Pharmaceutical Chemistry Journal最新文献

The aim of the present study was to evaluate the anti-pyelonephritis activity of naringenin alone or combined with ceftriaxone in a rat model. In all, 35 Wistar rats were randomly divided into five equal groups. Groups 2 – 5 underwent surgery and were infected with E. coli to induce pyelonephritis. Groups 1 and 2 were treated with normal saline and groups 3, 4, and 5 received ceftriaxone (60 mg/kg), naringenin (20 mg/kg), and ceftriaxone+naringenin, respectively for 1 week. Subsequently, the disc diffusion method and bacterial colony counting were performed. After six weeks, MDA and GSH levels, TOS, TAC, activities of GPx, CAT and SOD, and histopathological analyses were evaluated in the kidneys. A week after the ceftriaxone treatment and two weeks after the naringenin exposure, negative urinary bacterial colonies were observed. The combination of these drugs caused negative colonies during the first week. Naringenin alone or in combination with ceftriaxone significantly decreased renal MDAand TOS but increased TAC, GSH and activities of GPx, CAT and SOD compared with the pyelonephritic group. This combination revealed histopathological changes in the kidneys. Our data suggest synergism between naringenin and ceftriaxone in alleviating pyelonephritis-induced complications.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. The mechanism of miRNA action includes degradation of mRNA or suppression of its translation. MicroRNA-155 is one of the most studied miRNAs. Its expression increases on the background of tumor and inflammatory processes or infectious diseases, which is accompanied by increased production of proinflammatory cytokines. miRNA-155 often plays a negative role in the above conditions. Presumably, suppression or activation of mi-RNA-155 expression can lead to a change in the disease course by changing cellular metabolism. Therefore, a search for modulators of its expression is a relevant goal. Possible targets of miRNA-155 and its effects incurred in various cells and tissues and the possibility of pharmacological regulation of miRNA-155 are reviewed herein. Antisense oligonucleotides (anti-miRNAs, for example, an oligonucleotide called Cobomarsen) can act as direct inhibitors of miRNA-155. Moreover, compounds that suppress its expression (steroid hormones, bioflavonoids, and some others) are also being studied.

In the present work, synthesis of 4,5-dehydrospiulosine and its chain analogues (7-9) as potential Sphingosine Kinase I inhibitors has been achieved via the diastereoselective Grignard reaction and stereoselective cross-metathesis reaction followed by N-acylation with p-nitrophenyl butyrate to give the corresponding butyrate ceramides (10-12). All compounds were obtained in high yield and purity. Molecular docking simulation studies were performed for the synthesized compounds that indicated their varying binding affinities with the Sphingosine Kinase 1 (SPHK1) protein. Following, molecular dynamics simulations were performed for the SPHK1-compound (10) complex that indicated compound (10) to be structurally and energetically stable within the binding pocket of SPHK1. Further, the biological evaluation studies, as potential anti-prostate cancer agents and as anti-colon cancer agents by inhibiting the SPHK1 of all synthesized compounds (7-12) on PC-3 cell lines and HCT-116 cell lines by the SRB method were done. Compound N-((2S,3S,E)-3-hydroxyheptadec-4-en-2-yl) butyramide (10) exhibited remarkable cytotoxicity with an IC₅₀ value of 0.018 μM against PC-3 cell lines and 0.076 μM against HCT-116 cell lines, whereas compound (11) showed best cytotoxicity with an IC₅₀ value of 0.062 μM against HCT-116 cell lines.

Inconsistencies in literature data on the environmental features of the biosynthesis of polyphenol biologically active substances in medicinal plant raw materials were found particularly for flavonoids, which are important secondary metabolites that significantly contribute to the response to abiotic and anthropogenic stress. The goal of the study was to elucidate features of the accumulation of flavonoids in medicinal plant raw materials of the synanthropic flora of Rostov Region using Morozovsky District as an example. The accumulation of flavonoids in samples of knotgrass herb (Polygonum aviculare L.), wormwood (Artemisia absinthium L.), and common yarrow (Achillea millefolium L.) of the synanthropic flora of Rostov Region was characterized with a significant variability depending on the harvesting site. Samples of medicinal plant raw materials collected in several urbocenoses displayed induced flavonoid accumulation as compared with samples from control territories. This could be explained by activation under the anthropogenic load of the key enzyme for flavonoid biosynthesis (phenylalanine ammonia lyase), which is highly induced by stress. However, samples collected in areas of significant anthropogenic impact (mainly along a category IA highway or railroad trunkline) were characterized by a reduced content of flavonoids. This was probably due to excessive environmental pollution going beyond the endurance of the species and causing suppression of the enzyme systems.

