Synthesis, characterization, and biological activity of some 2,4-diketo esters containing dehydrozingerone fragment: DNA and protein binding study.

Due to the increased resistance to antibiotics, in recent years there has been a growing interest in the discovery of new antimicrobial agents from different sources. Bacteria that are resistant to most antibiotics are a global public health concern. In order to find a new antimicrobial drug, we synthesized a small series of 2,4-diketo esters and tested them on some gram-positive and gram-negative bacterial strains. Two compounds showed very good antibacterial activity against Staphylococcus aureus and Bacillus subtilis, respectively. Trichophyton mentagrophytes proved to be the most sensitive of the tested species regarding antifungal activity. Also, research was conducted on the biomolecule of bovine serum albumin. Examining these interactions, we concluded that all compounds have the appropriate binding affinity for bovine serum albumin, which is vital. Furthermore, to investigate the potential antitumor activity, interactions with DNA were carried out. Examining the interactions between our compounds and DNA using fluorescence, we concluded that all but one of the compounds interacts with the DNA molecule by intercalation. In addition, a molecular docking study was performed to investigate the binding mode of the tested compounds to DNA and bovine serum albumin. In conclusion, all the results indicate a great potential for the future application of these compounds in clinical practice in the future.

Investigation of the radical scavenging potential of vanillin-based pyrido-dipyrimidines: experimental and in silico approach.

Antioxidants have a significant contribution in the cell protection against free radicals which may induce oxidative stress, and permanently damage the cells causing different disorders such as tumors, degenerative diseases, and accelerated aging. Nowadays, a multi-functionalized heterocyclic framework plays an important role in drug development, and it is of great importance in organic synthesis and medicinal chemistry. Encouraged by the bioactivity of the pyrido-dipyrimidine scaffold and vanillin core, herein, we made an effort to thoroughly investigate the antioxidant potential of the vanillin-based pyrido-dipyrimidines A-E to reveal novel promising free radical inhibitors. The structural analysis and the antioxidant action of the investigated molecules were performed in silico by DFT calculations. Studied compounds were screened for their antioxidant capacity using in vitro ABTS and DPPH assays. All the investigated compounds showed remarkable antioxidant activity, especially derivative A exhibiting inhibition of free radicals at the IC50 value (ABTS and DPPH assay 0.1 mg ml-1 and 0.081 mg ml-1, respectively). Compound A has higher TEAC values implying its stronger antioxidant activity compared to a trolox standard. The applied calculation method and in vitro tests confirmed that compound A has a strong potential against free radicals and may be a novel candidate for application in antioxidant therapy.

Anticancer potential of some ß-diketonates: DNA interactions, protein binding properties, and molecular docking study.

With the goal to discover a new antitumor drug with the better or similar effects to existing, a small series of ß-diketonate was tested on a cisplatin-resistant MDA-MB-231 and HeLa tumor cell lines, and nontumor MRC-5 cell line. All compounds showed notable cytotoxicity against both tumor cell lines and good selectivity. Importantly, ß-diketonates displayed greater selectivity than cisplatin, which is the crucial factor for a new antitumor drug candidate. Further, investigations with biomacromolecules such as DNA and serum albumin were performed. Investigations showed that tested compounds bind to DNA through intercalation and have appropriate affinity for binding to bovine serum albumin. In addition, the molecular docking study was performed to investigate more specifically the sites and binding mode of tested ß-diketonate to DNA or bovine serum albumin. In conclusion, all results indicated the big potential of these compounds for application in clinical practice in future.

Synthesis, characterization, antitumor potential, and investigation of mechanism of action of copper(ii) complexes with acylpyruvates as ligands: interactions with biomolecules and kinetic study.

Considering the urgency of finding a cure for vicious diseases such as tumors, we have synthesized and characterized a small series of new copper(ii) complexes with biologically important ligands such as acylpyruvate. In addition to this, we used another four copper(ii) complexes, with ligands of the same type to examine the antitumor potential. The antitumor potential of the copper(ii) complexes was examined on three tumor cell lines and one normal human cell line using the MTT assay. All seven tested complexes showed very good cytotoxic effects. Two copper complexes that showed the best antitumor potential were selected for further testing that showed the best potential for potential application in the future. The mechanism of activity of these complexes was examined in detail using tests such as cell cycle, ROS level, oxidative DNA damage, and proteins related to hypoxia analysis. In addition, we examined the binding abilities of these complexes with biomolecules (Guo, Ino, 5'-GMP, BSA, and DNA). The results showed that the tested compounds bind strongly to DNA molecules through intercalation. Also, it has been shown that the tested compounds adequately bind to the BSA molecule, which indicates an even greater potential for some future application of these compounds in clinical practice.

Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action.

In this paper, the synthesis, characterization, and biological evaluation of the novel tetrahydropyrimidines-THPMs are described. THPMs are well-known for wide pharmacological activities such as antimicrobial, anticancer, antiviral, etc. This research includes obtained results of in vitro antimicrobial, anticancer, and α-glucosidase inhibitory activities of the eleven novel THPMs. An antibiotic assessment was done against five bacteria (two Gram-positive and three Gram-negative) and five fungi by determining the minimal inhibitory concentration (MIC), using the broth tube dilution method. The most active antibacterial compounds were 4a, 4b, and 4d, while the best antifungal activity was shown by 4e, 4f, and 4k. The lowest MIC value (0.20 mg/mL) was measured for 4e, 4f, and 4k against the Trichophyton mentagrophytes. Moreover, examining the α-glucosidase inhibitory activity revealed the compound 4g as the one with the best activity. The cytotoxic activity was performed on the tumor cell lines (HeLa, K562, and MDA-MB-231) and normal cells (MRC-5). The best antitumor activity was shown by compounds 4b and 4k against HeLa cell lines. The influence on cell cycle and mechanism of action of the most active compounds were examined too. Compound 4b had good antibacterial and anticancer activities, while 4k showed promising antifungal and anticancer activities.

Economic, ecological, and health aspects of ß-diketonate application in the process of water purification.

Water pollution is a constant challenge for humanity. Sustainable economic development and environmental protection through a green economy structure provide the opportunity to project a model of scientific, social, and economic flows. Considering new chemical use in water treatment, we tested two ß-diketonates that we previously synthesized in the reaction between methyl ketone and diethyl oxalate under basic conditions. For water treatment, we used the appropriate salts of the mentioned compounds due to better solubility in water. In cooperation with the partner organizations PUC (public utility companies) Kragujevac, LTD (Private Limited Company), "Rudnik," and FIAT (Fabbrica Italiana Automobili Torino), we conducted research on their wastewater treatment. The results appeared to be more convincing in practice than the conventional methods. As a result of the study, no negative effects exerted on living organisms were found. Therefore, we are on the right track for potential application in the treatment of drinking water. Appropriate ß-diketonates were tested on twelve microorganisms (isolates from the wastewater and standard strains of bacteria and yeast). One of the two tested compounds showed promising antimicrobial activity. Further investigations showed that the tested compounds significantly reduce the concentration of heavy metals, which was confirmed by statistical calculations. Also, the main advantage of this method is a small volume of waste requiring disposal, no need for driving off excess moisture, used recyclability of the coagulants, reducing hazardous waste, and therefore reducing the costs for water treatment.

Antioxidant and Antimicrobial Potential, BSA and DNA Binding Properties of Some 3-Hydroxy-3-Pyrrolin-2-Ones Bearing Thenoyl Fragment.

BACKGROUND: It is known that pyrrolidinone derivates belong to a class of biologically active compounds with a broad spectrum of biological actions. Nowadays, many scientists are making an effort in the discovery of more effective ways to eliminate reactive oxygen species (ROS) that cause oxidative stress or to eliminate the harmful microorganisms from the organism in humans. Therefore, pyrrolidinones seem to be great candidates for the research of this field. METHODS: The antimicrobial activity of tested compounds was estimated by the determination of the minimal inhibitory concentration by the broth micro-dilution method against four species of bacteria and five species of fungi. The antioxidant activity was evaluated by free radical scavenging and reducing power. RESULTS: Among the tested compounds, P22 showed marked antibacterial activity on Staphylococcus aureus with a MIC value of 0.312 mg/mL. Maximum antifungal activity with MIC value 0.625 mg/mL was shown by P23 and P25 compounds against Trichophyton mentagrophytes. Tested samples showed a relatively strong scavenging activity on DPPH radical (IC50 ranged from 166.75- 727.17 µg/mL). The strongest DPPH radical scavenging activity was shown by P3 compound with an IC50 value of 166.75 µg/mL. Moreover, the tested compounds had effective reducing power. Compounds P3, P10, and P13 showed the highest reducing power than those from the other samples. Results of the interactions between DNA and P3 indicated that P3 had the affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (1.4 ± 0.1) × 105 M-1], while Ka values obtained via titration of BSA with P23 or P25 [Ka = (6.2 ± 0.2) and (5.0 ± 0.2) × 105 M-1] indicate that the notable quantity of the drug can be transmitted to the cells. CONCLUSION: Achieved results indicate that our compounds are potential candidates for use as medicaments.

