorrhagic fever. Some compounds inhibited Junín virus in the range of 13.2-389.1⯵M. Two modified ribavirin analogues presented an effective concentration comparable to ribavirin but with a higher selectivity index.
Assuntos
Antivirais/farmacologia , Vírus Junin/efeitos dos fármacos , Ribavirina/análogos & derivados , Células A549 , Animais , Chlorocebus aethiops , Humanos , Células VeroRESUMO
The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds. Most of these derivatives exhibit significant antiproliferative activities in the micromolar range. Noteworthy, the most potent compound of the series showed better selectivity towards the more resistant colon cancer cell line WiDr.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Oxidiazóis/síntese química , Ribose/análogos & derivados , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Oxidiazóis/química , Oxidiazóis/farmacologia , Ribose/síntese química , Ribose/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized. RESULTS: The compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC50) values in the range 12.5-27.1 µM, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 µM. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2. CONCLUSIONS: The acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis.
Assuntos
Acridonas/farmacologia , Compostos Alílicos/farmacologia , Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , RNA Viral/metabolismoRESUMO
(1)H and (13)C spectroscopic data for 5H-[1,3]thiazolo[2,3-b]quinazolin-5-one and 12H-[1,3]benzothiazolo[2,3-b]quinazolin-12-one derivatives were fully assigned by combination of one- and two-dimensional experiments (DEPT, HMBC and HMQC). Both heterocyclic systems show similar spectroscopic properties with some remarkable differences.
Assuntos
Espectroscopia de Ressonância Magnética , Quinazolinas/química , Isótopos de Carbono , Espectroscopia de Ressonância Magnética/métodosRESUMO
Herein we describe the synthesis of imidazo[2,1-b][1,3,4]thiadiazoles from carbohydrates with D-ribo and D-xylo configuration. The antiviral activity of these compounds was tested against Junín virus (the etiological agent of Argentine hemorrhagic fever). The p-chlorophenyl derivatives showed antiviral activity in a range of micromolar concentration.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Ribose/química , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Xilose/química , Antivirais/química , Técnicas de Química Sintética , Vírus Junin/efeitos dos fármacos , Tiadiazóis/químicaRESUMO
BACKGROUND: In the present study, a series of N-substituted acridone derivatives was synthesized and evaluated against two haemorrhagic fever viruses (HFV). METHODS: Compounds were tested against Junin virus (JUNV), an arenavirus agent of Argentine haemorrhagic fever, and dengue virus (DENV), a flavivirus agent of the most prevalent arthropod-borne viral disease in humans. RESULTS: Among tested compounds, two N-allyl acridones (derivatives 3c and 3f) elicited a potent and selective antiviral activity against JUNV (strain 1V4454) and DENV-2 (strain NGC) with 50% effective concentration values between 2.5 and 5.5 microM, as determined by virus yield inhibition. No cytotoxicity was detected at concentrations up to 1,000 microM, resulting in selectivity indices >181.8-400.0. Both acridones were effective against a wide spectrum of arenaviruses and the four serotypes of DENV. Furthermore, 3c and 3f failed to inactivate virus before cell infection as well as to induce a refractory state by cell pretreatment, indicating that the inhibitory effect was exerted through a blockade in virus multiplication during the infectious process. CONCLUSION: These data are the first demonstration that acridone derivatives have a potent antiviral activity that block in vitro multiplication of HFV belonging to Arenaviridae and Flaviviridae, such as JUNV and DENV.
