Papers by Dimi Zheleva-Dimitrova
A new acylated flavonol glycoside, namely gomphrenol-3-O-(5'''-O-E-feruloyl)-β-D-apio... more A new acylated flavonol glycoside, namely gomphrenol-3-O-(5'''-O-E-feruloyl)-β-D-apiofuranosyl(1→2)[β-D-glucopyranosyl-(1→6)]-β-D-glucopyranoside (1) was isolated from the aerial parts of Chenopodium foliosum Asch. The structure of 1 was determined by means of spectroscopic methods (1D and 2D NMR, UV, IR, and HRESIMS). Radical scavenging and antioxidant activities of 1 were established using DPPH and ABTS radicals, FRAP assay and inhibition of lipid peroxidation (LP) in linoleic acid system by the ferric thiocyanate method. Compound 1 showed low activity (DPPH and ABTS) or lack of activity (FRAP and LP). In combination with CCl4, 1 reduced the damage caused by the hepatotoxic agent and preserved cell viability and GSH level, decreased LDH leakage and reduced lipid damage. Effects were concentration dependent, most visible at the highest concentration (100 μg/mL), and similar to those of silymarin.
Bioorganic & Medicinal Chemistry, 2015
The inhibitors of acetylcholinesterase are the main therapy against Alzheimer's disease. Among th... more The inhibitors of acetylcholinesterase are the main therapy against Alzheimer's disease. Among them, galantamine is the best tolerated and the most prescribed drug. In the present study, 41 galantamine derivatives with known acetylcholinesterase inhibitory activities expressed as IC 50 were selected from the literature and docked into a recombinant human acetylcholinesterase by GOLD. A linear relationship between GoldScores and pIC 50 values was found and used to design and predict novel galantamine derivatives with indole moiety in the side chain. The four best predicted compounds were synthesized and tested for inhibitory activity. All of them were between 11 and 95 times more active than galantamine. The novel galantamine derivatives with indole moiety have dual site binding to the enzyme-the galantamine moiety binds to the catalytic anionic site and the indole moiety binds to peripheral anionic site. Additionally, the indole moiety of one of the novel inhibitors binds in a region, close to the peripheral anionic site of the enzyme, where the X-loop of amyloid beta peptide adheres to acetylcholinesterase. This compound emerges as a promising lead compound for multi-target anti-Alzheimer therapy not only because of the strong inhibitory activity, but also because it is able to block the amyloid beta deposition on acetylcholinesterase.
The cytotoxic effects of hyperatomarin -a prenylated phloroglucinol isolated from Hypericum annul... more The cytotoxic effects of hyperatomarin -a prenylated phloroglucinol isolated from Hypericum annulatum Moris subsp. annulatum were assessed in a broad spectrum of tumor cell lines originating from leukemias, lymphomas and solid malignancies. The tested compound exerted strong concentration-dependent cytotoxic effects (IC50 values ranging 0.14-15.7 mM), comparable to and even outclassing in some cell lines those of the established anti-cancer drug daunorubicin. Exposure of different human tumor cell lines to hyperatomarin resulted in strong mono-and oligonucleosomal fragmentation of genomic DNA, as evidenced by 'Cell death detection' ELISA kit and by DNAelectrophoresis, which unambiguously indicates that the induction of apoptosis is implicated in the cytotoxic mode of action of the tested compound.
Biotechnology & Biotechnological Equipment, 2014
Piperazine nucleus is one of the most important heterocyclic systems exhibiting remarkable pharma... more Piperazine nucleus is one of the most important heterocyclic systems exhibiting remarkable pharmacological activities. Thus, in the current study six new aryl/aralkyl substituted piperazine derivatives, containing methylxanthine moiety were synthesized and their structures were confirmed by IR and 1 H NMR analysis. All compounds were in vitro screened for their activity as antioxidants using DPPH (2,2 0 -Diphenyl-1-picrylhydrazyl), ABTS (2,2 0 -azinobis-(3-ethylbenzo thiazine-6sulfonic acid)) and FRAP (ferric reducing/antioxidant power) methods. The antioxidant activity of the studied compounds against lipid peroxidation was also measured. The highest antioxidant activity was demonstrated by compound 3c. It is obvious that the presence of a hydroxyl group in the structure is essential for the antioxidant properties and should be taken into consideration in further design of structures with potential antioxidant properties.