Synthesis, Characterization, Antitumor Potential, BSA and DNA Binding Properties, and Molecular Docking Study of Some Novel 3-Hydroxy-3- Pyrrolin-2-Ones.

BACKGROUND: In order to make progress in discovering the new agents for cancer treatment with improved properties and considering the fact that 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, we tested series of eleven novels 1,5-diaryl-4-(2- thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones for their antitumor potential. METHODS: All novel compounds were characterized by spectral (IR, NMR, MS) and elemental analysis. All novel 3-hydroxy-3-pyrrolin-2-ones were screened for their cytotoxic activity on two cancer cell lines, SW480 and MDA-MB 231, and non-transformed fibroblasts (MRC-5). RESULTS: Compounds B8, B9, and B10 showed high cytotoxicity on SW480 cells together with good selectivity towards MRC-5 cells. It is important to empathize that the degree of selectivity of B8 and B10 was high (SI = 5.54 and 12.09, respectively). Besides, we explored the mechanisms of cytotoxicity of novel derivatives, B8, B9, and B10. The assay showed that tested derivatives induce an apoptotic type of cell death in SW480 cells, with a minor percent of necrotic cells. Additionally, to better understand the suitability of the compounds for potential use as anticancer medicaments, we studied their interactions with biomacromolecules (DNA or BSA). The results indicated that the tested compounds have a great affinity to displace EB from the EB-DNA complex through intercalation. Also, DNA and BSA molecular docking study was performed to predict the binding mode and the interaction region of the compounds. CONCLUSION: Achieved results indicate that our compounds have the potential to become candidates for use as medicaments.

Antitumor activity, DNA and BSA interactions of novel copper(II) complexes with 3,4-dihydro-2(1H)-quinoxalinones.

In order to discover new therapeutically active agents a series of novel copper(II) complexes with 3,4-dihydro-2(1H)-quinoxalinones were synthesized. All complexes were characterized by IR and EPR spectroscopic techniques and examined for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, three of them were chosen for analysing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that tested complexes lead to time-dependent accumulation of the cells in S and G2/M phases. The strongest accumulation effect showed complex 2d after 48 h of incubation. Competitive experiments with ethidium bromide (EB) indicated that tested compound 2d have affinity to displace EB from the EB-DNA complex through intercalation. Also, the binding parameters values for 2d-BSA complex showed that a reversible 2d-BSA complex is formed and ligand 2d can be stored and carried by BSA.

Synthesis, Characterization, Antioxidant Activity of ß-diketonates, and Effects of Coordination to Copper(II) Ion on their Activity: DNA, BSA Interactions and Molecular Docking Study.

BACKGROUND: In order to make some progress in discovering the more effective way to eliminate ROS which cause the oxidative stress in organism in humans and bearing in mind the fact that ethyl-2-hydroxy-4-aryl(alkyl)-4-oxo-2-butenoates (ß-diketonates) belong to a class of biologically active compounds, series of ß-diketonates were synthesized, characterized, and tested to evaluate there antioxidant activity. Further, to investigate how coordination to copper(II) ion affects the activity of ß-diketonates, appropriate complexes were synthesized and characterized. METHODS: All complexes were characterized by UV-Vis, IR, and EPR spectroscopy, MS spectrometry, and elemental analysis. Fluorescence spectroscopic method was used for investigations of the interactions between biomacromolecules (DNA or BSA) and compound 2E. Viscosity measurements and molecular docking study were performed to confirm the mode of interactions between DNA and BSA and compound 2E. RESULTS: Scavenging activity on DPPH radical revealed that compounds 2A, 2B, and 2E possess largest free radical scavenging, comparable to standard while results of superoxide anion scavenging activities of tested samples showed that maximum scavenging activity (IC50=168.92 µg/mL) was found for 2E, very similar to standard ascorbic acid, followed by 2B and 2G. Results of the interactions between biomacromolecules and 2E indicated that 2E has the affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (3.7 ± 0.1) × 103 M-1], while Ka value obtained via titration of BSA with 2E [Ka = (4.2 ± 0.2) × 105 M-1], support the fact that the significant amount of the drug could be transported and distributed through the cells. CONCLUSION: All ß-diketonates exhibited better scavenging activities than their corresponding copper complexes. Among all the tested compounds, 2E gave the highest reducing power, even higher than standard ascorbic acid, while reducing power for compounds 2A and 2B was also good but lower than standard. DNA and BSA binding study for 2E showed that this compound has the potential to be used as medicament.

