In vitro studies of the skin-lightening activity of molatonin and related indoleamines were condu... more In vitro studies of the skin-lightening activity of molatonin and related indoleamines were conducted an the frog, Rana, piviona. Using objective, photometric measurements of reflectance, the res ponse of the dermal malanocytes to these compounds was determined. Me'stonin consistently produced_j ficant lightening of skins at concentrations as low as 5 X 10 r Other indoleaminas found to possess skin-lightening activity were ranked in approximate order of potency relative to melatonin. the most potent of the coopounds studied. Studies of these and a number of related, but Inactive, compounds provided evidence ouggesting structural requirements for compounds having activity on the malatonis receptor. Among the least potent of the active compounds, a malatonin blocking agent, N-acetylo*rotoni. n, was discovered. This prompted the synthesis of a
Molecular Basis and Emerging Strategies for Anti-aging Interventions, 2018
Melatonin (N-acetyl-5-methoxy tryptamine, MLT) is a hormone that is produced by the pineal gland.... more Melatonin (N-acetyl-5-methoxy tryptamine, MLT) is a hormone that is produced by the pineal gland. It is synthesized regularly with high levels at night. Age-related decline in MLT contributes to an increased susceptibility to a number of pathophysiological disorders like neurodegenerative diseases, cancer, and aging. There are strong evidences that both Alzheimer’s disease and Parkinson’s disease are associated with low levels of MLT. Because of its wide-ranging antioxidant and radical scavenger effects, MLT may act as a protective agent against many age-related illnesses. MLT’s protection may be possible for both protein and fat tissues in the body by crossing all cell membrane. Currently available data make us to determine that MLT is beneficial for the aging process. Administration of MLT is able to increase the life span of several animals including some rodents. Although, to preserve health in old age becomes a primary goal for biomedicine, there is a necessity for extensive studies on the administration of MLT in order to increase the quality of life in advanced age. In this chapter experimental approaches to antiaging activity of MLT as well as its possible therapeutic significance are reviewed and discussed.
Background: Resistance developments against established antibiotics are an emerging problem for a... more Background: Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Novel antibiotics are urgently needed. Materials & methods: We developed novel small-molecule antibacterials which are easily accessible in a simple one-pot synthesis. The central cyclopentaindole core is substituted with two indole residues. Various indole and cyclopentane substituents have been introduced. Additionally, first indole substituted propene compounds as ring-open variants of the cyclopentaindoles have been yielded and evaluated as antibacterials against Staphylococcus aureus and Enterococcus strains. Results: Most effective compounds have been those with a bromo cyclopentane and a chloro indole substitution. First lead compounds were identified with promising activities similar to that observed in vitro for last resort antibiotics, so that the novel compounds enriche the pool of perspective small-molecule antibacterial drug candidates.
We previously synthesized a series of quinoline-2-carbaldehyde hydrazone derivatives and evaluate... more We previously synthesized a series of quinoline-2-carbaldehyde hydrazone derivatives and evaluated their antioxidant activities. In this study, the antimicrobial activities of these quinoline-2-car...
Brazilian Journal of Pharmaceutical Sciences, 2020
Melatonin (MLT) is a strong free radical scavenger that protects the body from the deleterious ef... more Melatonin (MLT) is a strong free radical scavenger that protects the body from the deleterious effects of excess oxidants. Synthesis of MLT analogue compounds with antioxidant potency has recently attracted the interest of researchers. In general, the strategy consists of modifying the groups in the different sites of the indole ring or replacing the indole ring with an analogue. As part of our ongoing research, the antioxidant capacity and cytotoxicity of newly synthesized MLT analogue naphthalene derivatives were evaluated. The radical scavenging activity was tested by a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Most of the synthesized compounds showed significant antioxidant activity in comparison to MLT. The structure-activity relationship was identified. The in vitro cytotoxic effects of the synthesized compounds were also investigated in CHO-K1 cells using the MTT assay.
Oxidative stress has been recognized as a contributing factor in ageing and various diseases incl... more Oxidative stress has been recognized as a contributing factor in ageing and various diseases including cancer and neuropathological disorders. Indole derivatives such as the neurohormone melatonin (MLT) constitute an important class of therapeutic agent in medicinal chemistry. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. As a part of our ongoing studies, a series of new indole-based hydrazide/hydrazone derivatives were synthesized as MLT analogues. Their antioxidant activity was investigated in human erythrocytes by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Possible inherent cytotoxicity of the compounds was investigated in CHO-K1 cells by lactate dehydrogenase leakage test. Protection of neuronal PC12 cells against amyloid β-induced damage was examined by MTT assay and their ability in reduction of ROS generation induced by amyloid β was tested. MLT analogues having a...
