8 research outputs found

    Synthesis, in vitro safety and antioxidant activity of new pyrrole hydrazones

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    Six new N-pyrrolylhydrazide hydrazones were synthesized under micro synthesis conditions, assuring about 59–93 % yield, low harmful emissions and reagent economy. The structures of the new compounds were elucidated by melting points, TLC characteristics, IR, 1H and 13C NMR spectral data followed by MS data. The purity of the obtained compounds was proven by the corresponding elemental analyses. “Lipinski’s rule of five” parameters were applied for preliminary evaluation of the pharmacokinetic properties of the target molecules. The initial in vitro safety screening for cytotoxicity (on HepG2 cells) and hemocompatibility (hemolysis assay) showed good safety of the new compounds, where ethyl 5-(4-bromophenyl)-1-(1-(2-(4-hydroxy-3-methoxybenzylidene)hydrazineyl)-1-oxo-3-phenylpropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate (4d) and ethyl 5-(4-bromophenyl)-1-(1-(2-(2-hydroxybenzylidene)hydrazineyl)-1-oxo-3-phenylpropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate (4a) were the least toxic. The antioxidant activity in terms of radical scavenging activity (DPPH test) and reducing ability (ABTS) was also evaluated. The antioxidant protective potential of the compounds was next determined in different in vitro cellular-based models, revealing compounds 4d and 3 [ethyl 5-(4-bromophenyl)-1-(1-hydrazineyl-1-oxo-3-phenylpropan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate] as the most promising compounds, with 4d having better safety profile

    Synthesis, druglikeness estimation and prediction of possible pharmacological effects of new pyrrole hydrazones

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    The synthesis of five new N-pyrrolyl derivatives is presented. A classical Paal-Knorr cyclization was used   for synthesis of the initial N-pyrrolyl hydrazide and the final hydrazones were obtained in a micro synthe- sis apparatus, assuring about 65 - 95% yields, low harmful emissions and reagent economy. The compounds were elucidated by IR and 1H NMR spectral analyses and the obtained results were consistent with the as- signed structures. The purity of the substances was proven by TLC characteristics and corresponding melt- ing points. In addition, an attempt to predict the pharmacokinetic behavior and possible pharmacological effects of the target compounds was made, based on the molecular descriptors, obtained by the Molinspira- tion Cheminformatics web-based tool

    Development of RP-HPLC methods for the analysis of Dexamethasone and Levofloxacin alone and in combinations used in the therapy of Covid-19

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    In December 2019, the World Health Organization was informed of an outbreak of pneumonia of unknown etiology in Wuhan, Hubei Province, China. On January 7, 2020, a new type of coronavirus was isolated, with the WHO later officially calling it “COVID-19” and the International Committee on Taxonomy of Viruses naming the virus “SARS-CoV-2”. On January 30, 2020, the WHO declared the severe acute respiratory syndrome coronavirus 2 outbreak a public health emergency of international concern, making it an unprecedented global public health challenge. From a scientific and literary reference, it was established that the main drugs in the therapy with Covid-19 are Dexamethasone and Levofluoxetine. For this reason, we pay attention to the analysis of these two medicinal products. In the literature, we did not find an analysis of a combination of Dexamethasone and Levofloxacin. Development and validation of a highperformance liquid chromatographic analytical procedure for simultaneously determining Dexamethasone and Levofloxacin in a synthetic mixture is described in this paper. The separation was made with a LiChrosorb RP 18 (250 × 4.6 mm) column, at 25 °C temperature,with isocratic mode andmobile phase,containingt acetonitrile and woter (70-30v/v). Eluent was monitored at 254 nm and the flow rate was 1.0 ml/min. Dexamethasone and Levofluoxetine were effectively separated with retention time (tr) of 4.69 min and 14.51 min,respectively,with in the selected chromatographic conditions.The method was validated for analytical parameters: specificity, linearity, precision, accuracy,andlimits of detection and quantitation. The calibration curves were linear inthe concentration range of 12.5 to 100.0 μg/ml for Dexamethasone and Levofloxacin, and the regression coefficientswere more than 0.999. For Dexamethasone and Levofloxacin the recovery was 100.01% and 100.04%, respectively. This analytical procedure is applicable for the quality control of drug formulations

    Doxorubicin and Quercetin Double Loading in Modified MCM-41 Lowered Cardiotoxicity in H9c2 Cardioblast Cells In Vitro

