Design,synthesis, characterization,antibacterial and antifungal activities of a novel class of 5,7-diaryl-4,4-dimethyl-4,5,6,7-tetrahydropyridino[3,4-d]-1,2,3-selenadiazoles

Compound 26 is more potent against Escherichia coli. and 24 is more active against Staphylococcus aureus, β-Heamolytic streptococcus, Vibreo cholerae, Salmonella typhii, and Shigella flexneri than the standard drug ciprofloxacin. Moreover, of all the compounds tested, 26 is more effective against Aspergillus flavus and Mucor, than the standard drug fluconazole.     

Design,synthesis, spectral analysis and in vitro microbiological evaluation of 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones

A series of novel 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones 23-33 were synthesized, and studied for their in vitro antibacterial and antifungal activities against clinically isolated strains. Generally compounds possessing electron donating groups showed good antibacterial activity. Compound 31, which contain both electron withdrawing chloro and electron donating methyl groups showed potent activity against all the tested Gram positive and Gram negative bacterial strains whereas compounds 32 and 33 which contain electron donating methoxy functional group at the para position of the phenyl ring attached to pyrimidine ring showed promising activity against S.aureus, S.typhii and E.coli. Compounds 32 and 33, both containing electron withdrawing groups (-Cl, -F) showed excellent activities against all the tested A. flavus, Mucor, Rhizopus and M.gypsuem fungal strains. while against Mucor, compound 27 which contains an electron donating methyl group at the para position of the phenyl ring attached to pyrimidine ring showed promising activity. Also compound 31, which contains both electron withdrawing chloro and electron donating methyl groups showed potent activity against A. flavus and Rhizopus.     

A convenient ‘one-pot’ synthesis and in vitro microbiological evaluation of novel 2,7-diaryl-[1,4]-diazepan-5-ones

A convenient method for the ‘one-pot’ synthesis of novel target molecule 2,7-diaryl-[1,4]-diazepan-5-ones from the respective 2,6-diaryl-piperidin-4-ones was catalyzed by NaHSO₄.Al₂O₃ heterogeneous catalyst in dry media under microwave irradiation in solvent-free conditions. Moreover, the catalyst could be recovered and re-used up to 4 times after washing with ethyl acetate. They were evaluated for potential antibacterial activity against Staphylococcus aureus, β-Haemolytic streptococcus, Vibreo cholerae, Salmonella typhii, Escherichia coli, Klebsiella pneumonia, Pseudomonas and antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Mucor, Candida albicans and Rhizopus. Structure-Activity Relationship (SAR) led to the conclusion that, of all the compounds 25–32 tested, compound 30 exerted strong in vitro antibacterial activity against S. aureus, S. typhii, and Pseudomonas and all the compounds 25–32 were less active against E. coli, whereas all the compounds 25–32 displayed potent in vitro antifungal activity against all the fungal strains used, except compound 30, which was more effectual against Mucor.     

Unexpected formation of 3-chloro-1-hydroxy-2,6-diarylpiperidin-4-ones: Synthesis,antibacterial and antifungal activities

New 3-chloro-1-hydroxy-2,6-diarylpiperidin-4-ones 18–22 were synthesized, characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional NMR (¹H & ¹³C) spectroscopic data and evaluated for their in vitro antibacterial and antifungal activities. All the newly synthesized compounds exerted a wide range of antibacterial activities against the entire tested gram-positive and gram-negative bacterial strains except Escherichia coli. Compounds 21 and 22 exerted strong antifungal activities against Aspergillus flavus, mucor and Microsporum gypsuem. In addition, compound 20 was more potent against Rhizopus.

     

Influence of Macrocyclic Chelators on the Targeting Properties of 68Ga-Labeled Synthetic Affibody Molecules: Comparison with 111In-Labeled Counterparts