Antioxidants scavenge and prevent the formation of free radicals so they are exceedingly importan... more Antioxidants scavenge and prevent the formation of free radicals so they are exceedingly important for the treatment and management of these kinds of diseases. Therefore, in recent years, there has been an increasing interest in finding new antioxidant compounds. Oxidant molecules can cause extensive damage to DNA, protein, and lipids. This is a major reason of aging and many degenerative diseases of aging such as cancer, cardiovascular disease, immune-system decline and brain dysfunction. Melatonin (0/7) synthesized mainly in the pineal gland, has a number of physiological functions. Main functions include regulating circadian rhythms, reimbursement of free radicals, help to improve immunity and generally inhibiting the oxidation of biomolecules directly or indirectly. With this study based on MLT, series of new indole imines were developed. Three parts of the MLT molecule were modified in order to find out better antioxidant behavior and structure activity relationship of the new ...
Diabetes mellitus is a chronic metabolic disorder, and diabetic complications lead to morbidity a... more Diabetes mellitus is a chronic metabolic disorder, and diabetic complications lead to morbidity and death in diabetic patients. Hyperglycemia has been shown to be the most important risk factor in charge for the systemic complications. Various biochemical pathways have been proposed to explain the adverse effects of hyperglycemia. Potential cellular mechanisms of hyperglycemia-induced complications are the activation of diacylglycerol-protein kinase C, increased polyol pathway, enhanced reactive oxygen species production, nonenzymatic glycation and advanced glycation end products pathway (1-4).
Journal of Chemical Crystallography - J CHEM CRYSTALLOGRAPHY, 2000
As part of a program investigating the conformations of potential anticarcinogens and antioxidant... more As part of a program investigating the conformations of potential anticarcinogens and antioxidants, the structure of the title compound C24H28N2O2·H2O is reported. The monohydrate crystallizes in the monoclinic space group P2/c with unit cell parameters a = 16.184(1),b = 7.937(1), c = 16.968(1), ß = 92.788(7)°, and Z = 4. The benzimidazole and tetrahydrotetramethylnaphthalene ring systems are inclined to one another by approximately 26°. The water molecule plays an important role in the crystal structure by hydrogen bonding to different functional groups of three organic moieties. Additional crystal stabilization is dueto p–p stacking of benzimidazole rings.
Some biologically important indolylthiohydantoin derivatives were investigated electroanalyticall... more Some biologically important indolylthiohydantoin derivatives were investigated electroanalytically by voltammetric determination. Based on this study, a simple, rapid, sensitive and validated voltammetric method was developed for the determination of the indolylthiohydantoin derivatives that ...
Over the last decade, there has been substantial interest in the use of melatonin (MLT) and MLT-l... more 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.
Oxidative Stress (OS) is involved in the development of many pathological conditions and diseases... more Oxidative Stress (OS) is involved in the development of many pathological conditions and diseases such as cancer, neurodegenerative diseases and aging by effecting various important components of cells. Although the multiple roles of OS in human biology and pathology have been intensely studied over the last decades, the problem is still far beyond our full understanding. Therefore, in a rather short history of oxidative medicine, the roles of free radicals and antioxidants have been entirely redefined.
Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the ... more Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the world. Thus, there is an urgent need for novel therapies targeting major cancer-related pathways. Nuclear factor-erythroid 2-related factor 2 (NRF2) and its major negative modulator Kelch-like ECH-associated protein 1 (KEAP1) are main players of the cellular defense mechanisms against internal and external cell stressors. However, NRF2/KEAP1 signaling pathway is dysregulated in various cancers, thus promoting tumor cell survival and metastasis. In the present review, we discuss the mechanisms of normal and deregulated NRF2 signaling pathway focusing on its cancer-related functions. We further explore activators and inhibitors of this pathway as cancer targeting drug candidates in order to provide an extensive background on the subject.
The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective r... more The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review.
Antioxidants are helpful in prevention of several diseases related with oxidative stress includin... more Antioxidants are helpful in prevention of several diseases related with oxidative stress including neurodegenerative disorders. In recent studies, carbazoles were given proof of promising antioxidant activities. In this article, 9-ethyl-9H-carbazole hydrazone derivatives were synthesized, characterized and their in vitro antioxidant activity and possible cytotoxic effects were investigated. Furthermore, protective effect of the synthesized derivatives against amyloid β-induced damage in PC12 neuronal cells was examined by using MTT assay. The newly synthesized carbazoles were found to have radical scavenging activity with a varying potency both in cell-free and cell-based in vitro assays. Several compounds, especially such as 3d and 3e, 3m and 3n bearing two halogen groups on the phenyl ring, were found to have cytotoxic activity. However, their cytotoxic activities were not higher than that of melatonin. Several compounds also significantly protected neuronal PC12 cells against amy...
The aim of this study was to synthesize and examine possible in vitro antioxidant effects of indo... more 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 H 2 O 2-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.
