RESUMO
N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.
Assuntos
Antineoplásicos , Etilenos , Compostos Heterocíclicos , Cetonas , Humanos , Linhagem Celular Tumoral , Etilenos/química , Etilenos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Cetonas/química , Cetonas/farmacologia , Cetonas/síntese química , Relação Estrutura-Atividade , Histona Desacetilases/metabolismo , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Acetais/química , Acetais/farmacologia , Acetais/síntese química , Proteínas RepressorasRESUMO
Despite the existing antibiotics, antimicrobial resistance is a major challenge. Consequently, the development of new drugs remains in great demand. Quinones is part of a broad group of molecules that present antibacterial activity besides other biological properties. The main purpose of this study was to evaluate the antibiofilm activities of synthetic N,O-acetals derived from 2-amino-1,4-naphthoquinone [7a: 2-(methoxymethyl)-amino-1,4-naphthoquinone; 7b: 2-(ethoxymethyl)-amino-1,4-naphthoquinone; and 7c: 2-(propynyloxymethyl)-amino-1,4-naphthoquinone] against methicillin-resistant Staphylococcus aureus (MRSA). The derivatives 7b and 7c, specially 7b, caused strong impact on biofilm accumulation. This inhibition was linked to decreased expression of the genes fnbA, spa, hla and psmα3. More importantly, this downregulation was paralleled by the modulation of global virulence regulators. The substitution of 2-ethoxymethyl (7b) in comparison with 2-propynyloxymethyl (7c) enhanced sarA-agr inhibition, decreased fnbA transcripts (positively regulated by sarA) and strongly impaired biofilm accumulation. Indeed, 7b triggered intensive autolysis and was able to eliminate vancomycin-persistent cells. Consequently, 7b is a promising molecule displaying not only antimicrobial effects, but also antibiofilm and antipersistence activities. Therefore, 7b is a good candidate for further studies involving the development of novel and more rational antimicrobials able to act in chronic and recalcitrant infections, associated with biofilm formation.
Assuntos
Acetais/química , Acetais/farmacologia , Biofilmes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Naftoquinonas/química , Naftoquinonas/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Linhagem Celular , Chlorocebus aethiops , Regulação para Baixo/efeitos dos fármacos , Farmacorresistência Bacteriana , Hemólise/efeitos dos fármacos , Humanos , Teste de Materiais , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Testes de Sensibilidade Microbiana/métodos , Infecções Estafilocócicas/microbiologia , Células Vero , Virulência/efeitos dos fármacosRESUMO
Three new isoaigialones, A, B, and C (1-3), along with aigialone (4), were isolated from the crude EtOAc extract of a Phaeoacremonium sp., an endophytic fungus obtained from the leaves of Senna spectabilis. The structures of these compounds were elucidated based on the analysis of spectroscopic data. Compounds 2 and 4 were active against the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum. This is the first report of metabolites produced by an Phaeoacremonium sp., associated with S. spectabilis.
Assuntos
Acetais/isolamento & purificação , Acetais/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Ascomicetos/química , Cladosporium/química , Cetonas/isolamento & purificação , Cetonas/farmacologia , Lactonas/isolamento & purificação , Folhas de Planta/química , Senna/química , Acetais/química , Antifúngicos/química , Cetonas/química , Lactonas/química , Lactonas/metabolismo , Lactonas/farmacologia , Estrutura MolecularRESUMO
This paper describes a novel series of N,O-acetals and N,S-acetals (7a-o) derived from 2-amino-1,4-naphthoquinones that were synthesized and evaluated as potential antimicrobial agents. These compounds were obtained in good yields using microwave irradiation, and several of them showed promising antibacterial profiles. Three of our biologically active 2-amino-1,4-naphthoquinone N,O-acetals and N,S-acetals tested against hospital bacterial strains were identified as potential lead compounds. Characterization of all compounds was performed using one-dimensional NMR techniques ((1)H, (13)C-APT), IR spectra, elemental analyses and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS).
Assuntos
Acetais/síntese química , Antibacterianos/síntese química , Micro-Ondas , Naftoquinonas/síntese química , Acetais/química , Acetais/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Modelos Químicos , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria InfravermelhoRESUMO
Research on antifungal compounds from the durable wood from French Guiana Amazonian forest trees highlights the correlation between the activity of their extracts against wood-rotting fungi and human pathogens. The fractionation of an ethyl acetate extract of Sextonia rubra wood led to the isolation of rubrenolide (1) and rubrynolide (2). The potential of compounds 1 and 2 is described through the evaluation of their activity against 16 pathogenic fungi and their cytotoxicity toward NIH-3T3 mammalian fibroblast cells.
Assuntos
Acetais/isolamento & purificação , Acetais/farmacologia , Alcenos/isolamento & purificação , Alcenos/farmacologia , Alcinos/isolamento & purificação , Alcinos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Basidiomycota/química , Polyporaceae/química , Árvores/microbiologia , Acetais/química , Alcenos/química , Alcinos/química , Animais , Antifúngicos/química , Guiana Francesa , Lauraceae/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células NIH 3T3 , Caules de Planta/química , Madeira/microbiologiaRESUMO
Despite the many existing crosslinking procedures, glutaraldehyde (GA) is still the method of choice used in the manufacture of bioprosthesis. The major problems with GA are: (a) uncontrolled reactivity due to the chemical complexity or GA solutions; (b) toxicity due to the release of GA from polymeric crosslinks; and (c) tissue impermeabilization due to polymeric and heterogeneous crosslinks formation, partially responsible for the undesirable calcification of the bioprosthesis. A new method of crosslinking glutaraldehyde acetals has been developed with GA in acid ethanolic solution, and after the distribution inside de matrix, GA is released to crosslinking. Concentrations of hydrochloride acid in ethanolic solutions between 0.1 and 0.001 mol/L with GA concentration between 0.1 and 1.0% were measured in an ultraviolet spectrophotometer to verify the presence of free aldehyde groups and polymeric compounds of GA. After these measurements, the solutions were used to crosslink bovine pericardium. The spectrophotometric results showed that GA was better protected in acetal forms for acid ethanolic solution with HCl at 0.003 mol/L and GA 1.0%(v/v). The shrinkage temperature results of bovine pericardium crosslinked with acetal solutions showed values near 85 degrees C after the exposure to triethylamine vapors.