Molecular docking and 3D-QSAR studies on the MAPKAP-K2 inhibitors

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) has been identified as a drug target for the treatment of inflammatory diseases. Therefore, there is an urgent need to develop new classes of MAPKAP-K2 inhibitors. To understand the structure activity correlation of MAPKAP-K2 inhibitors, we have carried out a molecular docking study and three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling. Both comparative molecular field analysis ( $r_{\text{cv}}^{2}$  = 0.602, $r_{\text{ncv}}^{2}$  = 0.955) and comparative molecular similarity indices analysis ( $r_{\text{cv}}^{2}$  = 0.546, $r_{\text{ncv}}^{2}$  = 0.891) models were generated using the training set on the basis of the common substructure-based alignment and gave reasonable results. The structural insights obtained from both the 3D-QSAR contour maps and molecular docking help to better interpret the structure activity relationship. The results obtained from this study will be useful in the design of potent MAPKAP-K2 inhibitors.     

Relationship of seminal reactive nitrogen and oxygen species and total antioxidant capacity with sperm DNA fragmentation in infertile couples with normal and abnormal sperm parameters

The objective of this study was to investigate the association between the amount of superoxide anion, peroxynitrite as oxidative stress (OS) markers and total antioxidant capacity (TAC) with sperm DNA fragmentation in infertile men with abnormal semen parameters. Semen samples were obtained from 102 infertile couples and divided into groups with normal and abnormal semen parameters according to the World Health Organization (WHO). Peroxynitrite and superoxide anions were detected using spectrofluorometric assays combined with 2,7 dicholorofluorescein (DCF)‐DA and 4‐chloro‐7‐nitrobenzo‐2‐oxa ‐1, 3‐diazole (NBD‐CL). Colorimetric assay was used for evaluation of TAC, while DNA fragmentation was studied by using sperm chromatin dispersion test. Superoxide anion, peroxynitrite and DNA fragmentation were significantly higher in infertile couples with abnormal semen parameters as compared to infertile couples with normal semen (P < 0.01). TAC was significantly lower in infertile men with abnormal semen parameters (P < 0.01). There was also a significant positive correlation between OS markers with sperm DNA fragmentation (r = 0.59, P < 0.01 and r = 0.67, P < 0.01, respectively). We have found that imbalance between superoxide anion and peroxynitrite with antioxidant capacity in infertile men with abnormal sperm parameters is associated with higher sperm DNA fragmentation.     

Synthesis,evaluation, and molecular docking studies of aryl urea‐triazole‐based derivatives as anti‐urease agents

Considering the importance of urease inhibitors in the treatment of ureolytic bacterial infections, in this work, the synthesis of novel, aryl urea‐triazole‐based derivatives as effective urease inhibitors is described. Dichloro‐substituted derivative 4o , with IC₅₀ = 22.81 ± 0.05 μM, is found to be the most potent urease inhibitor, determined by Berthelot colorimetric assay. Docking studies were also carried out for compound 4o to confirm the effective interactions with the urease active site.

     

Enhancement of indomethacin-induced gastric damage by mouth breathing in rabbits

Previous studies have reported that mouth breathing is associated with respiratory acidosis. Regarding to the reports that renal elimination of weak acids such as indomethacin is pH dependent, this study was carried out to evaluate the role of mouth breathing on plasma level of indomethacin and indomethacin-induced gastric damage in rabbits. Mouth breathing was induced by surgical ligation of nostrils under general anesthesia. One day after the operation, arterial blood samples were collected for acid–base balance analysis and indomethacin was administered intraperitoneally in a single dose of 40 mg/kg. The animals were killed 4 h after indomethacin administration and blood samples were collected for spectrofluorometric determination of indomethacin in plasma. The results showed that indomethacin induces more severe gastric damage in nose obstructed rabbits compared with sham and unoperated (UNOP) animals. Acid–base analysis revealed a respiratory acidosis in nose obstructed rabbits and indomethacin level of plasma was significantly higher in nose obstructed animals in comparison with control rabbits. The study shows that mouth breathing can increase the potentiation of indomethacin-induced gastric mucosal damage that may be due to higher level of indomethacin in plasma of nose obstructed animals.     

Synthesis,Molecular Docking and Biological Evaluation of Diaryl Pyrimidine Derivatives as Urease Inhibitors

Pharmaceutical Chemistry Journal - Urease is a dinickel enzyme that is responsible for the hydrolysis of urea to ammonia and carbon dioxide. A series of bacteria like Helicobacter pylori produce...     

