DSpace Repository :: Browsing by Author "Vladimirova S."

Browsing by Author "Vladimirova S."

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An access to new N-pyrrolylcarboxylic acids as potential COX-2 inhibitors via Paal-Knorr cyclization
(2014-01-01) Vladimirova S.; Bijev A.
Twenty new N-pyrrolylcarboxylic acids were designed to assume the architecture of contemporary selective COX-2 inhibitors as potential anti-inflammatory agents. The targeted products were synthesized in 70-82% yields by Paal-Knorr cyclization of a set of eight amino acids, acting as primary amines, and four 1,4-dicarbonyl compounds. The latter substrates were prepared by C-alkylation of three commercially available β-dicarbonyl compounds with two ω-bromoacetophenones and used in situ. These compounds inhibit carrageenin-induced rat paw edema and show analgesic activity.
Analgesic properties of newly synthesized N-pyrrolyl hydrazide hydrazones
(2023-01-01) Nocheva H.; Vladimirova S.; Tzankova D.; Peikova L.; Georgieva M.
Purpose: To screen a series of newly synthesized N-pyrrolyl hydrazide hydrazones for analgesic activity via Paw-pressure (PP) test and hot plate test (HPT). Methods: The compounds newly synthesized through the classical Paal-Knor cyclization, N-pyrrolyl hydrazide-hydrazones were administered intraperitoneally at a dose of 20 mg/kg. Paw pressure and hot plate tests were applied to assess the analgesic properties. In addition, stress-induced analgesia with naloxone as a non-selective opioid receptor antagonist was performed. Results: The compound (DI-5g), containing an izatine carbonyl fragment, was the most promising. It presented the highest paw pressure threshold (25 AU at 30th min) by exceeding the analgesic activity of the referent metamizole (23 AU at 30th min). The relative effect from the hot plate test was consistent with the paw pressure results. Opioid receptors were involved in the analgesic activities of N-pyrrolyl hydrazide-hydrazones. Conclusion: The N-pyrrolyl carboxylic acids are synthesized and identified as new compounds and their hydrazide-hydrazone derivatives as promising leads for future design and synthesis of drugs with possibly prolonged analgesic activity.
Attenuation of 1-chloro-2, 4-dinitrobenzene-induced inflammation in atopic dermatitis-like skin lesions in rats by a pyrrole containing FELL-NH2 bioconjugate: Cannabinoid receptor type 1 involvement
(2024-01-01) Papadakis K.; Bezirci K.; Borisova B.; Vladimirova S.; Danalev D.; Handjieva-Darlenska T.; Tafradjiiska-Hadjiolova R.; Nocheva H.
Atopic dermatitis (AD) is a chronic inflammatory skin condition of significant health and social importance, which justifies the search for new means of treatment. Since the endogenous cannabinoid system appears to be involved in the pathogenesis of AD, the proposed article summarizes the clinical impact on skin inflammation in a rat model of 1-chloro-2, 4-dinitrobenzene-induced atopic dermatitis-like condition after exogenous systemic administration of the cannabinoid receptor type 1 (CB1r) agonist anandamide, as well as after local treatment with a newly synthesized pyrrole moiety containing bioconjugate of FELL tetrapeptide with CB1r-dependent analgesic activity. The changes in skin lesions and ear thickness were estimated along with the CB1r expression immunohistochemically determined on skin punch biopsies. The results showed attenuation of skin lesions by anandamide and lack of positive effect after introduction of CB1r antagonist, accompanied by a change in CB1r expression, suggesting the involvement of the cannabinoid system in the defensive functions of the skin. The topically applied newly synthesized bioconjugate also favorably affected skin manifestations of inflammation, but without a change in CB1r expression, suggesting the involvement of other mechanisms in the reported effects.
Biological screening of novel structural analog of Celecoxib as potential anti-inflammatory and analgesic agent
(2019-04-01) Zlatanova H.; Vladimirova S.; Kostadinov I.; Delev D.; Deneva T.; Kostadinova I.
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
(2022-01-01) Maslarska V.; Bozhanov S.; Vladimirova S.; Peikova L.; Tzankova D.; Georgieva M.
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 (150x4 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.