Affibody molecules are a class of small (7 kDa) non-immunoglobulin scaffold-based affinity proteins, which have demonstrated substantial potential as probes for radionuclide molecular imaging. The use of positron emission tomography (PET) would further increase the resolution and quantification accuracy of Affibody-based imaging. The rapid in vivo kinetics of Affibody molecules permit the use of the generator-produced radionuclide ⁶⁸Ga (T_1/2 = 67.6 min). Earlier studies have demonstrated that the chemical nature of chelators has a substantial influence on the biodistribution properties of Affibody molecules. To determine an optimal labeling approach, the macrocyclic chelators 1,4,7,10-tetraazacylododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1-(1,3-carboxypropyl)-1,4,7- triazacyclononane-4,7-diacetic acid (NODAGA) were conjugated to the N-terminus of the synthetic Affibody molecule Z_HER2:S1 targeting HER2. Affibody molecules were labeled with ⁶⁸Ga, and their binding specificity and cellular processing were evaluated. The biodistribution of ⁶⁸Ga-DOTA-Z_HER2:S1, ⁶⁸Ga-NOTA-Z_HER2:S1 and ⁶⁸Ga-NODAGA-Z_HER2:S1, as well as that of their ¹¹¹In-labeled counterparts, was evaluated in BALB/C nu/nu mice bearing HER2-expressing SKOV3 xenografts. The tumor uptake for ⁶⁸Ga-DOTA-Z_HER2:S1 (17.9±0.7%IA/g) was significantly higher than for both ⁶⁸Ga-NODAGA-Z_HER2:S1 (16.13±0.67%IA/g) and ⁶⁸Ga-NOTA-Z_HER2:S1 (13±3%IA/g) at 2 h after injection. ⁶⁸Ga-NODAGA-Z_HER2:S1 had the highest tumor-to-blood ratio (60±10) in comparison with both ⁶⁸Ga-DOTA-Z_HER2:S1 (28±4) and ⁶⁸Ga-NOTA-Z_HER2:S1 (42±11). The tumor-to-liver ratio was also higher for ⁶⁸Ga-NODAGA-Z_HER2:S1 (7±2) than the DOTA and NOTA conjugates (5.5±0.6 vs.3.3±0.6). The influence of chelator on the biodistribution and targeting properties was less pronounced for ⁶⁸Ga than for ¹¹¹In. The results of this study demonstrate that macrocyclic chelators conjugated to the N-terminus have a substantial influence on the biodistribution of HER2-targeting Affibody molecules labeled with ⁶⁸Ga.This can be utilized to enhance the imaging contrast of PET imaging using Affibody molecules and improve the sensitivity of molecular imaging. The study demonstrated an appreciable difference of chelator influence for ⁶⁸Ga and ¹¹¹In.     

Immune regulatory molecules as modifiers of semen and fertility: A review

Declining fertility rates in both human and animals is a cause for concern. While many of the infertility cases are due to known causes, idiopathic infertility is reported in 30% of the infertile couples. In such cases, 18% of the infertile males carry antisperm antibodies (ASAs). Such data are lacking in livestock, wherein 20–30% of the animals are being culled due to low fertility. In males, the blood–testis barrier (BTB) and biomolecules in the semen provide an immuno‐tolerant microenvironment for spermatozoa as they traverse the immunologic milieu of both the male and female reproductive tracts. For example, insults from environmental contaminants, infections and inflammatory conditions are likely to impact the immune privilege state of the testis and fertility. The female mucosal immune system can recognize allogenic spermatozoa‐specific proteins affecting sperm kinematics and sperm‐zona binding leading to immune infertility. Elucidating the functions and pathways of the immune regulatory molecules associated with fertilization are prerequisites for understanding their impact on fertility. An insight into biomolecules associated with spermatozoal immune tolerance may generate inputs to develop diagnostic tools and modulate fertility. High‐throughput sequencing technologies coupled with bioinformatics analyses provides a path forward to define the array of molecules influencing pregnancy outcome. This review discusses the seminal immune regulatory molecules from their origin in the testis until they traverse the uterine environment enabling fertilization and embryonic development. Well‐designed experiments and the identification of biomarkers may provide a pathway to understand the finer details of reproductive immunology that will afford personalized therapies.     

Synthesis,spectral analysis and in vitro microbiological evaluation of 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones as a new class of antibacterial and antifungal agents

In the present work, a new series of bis hybrid heterocycle comprising both piperidine and thiohydantoin nuclei together namely 3-(3-alkyl-2,6-diarylpiperin-4-ylidene)-2-thioxoimidazolidin-4-ones 46–60 was synthesized by the treatment of the respective thiosemicarbazones 31–45 with chloroethyl acetate and anhydrous sodium acetate in refluxing ethanol for 4 h and were characterized by melting point, elemental analysis, MS, FT-IR, one-dimensional NMR (¹H, D₂O exchanged ¹H and ¹³C), two dimensional HOMOCOSY and NOESY spectroscopic data. In addition, the title compounds were screened for their antimicrobial activities against a spectrum of clinically isolated microbial organisms. Compounds 47–50, 52–55 and 57–60 with fluoro, chloro, methoxy or methyl functions at the para position of phenyl rings attached to C-2 and C-6 carbons of piperidine moiety along with and without methyl substituent at position C-3 of the piperidine ring exerted potent biological activities against Staphylococcus aureus, β-Hemolytic streptococcus, Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Aspergillus flavus, Candida albicans, Candida 6 and Candida 51 at a minimum inhibitory concentration.     