Preparation of ciprofloxacin-coated zinc oxide nanoparticles and their antibacterial effects against clinical isolates of Staphylococcus aureus and Escherichia coli

In the present research study, ciprofloxacin-coated zinc oxide nanoparticles were prepared using a precipitation method. The nature of interactions between zinc oxide nanoparticles and ciprofloxacin (CAS 85721-33-1) was studied by Fourier transform infrared spectroscopy. The results show that the carbonyl group in ciprofloxacin is actively involved in forming chemical--rather than physical--bonds with zinc oxide nanoparticles. Also the antibacterial activity of free zinc oxide nanoparticles and ciprofloxacin-coated zinc oxide nanoparticles have been evaluated against different clinical isolates of Staphylococcus aureus and Escherichia coli. The free zinc oxide nanoparticles did not show potent antibacterial activity against all test strains. In contrast, only the low concentrations of ciprofloxacin-coated zinc oxide nanoparticles (equivalent to the sub-minimum inhibitory concentrations of pure ciprofloxacin) considerably enhanced the antibacterial activity of zinc oxide nanoparticles against different isolates of Staphylococcus aureus and Escherichia coli (4 to 32 fold increase). The result is of particular value, since it demonstrates that, by using biocompatible zinc oxide nanoparticles in combination therapy, lower amounts of antibiotics may be needed.     

Synthesis and cloxacillin antimicrobial enhancement of 2-methylsulfonylimidazolyl-1,4-dihydropyridine derivatives

BACKGROUND AND THE PURPOSE OF THE STUDY: Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been a major problem worldwide in chemotherapy of infection disease. This study was designed to assess the enhancing effects of a new group of dihydropyridine-3,5dicarboxamides, in combination with cloxacillin with distinctly different mechanisms of action against MRSAs. MATERIAL AND METHODS: Dihydropyridine-3,5-dicarboxamides with 2-methylsulfonylimidazole at 4 position 6a-k were synthesized by the reaction of corresponding aldehyde 5 with different N-aryl acetoacetamides 3 in the presence of ammonium hydroxide. Agar disc diffusion method was used to determine the antibacterial and potentiating activity of different synthetic compounds in the presence and absence of cloxacillin to evaluate their activity as modulators of multidrugresistant (MDR). RESULTS AND MAJOR CONCLUSION: The antibacterial effect of cloxacillin was enhanced by compounds 6g and 6h against cloxacillin-resistant strains (MRSA(1) and MRSA(2)). The potentiation was found 1 2 to be statistically significant (p<0.01). Compound 6g at concentration of 1000 μg/disc, caused a 329 percent potentiation of the activity of cloxacillin against MRSA(1).     

Relationship of sperm DNA fragmentation, apoptosis and dysfunction of mitochondrial membrane potential with semen parameters and ART outcome after intracytoplasmic sperm injection

Purpose

The objective of this study was to assess the relationship of DNA damage, apoptosis and dysfunction of mitochondrial membrane potential (MMP) in ejaculated spermatozoa with semen parameters (sperm concentration, motility and normal morphology) and to evaluate their effects on assisted reproductive technology (ART) outcomes after intracytoplasmic sperm injection (ICSI).

Methods

Semen parameters in 120 infertile couples who underwent ICSI treatment were routinely analyzed and examined for the incidence of sperm DNA fragmentation (DF) by the sperm chromatin dispersion test (SCD). Whereas the incidences of sperm apoptosis and dysfunction of MMP were assessed by flow cytometry. The correlation among different sperm factors and ART outcomes was evaluated statistically.

Results

Sperm parameters were negatively related to DF (motility and normal morphology, p?<?0.01), apoptosis (concentration, motility and normal morphology, p?<?0.01, p?<?0.05 and p?<?0.05, p?<?0.01 respectively), and dysfunction of sperm MMP (concentration, motility and normal morphology, p?<?0.01). DF also showed a positive correlation with apoptosis and dysfunction of sperm MMP (p?<?0.05, and p?<?0.01 respectively). However, there was no significant correlation among DF, apoptosis and dysfunction of sperm MMP with ART outcomes, except early apoptosis which showed significant (p?<?0.05) negative correlation with pregnancy rate.

Conclusion

In the present study; DF, apoptosis and dysfunction of sperm MMP indicated negative relationship with sperm parameters. Although there was a negative correlation between early apoptosis and pregnancy rate, no significant correlation was observed between these parameters and ICSI outcomes.     

Synthesis and pharmacological activity of thebaine-derived mu-opioid receptor agonists

Thebaine-derived mu-opioid agonists were synthesized through the reaction of thebaine with N-aryl maleimide and tested for opioid activity. Morphine was used as reference compound. Our results show that an attachment of aryl succinimide group to thebaine produced series of compounds with mu-opioid agonist activity. The most active compound in smooth muscle preparation was compound 6 with an IC50 ratio of delta/mu = 248.69 and was as potent as morphine with ED50 value 26.65 mg kg-1 i.p. in hot-plate test and showed good antinociceptive activity.