Natural Product Research, 2012
The occurrence of three known benzophenones, namely annulatophenonoside, acetylannulatophenonosid... more The occurrence of three known benzophenones, namely annulatophenonoside, acetylannulatophenonoside and annulatophenone as well as a flavonol O-glycoside guajaverin in the aerial parts of Hypericum maculatum Crantz was established. In addition, hyperoside, isoquercitrin and miquelianin were isolated from this plant, as well. Radical scavenging and antioxidant activities of the isolated compounds were examined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) free radicals, ferric reducing antioxidant power (FRAP) assay and inhibition of lipid peroxidation in linoleic acid system by the ferric thiocyanate method. Isoquercitrin demonstrates the highest DPPH radical scavenging (96.6 ± 0.3%), FRAP (23.8 ± 0.2 Trolox equivalent, TE mol⁻¹) and antioxidant activity in linoleic acid system. Guajaverin and acetylannulatophenonoside show significantly strong ABTS radical scavenging activity (93.9 ± 0.4% and 93.4 ± 0.6%, respectively), which is comparable to that of ascorbic acid (96.2 ± 0.4%).
Biochemical Systematics and Ecology, 2007
Natural Product Research, 2009
Elegaphenonoside, a new benzophenone O-rhamnoside, together with two known benzophenone O-glycosi... more Elegaphenonoside, a new benzophenone O-rhamnoside, together with two known benzophenone O-glycosides, namely hypericophenonoside and neoannulatophenonoside, were isolated from the aerial parts of Hypericum elegans Stephan ex Willd. The structure of the new compound was established as 3',5',6-trihydroxy-4-methoxybenzophenone-2-O-alpha-L-rhamnopyranoside by means of chemical and physical evidence. In addition, the presence of kaempferol, quercetin, isoquercitrin, norathyriol, I-3,II-8-biapigenin, quercitrin, hyperoside and rutin were established in this plant.
Molecular Informatics, 2016
The enzyme acetylcholinesterase is a key target in the treatment of Alzheimer&amp... more The enzyme acetylcholinesterase is a key target in the treatment of Alzheimer's disease because of its ability to hydrolyze acetylcholine via the catalytic binding site and to accelerate the aggregation of amyloid-β peptide via the peripheral anionic site (PAS). Using docking-based predictions, in the present study we design 20 novel galantamine derivatives with alkylamide spacers of different length ending with aromatic fragments. The galantamine moiety blocks the catalytic site, while the terminal aromatic fragments bind in PAS. The best predicted compounds are synthesized and tested for acetylcholinesterase inhibitory activity. The experimental results confirm the predictions and show that the heptylamide spacer is of optimal length to bridge the galantamine moiety bound in the catalytic site and the aromatic fragments interacting with PAS. Among the tested terminal aromatic fragments, the phenethyl substituent is the most suitable for binding in PAS.
International Journal of Pharmacy and Pharmaceutical Sciences
Cited By (since 1996):2, Export Date: 18 October 2014
Export Date: 23 March 2014, Source: Scopus
Pharmacognosy Magazine, 2015
Bupleurum L. (Aspiaceae) species are used as herbal remedy in Chinese traditional medicine. The a... more Bupleurum L. (Aspiaceae) species are used as herbal remedy in Chinese traditional medicine. The aim was to investigate the flavonoids in three annual European Bupleurum species, including B. baldense, B. affine and B. flavum, and to test their antioxidant and possible hepatoprotective effects. Flavonoids from the methanol-aqueous extracts were quantified by solid-phase extraction-high-performance liquid chromatography. Bupleurum extracts (1-220 mg/ml) were tested for their antioxidant activity in DPPH and ABTS assays, as well as on isolated liver rat microsomes. In vitro hepatoprotective activity of B. flavum flavonoid (BFF) mixture and rutin, and narcissin, isolated from the same mixture, were evaluated on carbon tetrachloride (CCl4) and tert-butyl hydroperoxide (t-BuOOH) toxicity models in isolated rat hepatocytes. Narcissin was the dominant flavonol glycoside in B. flavum being present at 24.21 ± 0.19 mg/g, whilst the highest content of rutin (28.63 ± 1.57 mg/g) was found in B. baldense. B. flavum possessed the strongest DPPH (IC50 22.12 μg/ml) and ABTS (IC50 118.15 μg/ml) activity. At a concentration 1 mg/ml of BFF (rutin 197.58 mg/g, narcissin 75.74 mg/g), a stronger antioxidant effect in microsomes was evidenced in comparison with silymarin, rutin and narcissin. The hepatoprotective effect of BFF significantly reduced the elevated levels of lactate dehydrogenase and malondialdehyde, and ameliorated glutathione, being most active in t-BuOOH-induced injury model when compared with CCl4 toxicity (P < 0.001). In BFF, synergism of rutin and narcissin could be responsible for stronger protection against mitochondrial induced oxidative stress.