In vitro studies of the skin-lightening activity of molatonin and related indoleamines were condu... more In vitro studies of the skin-lightening activity of molatonin and related indoleamines were conducted an the frog, Rana, piviona. Using objective, photometric measurements of reflectance, the res ponse of the dermal malanocytes to these compounds was determined. Me'stonin consistently produced_j ficant lightening of skins at concentrations as low as 5 X 10 r Other indoleaminas found to possess skin-lightening activity were ranked in approximate order of potency relative to melatonin. the most potent of the coopounds studied. Studies of these and a number of related, but Inactive, compounds provided evidence ouggesting structural requirements for compounds having activity on the malatonis receptor. Among the least potent of the active compounds, a malatonin blocking agent, N-acetylo*rotoni. n, was discovered. This prompted the synthesis of a
Molecular Basis and Emerging Strategies for Anti-aging Interventions, 2018
Melatonin (N-acetyl-5-methoxy tryptamine, MLT) is a hormone that is produced by the pineal gland.... more Melatonin (N-acetyl-5-methoxy tryptamine, MLT) is a hormone that is produced by the pineal gland. It is synthesized regularly with high levels at night. Age-related decline in MLT contributes to an increased susceptibility to a number of pathophysiological disorders like neurodegenerative diseases, cancer, and aging. There are strong evidences that both Alzheimer’s disease and Parkinson’s disease are associated with low levels of MLT. Because of its wide-ranging antioxidant and radical scavenger effects, MLT may act as a protective agent against many age-related illnesses. MLT’s protection may be possible for both protein and fat tissues in the body by crossing all cell membrane. Currently available data make us to determine that MLT is beneficial for the aging process. Administration of MLT is able to increase the life span of several animals including some rodents. Although, to preserve health in old age becomes a primary goal for biomedicine, there is a necessity for extensive studies on the administration of MLT in order to increase the quality of life in advanced age. In this chapter experimental approaches to antiaging activity of MLT as well as its possible therapeutic significance are reviewed and discussed.
Background: Resistance developments against established antibiotics are an emerging problem for a... more Background: Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Novel antibiotics are urgently needed. Materials & methods: We developed novel small-molecule antibacterials which are easily accessible in a simple one-pot synthesis. The central cyclopentaindole core is substituted with two indole residues. Various indole and cyclopentane substituents have been introduced. Additionally, first indole substituted propene compounds as ring-open variants of the cyclopentaindoles have been yielded and evaluated as antibacterials against Staphylococcus aureus and Enterococcus strains. Results: Most effective compounds have been those with a bromo cyclopentane and a chloro indole substitution. First lead compounds were identified with promising activities similar to that observed in vitro for last resort antibiotics, so that the novel compounds enriche the pool of perspective small-molecule antibacterial drug candidates.
We previously synthesized a series of quinoline-2-carbaldehyde hydrazone derivatives and evaluate... more We previously synthesized a series of quinoline-2-carbaldehyde hydrazone derivatives and evaluated their antioxidant activities. In this study, the antimicrobial activities of these quinoline-2-car...
Brazilian Journal of Pharmaceutical Sciences, 2020
Melatonin (MLT) is a strong free radical scavenger that protects the body from the deleterious ef... more Melatonin (MLT) is a strong free radical scavenger that protects the body from the deleterious effects of excess oxidants. Synthesis of MLT analogue compounds with antioxidant potency has recently attracted the interest of researchers. In general, the strategy consists of modifying the groups in the different sites of the indole ring or replacing the indole ring with an analogue. As part of our ongoing research, the antioxidant capacity and cytotoxicity of newly synthesized MLT analogue naphthalene derivatives were evaluated. The radical scavenging activity was tested by a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Most of the synthesized compounds showed significant antioxidant activity in comparison to MLT. The structure-activity relationship was identified. The in vitro cytotoxic effects of the synthesized compounds were also investigated in CHO-K1 cells using the MTT assay.
Oxidative stress has been recognized as a contributing factor in ageing and various diseases incl... more Oxidative stress has been recognized as a contributing factor in ageing and various diseases including cancer and neuropathological disorders. Indole derivatives such as the neurohormone melatonin (MLT) constitute an important class of therapeutic agent in medicinal chemistry. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. As a part of our ongoing studies, a series of new indole-based hydrazide/hydrazone derivatives were synthesized as MLT analogues. Their antioxidant activity was investigated in human erythrocytes by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Possible inherent cytotoxicity of the compounds was investigated in CHO-K1 cells by lactate dehydrogenase leakage test. Protection of neuronal PC12 cells against amyloid β-induced damage was examined by MTT assay and their ability in reduction of ROS generation induced by amyloid β was tested. MLT analogues having a...
