RESUMEN
Over the last decade, there has been substantial interest in the use of melatonin (MLT) and MLT-like compounds in the treatment of several diseases. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. Our ongoing study relies on changing the groups in the different modifiable sites of the indole ring to increase the antioxidant activity. In this study a new approach for substitution of indole ring as indole based MLT analogue was proposed. We report the synthesis and characterization of a series of new indole-7-aldehyde hydrazide/hydrazone derivatives as indole-based MLT analogues. Anticancer potential of the compounds were evaluated both by their antioxidant and CYP1 inhibitory activities. In vitro antioxidant capacity of the compounds was investigated both in a cell-based (DCFH assay) and a cell-free (DPPH assay) assay. Potential inhibitory effects of the compounds on CYP1 catalytic activity were investigated via EROD assay. Cytotoxic activity of the compounds was further evaluated by the MTT assay in CHO-K1 cells. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any cytotoxic effect. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant agents.
Asunto(s)
Aldehídos/farmacología , Antioxidantes/farmacología , Indoles/farmacología , Melatonina/farmacología , Aldehídos/síntesis química , Aldehídos/química , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Células CHO , Células Cultivadas , Cricetulus , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Indoles/síntesis química , Indoles/química , Melatonina/síntesis química , Melatonina/química , Estructura Molecular , Picratos/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Overproduction of reactive oxygen species results in oxidative stress that can cause fatal damage to vital cell structures. It is known that the use of antioxidants could be beneficial in the prevention or delay of numerous diseases associated with oxidative stress. Melatonin (MLT) is known as a powerful free-radical scavenger and antioxidant. It was found that indole ring of MLT can be employed by bioisosteric replacement by other aromatic rings. Quinoline derivatives constitute an important class of compounds for new drug development. Owing to quinoline and hydrazones appealing physiological properties and are mostly found in numerous biologically active compounds a series of quinoline-2-carbaldehyde hydrazone derivatives were synthesized as bioisosteric analogues of MLT, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Cytotoxicity potential of all compounds was investigated both by lactate dehydrogenase leakage assay and by MTT assay.
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Hidrazonas/farmacología , Melatonina/análogos & derivados , Melatonina/farmacología , Quinolinas/farmacología , Animales , Antioxidantes/química , Células CHO , Supervivencia Celular/efectos de los fármacos , Cricetulus , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes/química , Colorantes Fluorescentes/metabolismo , Hidrazonas/síntesis química , Hidrazonas/química , Melatonina/química , Estructura Molecular , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Quinolinas/síntesis química , Quinolinas/química , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
Melatonin (MLT) is a well-known free-radical scavenger, involving in the prevention of cellular damage that can lead to cancer, ageing and a variety of neurodegenerative diseases. Research on MLT-related compounds has been required to optimise the maximum pharmaceutical activity with the lowest side effects. In our ongoing research, we have synthesized new indole-based MLT analogues as potential antioxidant agents by modifying the MLT molecule. In this study, we build on previous findings, through the synthesis, characterization and in vitro antioxidant profiling of a series of new indole-based MLT analogues which possess triazole, thiadiazole and carbothioamides on the third position on the indole ring. In vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox sensitive fluorescent probe and their radical scavenging activity was assessed via the DPPH assay. In addition, in vitro cytotoxic effects of newly synthesized compounds were investigated in CHO-K1 cells using the MTT assay.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Indoles/química , Melatonina/análogos & derivados , Tiadiazoles/química , Tioamidas/química , Triazoles/química , Animales , Células CHO , Espectroscopía de Resonancia Magnética con Carbono-13 , Quimioprevención , Cricetinae , Cricetulus , Melatonina/química , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Melatonin (MLT) is a strong free-radical scavenger, which protects the body from the effects of oxidants. In recent years, MLT have been described resulting in much attention in the development of synthetic compounds possessing. As a part of our ongoing study a series of indole-based MLT analogue hydrazide/hydrazone derivatives were synthesized, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox sensitive fluorescent probe. Membrane stabilizing effect of all compounds was also investigated by lactate dehydrogenase leakage assay. Furthermore voltammetric methods have been applied to the synthesized compounds to characterize oxidation potentials to get insight into their metabolism owing to the oxidation mechanisms taking place at the electrode and in the body share similar principles.