Assuntos
Acridonas/síntese química , Antivirais/síntese química , Vírus da Dengue/efeitos dos fármacos , Vírus Junin/efeitos dos fármacos , Acridonas/farmacologia , Animais , Antivirais/farmacologia , Infecções por Arenaviridae/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Dengue Grave/tratamento farmacológico , Células Vero , Ensaio de Placa ViralRESUMO
Two methods, the first physical and the other chemical, were investigated to modify the surface roughness of polydimethylsiloxane (PDMS) films. The physical method consisted of dispersing multi-walled carbon nanotubes (MWCNTs) and magnetic cobalt ferrites (CoFe2O4) prior to thermal cross-linking, and curing the composite system in the presence of a uniform magnetic field H. The chemical method was based on exposing the films to bromine vapours and then UV-irradiating. The characterizing techniques included scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), Fourier transform infrared (FTIR) spectroscopy, optical microscopy, atomic force microscopy (AFM) and magnetic force microscopy (MFM). The surface roughness was quantitatively analyzed by AFM. In the physical method, the random dispersion of MWCNTs (1% w/w) and magnetic nanoparticles (2% w/w) generated a roughness increase of about 200% (with respect to PDMS films without any treatment), but that change was 400% for films cured in the presence of H perpendicular to the surface. SEM, AFM and MFM showed that the magnetic particles always remained attached to the carbon nanotubes, and the effect on the roughness was interpreted as being due to a rupture of dispersion randomness and a possible induction of structuring in the direction of H. In the chemical method, the increase in roughness was even greater (1000%). Wells were generated with surface areas that were close to 100 µm² and depths of up to 500 nm. The observations of AFM images and FTIR spectra were in agreement with the hypothesis of etching by Br radicals generated by UV on the polymer chains. Both methods induced important changes in the surface roughness (the chemical method generated the greatest changes due to the formation of surface wells), which are of great importance in superficial technological processes.
RESUMO
A new biomedical material to be used as part of acrylic bone cement formulations is described. This new material is tough, its Young's Modulus is similar to the one of poly (methylmethacrylate) and the contrast agent, usually employed in acrylic bone cements, is homogeneously distributed among the polymeric matrix. Additionally, its wear coefficient is 66% lower than the one measured in poly(methyl methacrylate). The developed material is a branched polymer with polyisoprene backbone and poly(methyl methacrylate) side chains, which are capable of retaining barium sulphate nanoparticles thus avoiding their aggregation. The grafting reaction was carried out in presence of the nanoparticles, using methyl methacrylate as solvent. From the (1)H-NMR spectra it was possible to determine the average number of MMA units per unit of isoprene (3.75:1). The ability to retain nanoparticles (about 8wt.%), attributed to their interaction with the polymer branches, was determined by thermogravimetric analysis and confirmed by FTIR and microscopy techniques. By SEM microscopy it was also possible to determine the homogeneous spatial distribution of the barium sulphate nanoparticles along the polymer matrix.
Assuntos
Materiais Biocompatíveis/química , Cimentos Ósseos/química , Meios de Contraste/química , Polimetil Metacrilato/química , Módulo de Elasticidade , Teste de Materiais , Borracha/químicaRESUMO
Fused heterobicyclic systems have gained much importance in the field of medicinal chemistry because of their broad spectrum of physiological activities. Among the heterocyclic rings containing bridgehead nitrogen atom, imidazothiazoles derivatives are especially attractive because of their different biological activities. Since many imidazothiazoles derivatives are effective for treating several diseases, is interesting to analyze the behavior of some isosteric related heterocycles, such as pirrolothiazoles, imidazothiadiazoles and imidazotriazoles. In this context, this review summarizes the current knowledge about the syntheses and biological behavior of these families of heterocycles. Traditional synthetic methodologies as well as alternative synthetic procedures are described. Among these last methodologies, the use of multicomponent reaction, novel and efficient coupling reagents, and environmental friendly strategies, like microwave assistance and solvent-free condition in ionic liquids are also summarized. This review includes the biological assessments, docking research and studies of mechanism of action performed in order to obtain the compounds leading to the development of new drugs.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Proliferação de Células/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Imidazóis/química , Tiazóis/químicaRESUMO
Three isoxazoline tetracycles were obtained enantiomerically pure by intramolecular 1,3-dipolar cycloaddition. The characterization of the new compounds was performed by high-resolution 1H and 13C NMR spectroscopy. The relative configuration of the new chiral centers was determined by NOESY experiments and confirmed by single-crystal X-ray structural analysis.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Isoxazóis/síntese química , Cristalografia por Raios X , Compostos Heterocíclicos de 4 ou mais Anéis/química , Isoxazóis/química , Ressonância Magnética Nuclear Biomolecular , EstereoisomerismoRESUMO
Nanotechnology is an extremely powerful emerging technology, which is expected to have a substantial impact on biomedical technology, especially in tissue engineering and drug delivery. The use of nanocompounds and nanoparticles in the synthesis of improved bone cements to be applied in vertebroplasty/kyphoplasty and arthroplasty, is of great interest due to the increasing incidence of osteoporosis and osteoarthritis. This review reports new advances in the development of acrylic bone cements, using different radio-opalescent nanomaterials taking into consideration their influence on the mechanical behavior and biocompatibility of the resulting acrylic bone cement. Furthermore, other non-radiopaque nanoparticles capable of mechanically reinforcing the bone cement as well as induce osteointegration, are also reviewed. Additionally, nanoparticles used to improve the controlled release of antibiotics contained in acrylic bone cements are briefly described.