2,4-Diketo esters: Crucial intermediates for drug discovery.

Convenient structures such as 2,4-diketo esters have been widely used as an effective pattern in medicinal chemistry and pharmacology for drug discovery. 2,4-Diketonate is a common scaffold that can be found in many biologically active and naturally occurring compounds. Also, many 2,4-diketo ester derivatives have been prepared due to their suitable synthesis. These synthetic drugs and natural products have shown numerous interesting biological properties with clinical potential as a cure for the broad specter of diseases. This review aims to highlight the important evidence of 2,4-diketo esters as a privileged scaffold in medicinal chemistry and pharmacology. Herein, numerous aspects of 2,4-diketo esters will be summarized, including synthesis and isolation of their derivatives, development of novel synthetic methodologies, the evaluation of their biological properties as well as the mechanisms of action of the diketo ester derivates. This paperwork is expected to be a comprehensive, trustworthy, and critical review of the 2,4-diketo ester intermediate to the chemistry community.

Synthesis, Anticancer Evaluation and Synergistic Effects with cisplatin of Novel Palladium Complexes: DNA, BSA Interactions and Molecular Docking Study.

BACKGROUND: In order to discover new agents for chemotherapy with improved properties compared to the existing agents and bearing in mind the fact that some Pd complexes possess better antitumor activity and exhibit less kidney toxicity compared to cisplatin, a series of novel square-planar palladium(II) complexes [Pd (L)2] (3a-f) with O,O bidentate ligands [L = ethyl 2- hydroxy-alkyl(aryl)-4-oxo-2-butenoate] were synthesized. METHODS: All complexes were characterized by spectral (UV-Vis, IR, NMR, ESI-MS) and X-ray analysis and examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Fluorescence spectroscopic method was used for investigations of the interactions between CT-DNA or bovine serum albumin (BSA) and complex 3c. Viscosity measurements and molecular docking study were performed to confirm the mode of interactions between DNA and BSA and complex 3c. RESULTS: Complexes that showed the best results, 3c, 3d, and 3e, were placed under further investigations. Selected complexes induced apoptosis and cell cycle arrest in HeLa and MDA-MB 231 cells. Low concentrations of 3c and 3e showed strong to moderate synergism with low concentrations of cisplatin. The interaction of 3d with cisplatin was antagonistic in all used concentrations, but low IC50 value indicates its usefulness as a single cytotoxic agent. It was also noted that the change of viscosity is more pronounced in DNA solution after addition of complex 3c. CONCLUSION: Obtained results indicate that the novel palladium(II) complexes have the potential to become candidates for treatment in anticancer therapy.

Atorvastatin in Combination with Pegylated Interferon and Ribavirin Provided High Rate of Sustained Virological Response in Patients with Genotype 3 Hepatitis C Virus.

