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OBJECTIVES: Resistance to antibiotics is recognized as one of the biggest threats to human health worldwide. Frequent and unnecessary use of antibiotics has caused infectious agents to adapt to antibiotics and thus drugs have become less effective. The resistance to many antibiotics necessitates the discovery of new antibiotics. In this study, two new and 23 previously reported 2-pyrazoline derivatives and one hydrazone derivative were evaluated for their in vitro antibacterial and antifungal activities. MATERIALS AND METHODS: For the determination of the minimum inhibitory concentration (MIC) values of compounds, microbroth dilution was used. RESULTS: The antimicrobial activities of the compounds were found in a wide range with MIC values of 32-512 µg/mL. CONCLUSION: The synthesized compounds showed moderate antimicrobial activity compared with the standards. They can be used as lead molecules for the synthesis of more effective compounds.
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AIM AND OBJECTIVE: MAO inhibitors have a significant effect on the nervous system since they act in regulation of neurotransmitter concentrations. Neurotransmitter levels are critical for a healthy nervous system. MAO inhibitors can be used in the treatment of neurological disorders such as depression, Parkinson's disease and Alzheimer's disease, as the increase or decrease of some neurotransmitter concentrations is associated with these neurological disorders. This study was conducted to discover new and active MAO inhibitor drug candidates. MATERIALS AND METHODS: New pyrazoline derivatives have been designed with the molecular docking approach and interactions of our compounds with the MAO enzyme have been investigated using the Autodock 4.2 program. The designed pyrazoline derivative compounds were synthesized by the reaction of the chalcones and hydrazides in ethanol. hMAO inhibitory activities of the newly synthesized compounds were investigated by fluorimetric method. In vitro cytotoxicity of five most potent inhibitors were tested in HepG2 cells. RESULTS: (3-(5-bromo-2-hydroxyphenyl)-5-(4-methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5i) and (3-(2-hydroxy-4-methoxy phenyl)-5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone (5l) inhibited hMAO-A more potently than moclobemide (Ki values are 0.004±0.001 and 0.005±0.001, respectively). The same two compounds, 5i and 5l, inhibited hMAO-A more selectively than moclobemide (SI values are 5.55x10-5 and 0.003, respectively). Both of these compounds were found non toxic at 1 µM, 5 µM and 25µM concentrations. CONCLUSION: Two of the newly synthesized compounds, (3-(5-bromo-2-hydroxyphenyl)-5-(4- methoxyphenyl)-4,5-dihydropyrazol-1-yl)(phenyl)methanone and (3-(2-hydroxy-4-methoxy phenyl)- 5-p-tolyl-4,5-dihydropyrazol-1-yl)(phenyl) methanone were found to be promising MAO-A inhibitors due to their high inhibitory potency, high selectivity and low toxicity.
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Diseño de Fármacos , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Dosis-Respuesta a Droga , Células Hep G2 , Ensayos Analíticos de Alto Rendimiento , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de la Monoaminooxidasa/química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
AIM AND OBJECTIVE: Depression is a momentous disease that can greatly reduce the quality of life and cause death. In depression, neurotransmitter levels such as serotonine, dopamine and noradrenaline are impaired. Monoamine oxidases (MAO) are responsible for oxidative catalysis of these monoamine neurotransmitters. Because of this relation, MAO-A inhibitors show antidepressant activity by regulating neurotransmitter levels. This study was carried out to investigate the design, synthesis and activity of new antidepressant compounds in pyrazoline and hydrazone structure. MATERIAL AND METHOD: Chalcones and hydrazides were heated under reflux to give new pyrazoline and hydrazone derivatives. Docking simulations were performed using AutoDock4.2. hMAO activities were determined by a fluorimetric method. To determine cell viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used. Behavioral activities of the three compounds were determined by using Forced Swim Test, Step-Through Passive Avoidance Test, Elevated Plus Maze and Open Field Arena Tests. RESULTS: According to in vitro tests, all of the synthesized compounds were found more potent than moclobemide and six of the synthesized compounds were found more selective than moclobemide. Three of the synthesized compounds were investigated for their behavioral activities comparing with moclobemide after 7 days of i.p. treatment at 30 mg/kg. One of the three compounds elicited significant antidepressant properties. CONCLUSION: All of the synthesized compounds were found potent hMAO-A inhibitors in in vitro screening tests. Only one of the in vivo tested three compounds, (3-(2-hydroxy-5-methylphenyl)-5- p-tolyl-4,5-dihydropyrazol-1-yl)(pyridin-4-yl) methanone indicated significant antidepressant activity. This article opens a window for further development of new pyrazoline and hydrazone derivatives as antidepressant agents.