Assuntos
Cementoplastia/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Osseointegração/efeitos dos fármacos , Osseointegração/fisiologia , Polimetil Metacrilato/administração & dosagem , Polimetil Metacrilato/química , Animais , Força Compressiva , Desenho de Fármacos , Módulo de Elasticidade , Dureza , Humanos , Nanomedicina/métodos , Resistência à TraçãoRESUMO
New d-ribofuranoside derivatives containing two five membered heterocycles, isoxazole and triazole or two triazole rings, were synthesized. The final products as well as the synthetic precursors were physically and spectroscopically characterized. These new diheterocyclic derivatives together with other d-riboside compounds were assessed for their impact on PC3 cell line viability. We found that exposure of prostate cancer cells to some of these compounds caused a significant inhibition of cell growth and a G0/G1 cell cycle arrest, which was concomitant with alterations in the expression of proteins involved in cell cycle progression. Furthermore, the inhibitory activity was improved in di-heterocycles when the carbohydrate moiety was protected with a cyclopentylidene group compared to the isopropylidene analogues.
Assuntos
Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Alcenos/farmacologia , Carboidratos , Linhagem Celular Tumoral , Humanos , Isoxazóis/farmacologia , Masculino , Triazóis/farmacologiaRESUMO
Herein we report the design, synthesis and characterization of novel 1,2,4-triazole d-ribose derivatives, as well as their synthetic precursors. The antitumoral activity against T cell lymphoma cell line of these products was studied. Structures containing a 1,2,4-triazolic ring linked by sulfur to the carbohydrate moiety showed a moderate antiproliferative activity. The presence of the second heterocyclic ring did not show significant changes in their biological activity. Meanwhile, structures with 3-thiobenzyl-5-substituted-1,2,4-triazole ring linked by nitrogen leads to compounds with a biphasic behavior, stimulating cell proliferation at low concentrations and inhibiting it at higher ones. An increment in the polarity was associated with a decrease in the activity of the evaluated compounds. A preliminary antitumoral screening pointed the 1,2,4-triazolic structures linked to protected sugars as promising leaders for further studies.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Ribose/química , Triazóis/química , Triazóis/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Triazóis/síntese químicaRESUMO
There are no specific approved drugs for the treatment of agents of viral hemorrhagic fevers (HF) and antiviral therapies against these viruses are urgently needed. The present study characterizes the potent and selective antiviral activity against the HF causing arenavirus Junin virus (JUNV) of the compound 10-allyl-6-chloro-4-methoxy-9(10H)-acridone, designated 3f. The effectiveness of 3f to inhibit JUNV multiplication was not importantly affected by the initial multiplicity of infection, with similar effective concentration 50% (EC(50)) values in virus yield inhibition assays performed in Vero cells in the range of 0.2-40 plaque forming units (PFU)/cell. Mechanistic studies demonstrated that 3f did not affect the initial steps of adsorption and internalization. The subsequent process of viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR in compound-treated cells relative to non-treated cells. The addition of exogenous guanosine rescued the infectivity and RNA synthesis of JUNV in 3f-treated cells in a dose-dependent manner, but the reversal was partial, suggesting that the reduction of the GTP pool contributed to the antiviral activity of 3f, but it was not the main operative mechanism. The comparison of 3f with two other viral RNA inhibitors, ribavirin and mycophenolic acid, showed that ribavirin did not act against JUNV through the cellular enzyme inosine monophosphate dehydrogenase (IMPDH) inhibition whereas the anti-JUNV activity of mycophenolic acid was mainly targeted at this enzyme.