Phytochemical Analysis, 2007
The content of the benzophenones, hypericophenonoside, neoannulatophenonoside, annulatophenonosid... more The content of the benzophenones, hypericophenonoside, neoannulatophenonoside, annulatophenonoside, annulatophenone, acetylannulatophenonoside and the xanthone derivative gentisein have been determined in aerial parts, leaves, flowers and stems of Hypericum annulatum Moris. Extraction of samples with methanol by magnetic stirring at room temperature allowed a good recovery of analytes (from 90.70% for gentisein to 103.81% for annulatophenonoside) and the precision of the entire procedure was < 6.05%. The subsequent HPLC separation and quantification was achieved using a Hypersil ODS C18 column and UV detection at 290 nm. The mobile phase comprised methanol and 20 mm potassium dihydrogen phosphate (adjusted to a pH of 3.19 with o-phosphoric acid), and gradient elution mode was applied. The detection limits were 0.03, 0.02 and 0.001 microg/mL for hypericophenonoside, acetylannulatophenonoside and gentisein, respectively. The total amounts of the phenolic compounds assayed ranged from 10.92 mg/g in stems to 82.86 mg/g in leaves. Hypericophenonoside was the dominant benzophenone present in the majority of the plant samples, being present in amounts between 7.54 +/- 0.25 mg/g in stems and 64.22 +/- 2.44 mg/g in leaves. Hypericophenonoside accounted for up to 77.50% of the components found in the leaves, whereas annulatophenonoside (6.29 +/- 0.15 mg/g) and acetylannulatophenonoside (8.95 +/- 0.09 mg/g) were detected in much lower quantities. In contrast to leaves, flowers showed a tendency towards higher contents of gentisein (9.35 +/- 0.07 mg/g) and neoannulatophenonoside (4.72 +/- 0.04 mg/g) than the other parts assayed.
Natural Product Research, 2011
Two cytotoxic constituents, namely elegaphenone and 7-epi-clusianone, were isolated from the aeri... more Two cytotoxic constituents, namely elegaphenone and 7-epi-clusianone, were isolated from the aerial parts of Hypericum elegans Stepan ex Willd. Elegaphenone was identified as (E)-(2-(3,7-dimethylocta-2,6-dienyloxy)-4,6-dihydroxyphenyl)(phenyl)methanone by means of spectral evidence. Both compounds showed prominent cytotoxicity on HD-MY-Z, K-562 and KE-37 tumour cell lines. The IC(50) values for elegaphenone were 15.9 (HD-MY-Z), 13.9 (K-562) and 16.9 (KE-37) µmol while those of 7-epi-clusianone were 9.8 (HD-MY-Z), 11.8 (K-562) and 13.6 (KE-37) µmol. The established oligonucleosomal deoxyribonucleic acid (DNA) fragmentation of genomic DNA following short-term (6 h) or long-term (24 h) exposure to the tested compounds clearly indicates that the induction of apoptotic cell death is an important component for their cytotoxic mode of action.