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Antidepresivos/farmacología , Ensayos Analíticos de Alto Rendimiento , Hidrazonas/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Pirazoles/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Conducta Animal , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Células Hep G2 , Humanos , Hidrazonas/síntesis química , Hidrazonas/química , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-Actividad , NataciónRESUMEN
Twenty-seven previously reported chalcones and their pyrazoline and hydrazone derivatives as well as two further chalcones have been screened for their antimicrobial, antifungal and antimycobacterial activities against standard microbial strains and drug resistant isolates. The minimum inhibitory concentration (MIC) value of each compound was determined by a two-fold serial microdilution technique. The compounds were found to possess a broad spectrum of antimicrobial activities with MIC values of 8-128 µg/mL. One compound [(E)-1-(4-hydroxyphenyl)-3-p-tolylprop-2-en-1-one] had equal activity with gentamycin (8 µg/mL) against Enterococcus faecalis. Chalcones were found to be more active than their hydrazone and 2-pyrazoline derivatives against Staphylococcus aureus ATCC 29213 and E. faecalis ATCC 29212.
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A group of 3,5-diaryl-2-pyrazoline and hydrazone derivatives was prepared via the reaction of various chalcones with hydrazide compounds in ethanol. Twenty original compounds were synthesized. Ten of these original compounds have a pyrazoline structure, nine of these original compounds have a hydrazone structure, and one of these original compounds has a chalcone structure. Structural elucidation of the compounds was performed by IR, (1)H NMR, (13)C NMR, mass spectral data, and elemental analyses. These compounds were tested for their inhibitory activities toward the A and B isoforms of human monoamine oxidase (MAO). Except for 3k and 6c, all compounds were found to be competitive, reversible, and selective inhibitors for either one of the isoforms (hMAO-A or MAO-B). Compounds 3k and 6c were found to be competitive, reversible, but non-selective MAO inhibitors. Compound 6h showed hMAO-B inhibitory activity whereas the others potently inhibited hMAO-A. Compound 5c showed higher selectivity than the standard drug moclobemide. According to the experimental K(i) values, compounds 6i, 6d, and 6a exhibited the highest inhibitory activity toward hMAO-A. The AutoDock 4.2 program was employed to perform automated molecular docking. The calculated results obtained computationally were in good agreement with the experimental values.
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Hidrazonas/síntesis química , Hidrazonas/farmacología , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Diseño de Fármacos , Humanos , Cinética , Moclobemida/farmacología , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Conformación Proteica , Relación Estructura-ActividadRESUMEN
A novel series of 2-pyrazoline and hydrazone derivatives were synthesized and investigated for their human monoamine oxidase (hMAO) inhibitory activity. All compounds inhibited the hMAO isoforms (MAO-A or MAO-B) competitively and reversibly. With the exception of 5i, which was a selective MAO-B inhibitor, all derivatives inhibited hMAO-A potently and selectively. According to the experimental Ki values, compounds 6e and 6h exhibited the highest inhibitory activity towards the hMAO-A, whereas compound 5j, which carries a bromine atom at R(4) of the A ring of the pyrazoline, appeared to be the most selective MAO-A inhibitor. Tested compounds were docked computationally into the active site of the hMAO-A and hMAO-B isozymes. The computationally obtained results were in good agreement with the corresponding experimental values.