BACKGROUND: Chronic hepatitis C virus infection represents a more frequent cause of liver cirrhosis and hepatocellular carcinoma. Statins, inhibit HCV replication in vitro, enhance the antiviral effect of the already known antiviral drugs and reduce their resistance. AIM: To determine the impact of additional therapy (treatment with Atorvastatin 20 mg) to the standard antiviral therapy (pegylated interferon alpha-peg-IFN α and ribavirin) on achieving sustained virological response (SVR). MATERIAL AND METHODS: In the study which is comparative, open-label, prospective-retrospective, 70 patients diagnosed with chronic hepatitis C virus infection who met criteria for treatment with standard antiviral therapy combined with anti-lipemic therapy (Atorvastatin 20 mg) were included. Patients in the study were divided into two groups: one group of 35 patients receiving combination therapy (Atorvastatin + peg-IFN α + Ribavirin) and another group of 35 patients received only standard antiviral therapy. Those parameters were followed in all patients: genotyping, quantification of the virus, histological assessment of liver inflammation and fibrosis degree (before starting treatment), the presence of steatosis, laboratory analysis: hematology, liver, lipid and carbohydrate status, insulin blood level (the calculation of HOMA-IR) and body mass index (BMI) calculation. The overall treatment of the patients depends from the virus genotype, thus, patients with genotype 1 and 4 received 48 weeks standard antiviral therapy, but patients with genotypes 2 and 3 received 24 weeks of antiviral therapy. SVR was considered an undetectable level of HCV RNA levels 24 weeks after completion of antiviral therapy. The results were statistically analysed, and all results for p < 0.05 were considered statistically significant. RESULTS: Combination therapy leads to a slightly higher percentage of SVR (85.71%) in patients with chronic hepatitis C versus standard therapy (74.29%), but in a group of patients with genotype 3 this rate of SVR amounting to 95.83%. Combination therapy leads to significant improvement of lipid and glucose status after treatment, and in terms of side effects, there was no appearance of serious adverse events that would be a reason for discontinuation of the therapy. CONCLUSION: Combination therapy Atorvastatin + pegylated interferon alpha + Ribavirin leads to high rate of SVR of 95.83% in patients with chronic hepatitis C, genotype 3. Statins can be used safely in patients with chronic hepatitis C.

Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study.

In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV-Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (3.7 ±â€¯0.1) and (3.4 ±â€¯0.1) × 103 M-1, respectively], an intercalative mode also confirmed through viscosity measurements. Ka values, obtained as result of fluorescence titration of BSA with D13 and D15 [Ka = (4.2 ±â€¯0.2) and (2.6 ±â€¯0.2) × 105 M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region.

Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels.

In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.

Biological evaluation of selected 3,4-dihydro-2(1H)-quinoxalinones and 3,4-dihydro-1,4-benzoxazin-2-ones: Molecular docking study.

In order to investigate new potential therapeutically active agents, we investigated the biological properties of two small libraries of quinoxalinones and 1,4-benzoxazin-2-ones. The results obtained showed that compounds 5, 9-11 have good cytotoxic activity against HeLa cells where the lowest IC50 value (10.46 ± 0.82 µM/mL) was measured for compound 10. Additionally, the most active compounds (5, 9-11) showed much better selectivity for MRC-5 cells (up to 17.4) compared to cisplatin. In vitro evaluation of the inhibition of the enzyme α-glucosidase showed that compounds 10 and 11 exert significant inhibition of the enzyme at 52.54 ± 0.09 and 40.09 ± 0.49 µM, respectively. Competitive experiments with ethidium bromide (EB) indicated that all tested compounds have affinity to displace EB from the EB-DNA complex through intercalation, suggesting good competition with EB (Ksv = (3.1 ± 0.2), (5.1 ± 0.1), (5.6 ± 0.2), and (6.3 ± 0.2) × 103 M-1 ). A molecular docking study was also performed to better understand the binding modes and to conclude the structure-activity relationships of the synthesized compounds.

Factors That Influence the Virological Response in Patients with Chronic Hepatitis C Treated with Pegylated Interferon and Ribavirin.

INTRODUCTION: The success of the antiviral treatment in patients with chronic hepatitis C depends on the factors related to the virus and the host. The aim of the study is the analysis of the antiviral therapy which is a combination of pegylated interferon and ribavirin, considering various factors that will identify the predictors of the sustained virological response. MATERIAL AND METHODS: This retrospective study included 226 patients, divided in two groups. Patients with sustained virological response and patients without sustained virological response were compared in terms of the following factors: genotype, viral load, gender, age, inflammatory and fibrotic changes in the liver, metabolic abnormalities, obesity and fatty liver. RESULTS: The rate of the sustained virological response is 83.6%, more frequently in patients with genotype 3, with evidenced statistical significance (90.54%). The factors that significantly contribute to sustained virological response are related to the age (p = 0.0001), genotype (p = 0.002), mode of transmission (p = 0.005), inflammatory changes in the liver (p = 0.028), body mass index (p = 0.022) and insulin resistance (p = 0.039). The high rate of sustained virological response is related to the younger age of the patients which indirectly means short Hepatitis C Virus infection duration, absence of advanced liver disease and lack of significant co-morbid conditions. Single confirmed independent predictors of sustained virological response are the age (OR 0.928, p = 0.0001) and genotype (OR 3.134, p = 0.005). CONCLUSIONS: Factors that are related to the virological response are the age, genotype, mode of transmission, inflammatory changes in the liver, body mass index and insulin resistance, but still, independent predictors of sustained virologic response are the age and the genotype.