Medicinal Chemistry, 2006
A new benzophenone O-glucoside neoannulatophenonoside (1) together with the known pinocembrin-7-O... more A new benzophenone O-glucoside neoannulatophenonoside (1) together with the known pinocembrin-7-O-glucoside were isolated from the aerial parts of Hyperium annulatum Moris (Guttiferae). The former was identified as 3',5',6-trihydroxy-4-methoxybenzophenone-2-O-beta-D-glucopyranoside by means of chemical and physical evidence. The cytoprotective effects of the new compound together with the previously isolated from this species hypericophenonoside (2), annulatophenone (3), annulatophenonoside (4), acetylannulatophenonoside (5) and 1,3,7-trihydroxyxanthone (6) were evaluated in a model of epirubicin-induced cellular toxicity in K-562 cells. While the benzophenone O-glycosides 1, 2, 4 and 5 exerted substantial cytoprotective effects against the epirubicin cytotoxicity in K-562 cells the aglycones 3 and 6 lacked any significant cytoprotective activity. Biochemical investigations aimed at evaluating the free-radical scavenging activity of the tested compounds as well as their effects on the cellular glutathione stores were carried out as well, aiming at unravelling the mechanisms of cytoprotection. Finally, the ability of 1, 4 and 5 to ameliorate epirubicin-induced anticlonogenic effects on bone marrow cells colony forming units, in vitro were also evaluated. Taken together, the experimental data indicate that the benzophenone glycosides isolated from H. annulatum have a substantial cytoprotective potential against the toxic effects induced by epirubicin and necessitates further detailed pharmacological evaluation of these compounds as possible chemoprotective/radioprotective agents.
Current Medicinal Chemistry, 2013
Oxidative stress is implicated in the pathogenesis of different human diseases: Alzheimer, Parkin... more Oxidative stress is implicated in the pathogenesis of different human diseases: Alzheimer, Parkinson, Huntington, amyotrophic lateral sclerosis (Lou Gehrig's disease), Down's syndrome, atherosclerosis, vascular disease, cancer, diabetes mellitus type 1 and type 2, age - related macular degeneration, psoriatic arthritis. The aim of current study is to summarize the scientific evidences for the antioxidant and neuroprotective activity of Galantamine and some of its derivatives. Galantamine is a scavenger of reactive oxygen species and causes neuroprotective effect by lowering the oxidative neuronal damage, through the following pathways: 1) prevention of the activation of P2X7 receptors; 2) protection of mitochondrial membrane potential; 3) pre - vention of the membrane fluidity disturbances. Another mechanism is the decreasing of the overproduction of reactive oxygen species, a result from the increasing of acetylcholine level due to: 1) acethylcholinesterase inhibition; 2) allosteric potentiation of α7 - subtype of nicotinic acetylcholine receptors. A close relationship between acethylcholinesterase inhibition and reduced oxidative injury is observed. Through allosteric potentiation of the α7 - subtype of nicotinic acetylcholine receptors, the drug leads to induction of phosphorylation of serine - threonine protein kinase, stimulates phosphoinositide 3 - kinase and elevates the expression of protective protein Bcl - 2. By activation of these important neuroprotective cascades, Galantamine exerts neuroprotection against a variety of cytotoxic agents (β- amyloid peptide, glutamate, hydrogen peroxide, oxygen and glucose deprivation). The new trend in therapy of Alzheimer's disease will be the investigation and application of compounds such as Galantamine derivatives, which possess acethylcholinesterase and γ- secretase inhibitory activity and antioxidant properties.
Pharmacognosy Magazine, 2010
The antioxidant activities of eighteen different essential oil components have been determined us... more The antioxidant activities of eighteen different essential oil components have been determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicalscavenging assay, the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation assay, and the ferric reducing antioxidant power (FRAP) assay. The phenolic compounds, carvacrol, thymol, and eugenol, showed the best antioxidant activities, while camphor, menthol, and menthone were the least active. The structural and electronic properties of the essential oil components were assessed using density functional theory (DFT) at the B3LYP/6-311++G** level. Correlations between calculated electronic properties and antioxidant activities were generally poor, but bond-dissociation energies (BDEs) seem to correlate with DPPH radical-scavenging activities, and the ferric reducing antioxidant power (FRAP) assay correlated with vertical ionization potentials calculated at the Hartree-Fock/6-311++G** level.
Biotechnology & Biotechnological Equipment, 2014
Piperazine nucleus is one of the most important heterocyclic systems exhibiting remarkable pharma... more Piperazine nucleus is one of the most important heterocyclic systems exhibiting remarkable pharmacological activities.
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Papers by Dimi Zheleva-Dimitrova