Development and validation of RP-HPLC method for stability evaluation of model hydrazone, containing a pyrrole ring
(2019-01-01) Tzankova D.; Peikova L.; Vladimirova S.; Georgieva M.
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.
Effect of H3Po3 and Nah2Po2 in the electrolyte on the composition and microstructure of Ni-Co-P alloys
(2019-01-01) Ignatova K.; Alakushev M.; Kozhukharov S.; Marcheva Y.; Vladimirova S.; Avdeev G.
The effect of two phosphorus-containing additives (phosphorous acid, H3PO3 and sodium hypophosphite, NaH-2PO2) in modified Watt's electrolyte (pH = 2; 80°S) on the deposition kinetics, morphology, component and phase composition of Ni-Co-P coatings was studied. When only one of the studied additives is present in the solution, the P content in the coatings reaches maximum of 15 % and their structure is amorphous. The P and Ni incorporation in the coatings is facilitated when the electrolytes with prevailing concentrations of H3PO3 are used. The maximal P content (over 30 %) in the coatings was reached when both additives were present in the electrolyte. These coatings possess mixed structure with nano-dimensional amorphous phase and crystal hexagonal phase of solid solutions Ni2P and Ni2P-Co2P. The increasing of the current density causes P content decrement and the resulting crystal phase is tetragonal, composed by solid solutions of Ni3P and Ni3P-Co3P.
EVALUATION OF THE IN VITRO NEUROTOXIC AND NEUROPROTECTIVE EFFECTS AT CELLULAR AND SUBCELLULAR LEVELS OF NEWLY SYNTHESIZED N-PYRROLYL HYDRAZONES
(2022-01-01) Tzankova D.; Vladimirova S.; Stefanova D.; Peikova L.; Kondeva-Burdina M.; Georgieva M.
The study presents the safety, antioxidant activity and neuroprotective effects of a series of newly synthesized N-pyrrolyl hydrazide-hydrazones (5, 5a-g) in two in vitro models: human neuronal cells SH-SY5Y and isolated rat brain synaptosomes. The performed in vitro toxicological evaluation in neuronal SH-SY5Y cell line models determined the lowest cytotoxicity and best safety profile for compound 5a, followed by 5d on both evaluated parameters. The protective effect of the newly synthesized hydrazone 5a was found to be comparable to melatonin used as a standard. The obtained results indicate that the presence of pyrrole ring, containing multiple phenyl nuclei and hydrazide-hydrazone group in the side chain, leads to increase in the antioxidant effect.
Experimental screening for analgesic and antiinflammatory effect of novel compounds with a pyrrole heterocycle
(2024-01-01) Zlatanova-Tenisheva H.; Vladimirova S.
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.
In Vivo Evaluation of Anti-inflammatory Activity of 2-[3-Acetyl- 5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-4-methylsulfanylbutyric Acid
(2018-06-01) Zlatanova H.; Vladimirova S.; Kostadinov I.; Bijev A.T.
BACKGROUND: Persisting inflammatory stimuli cause chronic inflammation recognized as the major factor contributing to the development of a number of diseases. One group of drugs used in the treatment of chronic inflammation is the group of non-steroidal anti-inflammatory drugs and, more specifically, the selective COX-2 inhibitors (coxibs). However, most of the coxibs were withdrawn from the market in view of their safety profile. In the present study, 2-[3-Acetyl-5-(4-chlorophenyl)- 2-methyl-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (compound 3e), an Npyrrolylcarboxylic acid derivative structurally related to celecoxib, is evaluated for anti-inflammatory activity after single and multiple (14 days) administration using an animal inflammation model. AIM: To evaluate the anti-inflammatory properties of 2-[3-Acetyl-5-(4-chlorophenyl)-2-methyl-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (compound 3e) after single and multiple (14 days) administration using an animal inflammation model. MATERIALS AND METHODS: Forty Wistar rats were allocated into 5 groups (n=8) treated with saline (controls), diclofenac (25 mg/kg b.w.), compound 3e (10, 20 and 40 mg/kg b.w.) intraperitoneally. The volume of the right hind paw of the animals of all groups is measured prior to treatment and two, three and four hours after administration of carrageenan using a plethysmometer (Ugo Basile, Italy). The percentage of paw edema is calculated using the Trinus formula. RESULTS: In a single administration, compound 3e in doses of 10 and 20 mg/kg b.w. did not inhibit paw edema, while a dose of 40 mg/kg b.w. significantly inhibited carrageenan-induced paw edema at 2 hours in comparison with the control group. After continuous administration, compound 3e in doses of 10, 20 and 40 mg/kg b.w. significantly reduced paw edema at 2, 3, and 4 hours compared to animals treated with saline. CONCLUSIONS: Compound 3e shows anti-inflammatory properties similar to those of diclofenac after continuous administration.