Synthesis, characterization, biological activity, DNA and BSA binding study: novel copper(ii) complexes with 2-hydroxy-4-aryl-4-oxo-2-butenoate.

A serie of novel square pyramidal copper(ii) complexes [Cu(L)2H2O] (3a-d) with O,O-bidentate ligands [L = ethyl-2-hydroxy-4-aryl-4-oxo-2-butenoate; aryl = 3-methoxyphenyl-2a, (E)-2-phenylvinyl-2b, (E)-2-(4'-hydroxy-3'-methoxyphenyl)vinyl-2c, 3-nitrophenyl-2d, 2-thienyl-2e] were synthesized and characterized by spectral (UV-Vis, IR, ESI-MS and EPR), elemental and X-ray analysis. The antimicrobial activity was estimated by the determination of the minimal inhibitory concentration (MIC) using the broth microdilution method. The most active antibacterial compounds were 3c and 3d, while the best antifungal activity was showed by complexes 3b and 3e. The lowest MIC value (0.048 mg mL-1) was measured for 3c against Proteus mirabilis. The cytotoxic activity was tested using the MTT method on human epithelial carcinoma HeLa cells, human lung carcinoma A549 cells and human colon carcinoma LS174 cells. All complexes showed extremely better cytotoxic activity compared to cisplatin at all tested concentrations. Compound 3d expressed the best activity against all tested cell lines with IC50 values ranging from 7.45 to 7.91 µg mL-1. The type of cell death and the impact on the cell cycle for 3d and 3e were evaluated by flow cytometry. Both compounds induced apoptosis and S phase cell cycle arrest. The interactions between selected complexes (3d and 3e) and CT-DNA or bovine serum albumin (BSA) were investigated by the fluorescence spectroscopic method. Competitive experiments with ethidium bromide (EB) indicated that 3d and 3e have a propensity to displace EB from the EB-DNA complex through intercalation suggesting strong competition with EB [Ksv = (1.4 ± 0.2) and (2.9 ± 0.1) × 104 M-1, respectively]. Ksv values indicate that these complexes bind to DNA covalently and non-covalently. The achieved results in the fluorescence titration of BSA with 3d and 3e [Ka = (2.9 ± 0.2) × 106 and (2.5 ± 0.2) × 105 M, respectively] showed that the fluorescence quenching of BSA is a result of the formation of the 3d- and 3e-BSA complexes. The obtained Ka values are high enough to ensure that a significant amount of 3d and 3e gets transported and distributed through the cells.

Genetic predictors of the response to the treatment of hepatitis C virus infection.

The genome-wide association studies have identified a strong association between interleukin 28B (IL28B) gene polymorphisms and the response to treatment in patients with hepatitis C virus (HCV) infection. The aim of the study was to evaluate the association between three most widely studied IL28B gene polymorphisms and the response to antiviral treatment of chronic hepatitis C. We performed the genotyping of the three IL28B gene polymorphisms: rs12979860, rs8099917, and rs12980275 in 72 Caucasian patients with chronic hepatitis C, previously treated with the combination therapy of pegylated interferon alpha (PEGIFN α) and ribavirin (RBV). The patients included in the study had finished the treatment regimen at least 6 months before enrolling in the study. We used the sustained viral response (SVR) for the evaluation of the effectiveness of the antiviral treatment, and it was tested with an assay with a sensitivity of 20 IU/mL. An SVR was achieved in 59.7% (43/72) of the treated patients. The three IL28B gene polymorphisms (CC genotype of rs12979860, TT genotype of rs8099917, and AA genotype of rs12980275) were associated with the SVR (p=0.029, p=0.016, and p=0.028, respectively) in the study patients with chronic hepatitis C treated with the combination therapy of PEGIFN α and RBV. The association of IL28B gene polymorphisms with the treatment response points to the possibility of personalized medicine for the treatment of HCV infection.