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

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

Experimental screening for analgesic and anti-inflammatory effect of novel compounds with a pyrrole heterocycle

The pyrrole heterocycle is found in the chemical structure of numerous drugs with various effects, and it has a reasonably high tolerance and safety profile. The objectives of our study were to assess the analgesic and anti-inflammatory efficacy of six novel compounds with pyrrolic structures. Methods: All trials were carried out on 6-week-old male Wistar rats. Animal pain models using thermal (paw withdrawal, tail-flick) and chemical stimuli (formalin test) were used to examine antinociception. A carrageenan-induced paw edema model was used to assess anti-inflammatory activity. Results: Significant differences between the experimental groups were observed in both early and late phase of the formalin test. Conclusions: The six novel pyrrolic compounds have analgesic action against chemical stimuli in experimental conditions. They do not possess anti-inflammatory activity, or antinociceptive properties against thermal stimuli

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

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 and validation of RP-HPLC method for stability evaluation of model hydrazone, containing a pyrrole ring

RP-HPLC method with UV detection was developed and validated for determination of the chemical stability and stability in close to physiological conditions of a model pyrrole hydrazone ethyl 5-(4-bromophenyl)-1-(1-(2-(4-hydroxy-3-methoxybenzylidene) hydrazineyl)-4-methyl-1-oxopentan-2-yl)-2-methyl-1H-pyrrole-3-carboxylate (D_5d), containing susceptible to hydrolysis hydrazone group. The evaluated substance was subjected to the influence of a variety of pH , representing the main physiological values of 37°C and corresponding pH values in the stomach (pH 2.0), blood (pH 7.4) and small intestine (pH 9.0). Chemical stability in a highly alkaline medium with a pH of 13.0 was also evaluated. The hydrazone I tested was found to be stable at pH 7.4 and pH 9.0 and 37 ° C and hydrolyzed under strong acidic (pH 2.0) and highly alkaline media (pH 13.0) and at the same temperature.The products of hydrolysis were identified to be the initial hydrazide and aldehyde, pointing the hydrazone group as most liable

Biological Screening of Novel Structural Analog of Celecoxib as Potential Anti-Inflammatory and Analgesic Agent

Background and objectives: The clinical use of non-steroidal anti-inflammatory drugs is limited due to high incidence of adverse drug reactions. The pyrrole heterocycle is included in the chemical structure of a number of drugs with various activities and shows relatively good tolerability and safety. The objectives of our study were to evaluate the analgesic and anti-inflammatory activity, as well as possible organ toxicity, of 2-[3-acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid (compound 3g), a novel N-pyrrolylcarboxylic acid structurally similar to celecoxib. Materials and methods: All experiments were performed on 6-week-old male Wistar rats divided into parallel groups (n = 8). Antinociception was assessed using animal pain models with thermal and chemical stimuli (paw withdrawal, tail-flick, and formalin tests). Criteria for the analgesic effect were increased latency in the paw withdrawal and tail-flick tests and decreased paw licking time in the formalin test compared to animals treated with saline (control). Anti-inflammatory activity was measured using a carrageenan-induced paw edema model; the criterion for anti-inflammatory effect was decreased edema compared to control. Blood samples were obtained after animals were sacrificed to assess possible organ toxicity. Statistical analysis was performed with IBM SPSS 20.0. Results: 2-[3-Acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid had analgesic action against chemical stimulus after single and multiple administration and against thermal stimulus after single administration. Compound 3g significantly suppressed carrageenan-induced paw edema after both single and continuous administration. After continuous administration, hematological tests showed that compound 3g decreased leukocyte and platelet levels and elevated serum creatinine levels. Conclusions: Antinociception with the tested compound is most likely mediated by spinal, peripheral, and anti-inflammatory mechanisms. Possible tolerance of the analgesic action at the spinal level develops after continuous administration. Anti-inflammatory activity is significant and probably the leading cause of antinociception. After multiple administration, compound 3g showed signs of potential nephrotoxicity and antiplatelet activity, as well as suppression of leukocyte levels

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

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