Asunto(s)
Antioxidantes/química , Antioxidantes/metabolismo , Técnicas Electroquímicas , Eritrocitos/química , Indoles/química , Melatonina/análogos & derivados , Melatonina/metabolismo , Antioxidantes/síntesis química , Electrodos , Eritrocitos/metabolismo , Colorantes Fluorescentes , Humanos , Hidroliasas/metabolismo , Melatonina/síntesis química , Melatonina/química , Estructura MolecularRESUMEN
There has been an increasing importance of drug-resistant pathogens in clinical microbiological and antibacterial research. Indoles and hydrazone-type compounds constitute important classes of compounds in the search for effective agents against multidrug-resistant microbial infections. In this study a series of 1-methylindole-3-carboxaldehyde hydrazone derivatives were evaluated for their in vitro antimicrobial activities using the two-fold serial dilution technique against Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-resistant S. aureus isolate, Escherichia coli, Bacillus subtilis, and Candida albicans. The minimum inhibitory concentration (MIC) of the test compounds and the reference standards sultamicillin, ampicillin, fluconazole, and ciprofloxacin was determined. All compounds possessed a broad spectrum of activity having MIC values of 6.25-100 microg/ml against the tested microorganisms. Aromaticity and disubstitution of the phenyl ring with especially fluorine and chlorine atoms were found to be significant for the antimicrobial activity
Asunto(s)
Antiinfecciosos/farmacología , Hidrazonas/farmacología , Indoles/análisis , Antiinfecciosos/química , Bacterias/efectos de los fármacos , Candida albicans/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Hidrazonas/química , Pruebas de Sensibilidad MicrobianaRESUMEN
The aim of this study was to synthesize and examine possible in vitro antioxidant effects of indole-based melatonin analogue compounds. As a part of our ongoing study nineteen indole hydrazide/hydrazone derivatives were synthesized, characterized and their in vitro antioxidant activity was investigated by three different assays: by evaluating their reducing effect against oxidation of a redox sensitive fluorescent probe, by examining their protective effect against H2O2-induced membrane lipid peroxidation and by determining their inhibitory effect on AAPH-induced hemolysis of human erythrocytes. The results indicated significant strong antioxidant activity for most of the compounds, when compared to melatonin.
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Indoles/química , Melatonina/análogos & derivados , Melatonina/farmacología , Eritrocitos/efectos de los fármacos , Humanos , Hidrazonas/síntesis química , Hidrazonas/farmacologíaRESUMEN
OBJECTIVES: In new antimicrobial drug development studies, indole and its derivatives create an important class of compounds. In addition, azoles and their derivatives were recognized to be associated with a variety of biologic activities such as antibacterial and antifungal. In this study antimicrobial activities of some indole derivatives mainly substituted with 1,2,4-triazole, 1,3,4-thiadiazole and hydrazinecarbothioamide were investigated to evaluate their efficacy. MATERIALS AND METHODS: The efficacy of new compounds was evaluated using 2-fold serial dilutions against Staphylococcus aureus, MRSA, Escherichia coli, Bacillus subtilis, Candida albicans, and Candida krusei. RESULTS: The MIC was determined for test compounds and for the reference standards sultamicillin, ampicillin, fluconazole, and ciprofloxacin. CONCLUSION: The compounds possessed a broad spectrum of activity having MIC values of 3.125-50 µg/mL against the tested microorganisms. This study provides valuable evidence that the indole-triazole derivative compound 3d holds significant promise as a novel antibacterial and antifungal lead compound.