Antioxidants scavenge and prevent the formation of free radicals so they are exceedingly importan... more Antioxidants scavenge and prevent the formation of free radicals so they are exceedingly important for the treatment and management of these kinds of diseases. Therefore, in recent years, there has been an increasing interest in finding new antioxidant compounds. Oxidant molecules can cause extensive damage to DNA, protein, and lipids. This is a major reason of aging and many degenerative diseases of aging such as cancer, cardiovascular disease, immune-system decline and brain dysfunction. Melatonin (0/7) synthesized mainly in the pineal gland, has a number of physiological functions. Main functions include regulating circadian rhythms, reimbursement of free radicals, help to improve immunity and generally inhibiting the oxidation of biomolecules directly or indirectly. With this study based on MLT, series of new indole imines were developed. Three parts of the MLT molecule were modified in order to find out better antioxidant behavior and structure activity relationship of the new ...
Diabetes mellitus is a chronic metabolic disorder, and diabetic complications lead to morbidity a... more Diabetes mellitus is a chronic metabolic disorder, and diabetic complications lead to morbidity and death in diabetic patients. Hyperglycemia has been shown to be the most important risk factor in charge for the systemic complications. Various biochemical pathways have been proposed to explain the adverse effects of hyperglycemia. Potential cellular mechanisms of hyperglycemia-induced complications are the activation of diacylglycerol-protein kinase C, increased polyol pathway, enhanced reactive oxygen species production, nonenzymatic glycation and advanced glycation end products pathway (1-4).
Journal of Chemical Crystallography - J CHEM CRYSTALLOGRAPHY, 2000
As part of a program investigating the conformations of potential anticarcinogens and antioxidant... more As part of a program investigating the conformations of potential anticarcinogens and antioxidants, the structure of the title compound C24H28N2O2·H2O is reported. The monohydrate crystallizes in the monoclinic space group P2/c with unit cell parameters a = 16.184(1),b = 7.937(1), c = 16.968(1), ß = 92.788(7)°, and Z = 4. The benzimidazole and tetrahydrotetramethylnaphthalene ring systems are inclined to one another by approximately 26°. The water molecule plays an important role in the crystal structure by hydrogen bonding to different functional groups of three organic moieties. Additional crystal stabilization is dueto p–p stacking of benzimidazole rings.
Some biologically important indolylthiohydantoin derivatives were investigated electroanalyticall... more Some biologically important indolylthiohydantoin derivatives were investigated electroanalytically by voltammetric determination. Based on this study, a simple, rapid, sensitive and validated voltammetric method was developed for the determination of the indolylthiohydantoin derivatives that ...
Over the last decade, there has been substantial interest in the use of melatonin (MLT) and MLT-l... more 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.
Oxidative Stress (OS) is involved in the development of many pathological conditions and diseases... more Oxidative Stress (OS) is involved in the development of many pathological conditions and diseases such as cancer, neurodegenerative diseases and aging by effecting various important components of cells. Although the multiple roles of OS in human biology and pathology have been intensely studied over the last decades, the problem is still far beyond our full understanding. Therefore, in a rather short history of oxidative medicine, the roles of free radicals and antioxidants have been entirely redefined.
Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the ... more Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the world. Thus, there is an urgent need for novel therapies targeting major cancer-related pathways. Nuclear factor-erythroid 2-related factor 2 (NRF2) and its major negative modulator Kelch-like ECH-associated protein 1 (KEAP1) are main players of the cellular defense mechanisms against internal and external cell stressors. However, NRF2/KEAP1 signaling pathway is dysregulated in various cancers, thus promoting tumor cell survival and metastasis. In the present review, we discuss the mechanisms of normal and deregulated NRF2 signaling pathway focusing on its cancer-related functions. We further explore activators and inhibitors of this pathway as cancer targeting drug candidates in order to provide an extensive background on the subject.
The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective r... more The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review.
Antioxidants are helpful in prevention of several diseases related with oxidative stress includin... more Antioxidants are helpful in prevention of several diseases related with oxidative stress including neurodegenerative disorders. In recent studies, carbazoles were given proof of promising antioxidant activities. In this article, 9-ethyl-9H-carbazole hydrazone derivatives were synthesized, characterized and their in vitro antioxidant activity and possible cytotoxic effects were investigated. Furthermore, protective effect of the synthesized derivatives against amyloid β-induced damage in PC12 neuronal cells was examined by using MTT assay. The newly synthesized carbazoles were found to have radical scavenging activity with a varying potency both in cell-free and cell-based in vitro assays. Several compounds, especially such as 3d and 3e, 3m and 3n bearing two halogen groups on the phenyl ring, were found to have cytotoxic activity. However, their cytotoxic activities were not higher than that of melatonin. Several compounds also significantly protected neuronal PC12 cells against amy...
The aim of this study was to synthesize and examine possible in vitro antioxidant effects of indo... more 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 H 2 O 2-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.
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