SYNTHESIS OF 2-HYDROXYNAPHTHYL PYRROLES BY ONE-POT THREE-COMPONENT REACTION UNDER SOLVENT-FREE CONDITIONS
(2020-01-01) Vladimirova S.
An efficient green synthesis of 2-hydroxynaphthyl pyrroles using citric or trichloroacetic acid as a catalyst for the three-component condensation reaction of benzaldehyde, β-naphthol and pyrrolyl benzamide under solvent-free conditions is described. Its advantages refer to high yields, short reaction time and simple work-up.
SYNTHESIS OF NEW PYRROLE COMPOUNDS WITH POTENTIAL ANTIHYPERLIPIDEMIC EFFECT
(2021-01-01) Vladimirova S.
Four new pyrrole compounds were designed to assume the architecture of contemporary antihyperlipidemic atorvastatine. The targeted products were synthesized via Paal-Knorr cyclization by condensation of a N1, N1-dimethylpropane-1,3-diamine, acting as primary amine and four 1,4-dicarbonyl compounds. The structures of these compounds were established by IR and 1H NMR spectra.
Synthesis of pyrrole and substituted pyrroles (Review)
(2018-01-01) Tzankova D.; Vladimirova S.; Peikova L.; Georgieva M.
Pyrrole is widely known as a biologically active scaffold which possesses a diverse nature of activities. The combination of different pharmacophores in a pyrrole ring system has led to the formation of more active compounds. Pyrrole containing analogs are considered as a potential source of biologically active compounds that contains a significant set of advantageous properties and can be found in many natural products. The present review highlights the synthetic methods of representatives of nitrogen heterocycles such as pyrrole, substituted pyrroles and other related compounds. The aim of this review is to indicate and summarise the different methods for the synthesis of nitrogen containing heterocycles from the group of pyrrole and pyrrole related structures.
Synthesis, Hydrolytic Stability and In Vivo Biological Study of Bioconjugates of the Tetrapeptides FELL Containing Pyrrole Moiety
(2023-12-01) Borisova B.; Vladimirova S.; Nocheva H.; Laronze-Cochard M.; Gérard S.; Petrin S.; Danalev D.
Background: Bioconjugates are promising alternatives for the multiple targeting of any disease. Pyrrole heterocycle is well known with many activities and is a building block of a lot of medical drugs. On the other hand, peptides are short molecules with many advantages such as small size, ability to penetrate the cell membrane and bond-specific receptors, vectorizing potential, etc. Thus, hybrid molecules between peptide and pyrrole moiety could be a promising alternative as an anti-pain tool. Methods: New bioconjugates with a general formula Pyrrole (α-/β-acid)-FELL-OH (NH2) were synthesized using Fmoc/OtBu peptide synthesis on solid support. HPLC was used to monitor the purity of newly synthesized bioconjugates. Their structures were proven by electrospray ionization mass spectrometry. The Paw Pressure test (Randall–Selitto test) was used to examinate the analgesic activity. Hydrolytic stability of targeted structures was monitored in three model systems with pH 2.0, 7.4 and 9.0, including specific enzymes by means of the HPLC-UV method. Results: The obtained results reveal that all newly synthesized bioconjugates have analgesic activity according to the used test but free pyrrole acids have the best analgesic activity. Conclusions: Although free pyrrole acids showed the best analgesic activity, they are the most unstable for hydrolysis. Combination with peptide structure leads to the hydrolytic stabilization of the bioconjugates, albeit with slightly reduced activity.
Synthesis, in vitro safety and antioxidant activity of new pyrrole hydrazones
(2020-09-01) Tzankova D.; Vladimirova S.; Aluani D.; Yordanov Y.; Peikova L.; Georgieva M.
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-pyr-role-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.

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