Biocidal activity of formaldehyde and nonformaldehyde biocides toward Mycobacterium immunogenum and Pseudomonas fluorescens in pure and mixed suspensions in synthetic metalworking fluid and saline

The microbicidal activity of four different biocides was studied in synthetic metalworking fluid (MWF) against Mycobacterium immunogenum, a suspected causative agent for hypersensitivity pneumonitis, and Pseudomonas fluorescens, a representative for the predominant gram-negative bacterial contaminants of MWF. The results indicated that M. immunogenum is more resistant than P. fluorescens to the tested formaldehyde-releasing biocides (Grotan and Bioban), isothiazolone (Kathon), and phenolic biocide (Preventol). Kathon was effective against mycobacteria at lower concentrations than the other three test biocides in MWF. In general, there was a marked increase in biocidal resistance of both the test organisms when present in MWF matrix compared to saline. Increased resistance of the two test organisms to biocides was observed when they were in a mixed suspension (1:1 ratio). The results indicate the protective effect of the MWF matrix against the action of commonly used biocides on the MWF-colonizing microbial species of occupational health significance, including mycobacteria.     

Effect of dietary energy on seminal plasma insulin-like growth factor-I (IGF-I), serum IGF-I and testosterone levels, semen quality and fertility in adult rams

The objective of the present study was to modulate seminal plasma insulin-like growth factor-I (IGF-I) by dietary energy and assess the relationship among testosterone and IGF-I levels, semen quality and fertility in adult rams. Twenty-four 1-yr old adult Nellore rams were equally divided into three groups (n = 8) and fed with three different concentrate mixtures formulated using conventional ingredients and finger millet (Eleucine corocana) straw to ensure rams received with similar amount of crude protein with three levels of energy. Rams in low-energy group were offered diets with 20% less energy than the control energy group (optimum energy, 100%, recommended energy level), whereas rams in high energy group were offered diets with 20% more energy than the optimum energy group. Semen was collected from rams 60 days after start of the experimental feeding. The percentages of progressive forward motility, functional membrane integrity and mitochondrial membrane potential of the spermatozoa were significantly (P < 0.05) higher in control and high energy groups as compared to low-energy group. Feeding of low-energy diet significantly (P < 0.05) decreased spermatozoa VSL, VCL and VAP when compared to control and high energy fed groups. The number of spermatozoa binding/oocyte was significantly (P < 0.05) higher in control (11.23 ± 0.20) and high energy (10.57 ± 0.19) groups as compared to the low energy (6.14 ± 0.01) group. The serum and seminal plasma IGF-I levels were significantly (P < 0.05) higher in control and high energy fed groups as compared to the low-energy group. The serum testosterone and cholesterol levels were significantly (P < 0.05) higher in the control group as compared to the low-energy group. The seminal plasma fructose levels in optimum energy fed animals were significantly (P < 0.05) higher as compared to other two groups. The seminal plasma IGF-I level had positive correlation with progressive forward motility (r = 0.7) and other velocity (linearity, r = 0.7; straightness, r = 0.7) parameters. The study suggested that the modulation of seminal plasma IGF-I levels by dietary energy is possible and the optimum level of seminal plasma IGF-I is necessary and sufficient to influence semen quality.     

Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction

Oxidative stress plays a critical role in the pathophysiology of cardiac failure, including the modulation of neovascularization following myocardial infarction (MI). Redox molecules thioredoxin (Trx) and glutaredoxin (Grx) superfamilies actively maintain intracellular thiol-redox homeostasis by scavenging reactive oxygen species. Among these two superfamilies, the pro-angiogenic function of Trx-1 has been reported in chronic MI model whereas similar role of Grx-1 remains uncertain. The present study attempts to establish the role of Grx-1 in neovascularization and ventricular remodeling following MI. Wild-type (WT) and Grx-1 transgenic (Grx-1(Tg/+)) mice were randomized into wild-type sham (WTS), Grx-1(Tg/+) Sham (Grx-1(Tg/+)S), WTMI, Grx-1(Tg/+)MI. MI was induced by permanent occlusion of the LAD coronary artery. Sham groups underwent identical time-matched surgical procedures without LAD ligation. Significant increase in arteriolar density was observed 7 days (d) after surgical intervention in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Further, improvement in myocardial functional parameters 30 d after MI was observed including decreased LVIDs, LVIDd, increased ejection fraction and, fractional shortening was also observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Moreover, attenuation of oxidative stress and apoptotic cardiomyocytes was observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Increased expression of p-Akt, VEGF, Ang-1, Bcl-2, survivin and DNA binding activity of NF-κB were observed in the Grx-1(Tg/+)MI group when compared to WTMI animals as revealed by Western blot analysis and Gel-shift analysis, respectively. These results are the first to demonstrate that Grx-1 induces angiogenesis and diminishes ventricular remodeling apparently through neovascularization mediated by Akt, VEGF, Ang-1 and NF-κB as well as Bcl-2 and survivin-mediated anti-apoptotic pathway in the infarcted myocardium.