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    Background: One of the therapeutic limitations of the use of doxorubicin (DOX) as an anticancer drug is its cardiotoxicity. Its hydrophilicity also causes difficulties in achieving sustained release. The simultaneous delivery with the well-known natural antioxidant quercetin could ameliorate its cardiotoxicity. Thus, the main aim of this work is to study the potential of carboxylated and non-carboxylated mesoporous silica MCM-41 nanoparticles for double loading of the hydrophilic doxorubicin hydrochloride and hydrophobic quercetin (Q) in one nanocarrier with a modified release pattern to reduce the cardiotoxic side effects of doxorubicin in vitro. Methods: The methods included the modification of MCM-41, single and double loading of modified and non-modified MCM-41, physicochemical characterization, in vitro release tests and kinetic study, and in vitro cell viability studies. Results: Doxorubicin and quercetin were successfully double-loaded with encapsulation efficiency (EE) of 43 ± 4.1% and 37 ± 4.5%, respectively, in native MCM-41. The post-synthetic carboxylation led to 49 ± 4.3% EE (DOX) and 36 ± 4.0% (Q) and double lowering of the cardiotoxicity on H9c2 (IC50 = 5.96 µm). Sustained release profiles over 72 h were achieved. Conclusions: A successful procedure was proposed for the efficient double loading of a hydrophilic drug and a hydrophobic drug. The carboxy-modified double-loaded nanosystems demonstrate a decreased in vitro cardiotoxicity of doxorubicin and can be considered as a potential chemotherapeutic formulation

    Thermosensitive Hydrogel-Functionalized Mesoporous Silica Nanoparticles for Parenteral Application of Chemotherapeutics

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    Hydrogels can offer many opportunities for drug delivery strategies. They can be used on their own, or their benefits can be further exploited in combination with other nanocarriers. Intelligent hydrogels that react to changes in the surrounding environment can be utilized as gatekeepers and provide sustained on-demand drug release. In this study, a hybrid nanosystem for temperature- and pH-sensitive delivery was prepared from MCM-41 nanoparticles grafted with a newly synthesized thermosensitive hydrogel (MCM-41/AA-g-PnVCL). The initial particles were chemically modified by the attachment of carboxyl groups. Later, they were grafted with agar (AA) and vinylcaprolactam (VCL) by free radical polymerization. Doxorubicin was applied as a model hydrophilic chemotherapeutic drug. The successful formulation was confirmed by FT-IR and TGA. Transmission electron microscopy and dynamic light scattering analysis showed small particles with negative zeta potential. Their release behaviour was investigated in vitro in media with different pH and at different temperatures. Under tumour simulating conditions (40 °C and pH 4.0), doxorubicin was almost completely released within 72 h. The biocompatibility of the proposed nanoparticles was demonstrated by in vitro haemolysis assay. These results suggest the possible parenteral application of the newly prepared hydrogel-functionalized mesoporous silica nanoparticles for temperature-sensitive and pH-triggered drug delivery at the tumour site

    Development and validation of an RP-HPLC method for analysis of 2-(5-(4-chlorophenyl)-3-(ethoxycarbonyl)-2-methyl-1H-pyrrol-1-yl)propanoic acid and its impurities under different pH

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    A simple, fast and selective stability indicating RP-HPLC method was applied for following the degradation and appearance of impurities of previously synthesized 2-(5-(4-chlorophenyl)-3-(ethoxycarbonyl)-2-methyl-1H-pyrrol-1-yl)propanoic acid. The chromatographic separation was achieved on a C18 column (150×4 mm i.d., 5 μm) using a mobile phase consisting of Acetonitrile: Phosphate buffer, pH=3, (50:50% v/v) with isocratic elution at a flow rate of 1.0 mL min−1 and temperature of the column of 30 °C applying a UV/VIS detector at 225 nm. The method was validated according to the ICH guidelines. A process related impurity was determined at pH 9.0 corresponding to ethyl 2-acetyl-4-(4-chlorophenyl)-4-oxobutanoate. No change in the structure was detected at pH = 7.4

    Synthesis, DFT Study, and In Vitro Evaluation of Antioxidant Properties and Cytotoxic and Cytoprotective Effects of New Hydrazones on SH-SY5Y Neuroblastoma Cell Lines

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    A series of ten new hydrazide–hydrazone derivatives bearing a pyrrole ring were synthesized and structurally elucidated through appropriate spectral characteristics. The target hydrazones were assessed for radical scavenging activity through 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) tests, with ethyl 5-(4-bromophenyl)-1-(2-(2-(4-hydroxy-3,5-dimethoxybenzylidene)hydrazine-yl)-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate (7d) and ethyl 5-(4-bromophenyl)-1-(3-(2-(4-hydroxy-3,5-dimethoxybenzylidene) hydra zine-yl)-3-oxopropyl)-2-methyl-1H-pyrrole-3-carboxylate (8d) highlighted as the best radical scavengers from the series. Additional density functional theory (DFT) studies have indicated that the best radical scavenging ligands in the newly synthesized molecules are stable, do not decompose into elements, are less polarizable, and with a hard nature. The energy of the highest occupied molecular orbital (HOMO) revealed that both compounds possess good electron donation capacities. Overall, 7d and 8d can readily scavenge free radicals in biological systems via the donation of hydrogen atoms and single electron transfer. The performed in vitro assessment of the compound’s protective activity on the H2O2-induced oxidative stress model on human neuroblastoma cell line SH-SY5Y determined 7d as the most perspective representative with the lowest cellular toxicity and the highest protection
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