Assuntos
Acridonas/farmacologia , Compostos Alílicos/farmacologia , Antivirais/farmacologia , Vírus Junin/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Acridonas/química , Compostos Alílicos/química , Animais , Antivirais/química , Chlorocebus aethiops , Efeito Citopatogênico Viral/efeitos dos fármacos , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Guanosina/farmacologia , Vírus Junin/genética , Testes de Sensibilidade Microbiana , RNA Viral/biossíntese , Células VeroRESUMO
Malaria is one of the major threats concerning world public health. Resistance to the current antimalarial drugs has led to searches for new antimalarial compounds. Acridinone derivatives have recently demonstrated to be active against malaria parasite. We focused our attention on synthesized new acridinone derivatives, some of them resulting with high antiviral and trypanocidal activity. In this study new derivatives of 10-alyl-, 10-(3-methyl-2-butenyl)- and 10-(1,2-propadienyl)-9(10H)-acridinone were evaluated for their antimalarial activity against Plasmodium falciparum. To assess the selectivity, cytotoxicity was assessed in parallel against human MRC-5 cells. Inhibition of ß-hematin formation was determined using a spectrophotometric assay. Mitochondrial bc(1) complexes were isolated from yeast and bovine heart cells to test acridinone inhibitory activity. This study resulted in the identification of three compounds with submicromolar efficacy against P. falciparum and without cytotoxic effects on human cellular line. One compound, IIa (1-fluoro-10-(3-methyl-2-butenyl)-9(10H)-acridinone), can be classified as hit for antimalarial drug development exhibiting IC(50) less than 0.2 µg/mL with SI greater than 100. In molecular tests, no relevant inhibitory activity was obtained for our compounds. The mechanism of acridinones antimalarial action remains unclear.
Assuntos
Acridinas/síntese química , Acridinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/farmacologia , Animais , Bovinos , Linhagem Celular , Resistência Microbiana a Medicamentos , Hemeproteínas/antagonistas & inibidores , Humanos , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , LevedurasRESUMO
An intensive effort has been directed toward finding alternative drugs for treatment of Chagas' disease, caused by Trypanosoma cruzi (T. cruzi), and prophylaxis of blood in endemic areas. The preparation and in vitro evaluation as potential anti-protozoal agent of (2E)-N-(1,3-benzothiazol-2-yl)-3-(2,5-dimethoxyphenyl)-2-propenamide (CAD-1) is presented. The results show that 0.05 mM CAD-1 induced 58.1% of T. cruzi epimastigotes death; mainly by apoptosis. The diminution in the transmembrane mitochondrial electrical potential together with the increase in the intracellular generation/accumulation of reactive oxygen species, suggest the parasites mitochondria as the main target for CAD-1-induced death. The concentration of 0.05 mM CAD-1 is not low enough to consider it as a potent tripanocydal agent. However the novel mechanism that induces T. cruzi death, together with the novelty of its chemical structure, point out CAD-1 as a head group compound that could serve as a template to obtain new, more potent anti-Chagas disease agents.
Assuntos
Amidas/farmacologia , Benzotiazóis/farmacologia , Cinamatos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Amidas/isolamento & purificação , Animais , Anexina A5 , Benzotiazóis/isolamento & purificação , Cinamatos/isolamento & purificação , Corantes , Inibidores Enzimáticos , Citometria de Fluxo , Indicadores e Reagentes , Potenciais da Membrana/efeitos dos fármacos , Propídio , Espécies Reativas de Oxigênio/metabolismo , Tripanossomicidas/isolamento & purificação , Trypanosoma cruzi/metabolismoRESUMO
Elaphoside-A [p-vinylphenyl (beta-D: -glucopyranosyl)-(1-->3)-beta-D: -allopyranoside], a Mediterranean fruit fly oviposition deterrent, was previously isolated from an Argentine collection of the fern Elaphoglossum piloselloides. In order to establish the structural requirements for the observed oviposition inhibition, we synthesized and characterized 4 known and 21 new aromatic glycosides structurally related to elaphoside-A. Their effects on the oviposition behavior of Ceratitis capitata females are discussed.