Montelukast, a leukotriene receptor antagonist with a high affinity and selectivity for the cysteinyl leukotriene receptor type-1, was radiolabeled with ^99mTc using a direct tagging procedure. The processing parameters—amounts of both montelukast and reducing agent, pH of the reaction mixture, reaction temperature, time of reaction, and in vitro stability of the ^99mTc-montelukast complex—were thoroughly investigated. The ^99mTc-montelukast complex had a percent radiolabeling yield of 92 ± 0.23 and an in vitro stability of 6 hours. According to biological distribution studies, the maximum uptake of ^99mTc-montelukast complex for the lungs was 35.89 ± 1.03 % injected activity/gm tissue at 15 minutes following injection and remained high in the lungs for another hour (15.88 ± 0.39%), whereas the washout of mice organs appeared to primarily occur via the urinary tract. Because the ^99mTc-montelukast complex is not a blood product, it is safer. To summarize, the ^99mTc-montelukast complex is a new radiopharmaceutical that might be utilized for perfusion imaging of the lungs that is both safer and more useful.

Isosteviol has been investigated with a cardio-treating effect on cardiomyocyte hypertrophy. However, its hydrophilicity suppressed its efficient cellular uptake for targeting the heart. Exosomes were seen as delivery vesicles with excellent histocompatibility; thus, an isosteviol-loaded exosome (Istv-exo) was prepared for cardiopulmonary delivery in this study. For in vivo evaluation, the Istv-exo and isosteviol saline solution was used for inhalation or intragastric administration on Sprague–Dawley rats for an assay of dynamic distribution. The higher biodistribution of Istv-exo in the lung and heart has been confirmed by the dynamic content curve. Istv-exo/isosteviol solution was administered by inhalation/intragastrically to Myh6^-/- mice, a cardiomyocyte hypertrophy model, to explore the therapeutic effect. The heart function of the mice was measured using echocardiography and in situ imaging was used to analyze the morphology of the heart. The higher level of left ventricular internal dimension, ejection fraction, and cardiac output in echocardiography indicated that Istv-exo enhanced improvement of myocardial function. The attenuation of cardiomyocyte hypertrophy in mice treated with inhalation of Istv-exo determined that it contributed to the reversal of pathological hypertrophy phenotypes. Wheat germ agglutinin staining confirmed that cardiomyocyte hypertrophy was reversed to varying degrees in the Istv-exo, intragastrical isosteviol, and positive control groups. Hematoxylin and eosin staining exhibited the enlarging left ventricular and thinning ventricular wall of the treated mice. Drastically less collagen fiber was observed in the positive control group and Istv-exo group. The inhalation administration of isosteviol-loaded exosomes may be better in therapy for cardiomyocyte hypertrophy than intragastric usage of isosteviol.

There is good evidence that fatty acid derivatives have antibacterial activity and represent a promising approach to developing the next generation of antibacterial agents. In the present work, some new isoquinolin derivatives were synthesized via the Betti reaction. Three-component reaction of aryl aldehydes, 2,7-naphthalenediol and ammonium carboxylate of fatty acids with different chains in EtOH under reflux conditions offered related isoquinolin compounds in good to excellent yields. Some advantages of this procedure are short reaction times, free catalyst, high yield of products and easy work-up. The structure of synthesized compounds was characterized by IR, ¹H, and ¹³C NMR data as well as microanalysis results. In addition, these novel materials were evaluated for their biological activities against Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) bacteria. The obtained data confirm that isoquinolin derivatives 4c, 4e, 4f, 4g, 4m, 4n, 4p, 4q exert excellent antimicrobial activity against these tested bacterial strains.

Ondansetron (OND), a serotonin type-3 receptor antagonist exhibits antiemetic activity by blocking both centrally as well as peripherally. It is one of the most common empiric options for the treatment of nausea and vomiting of different etiologies such as chemotherapy-induced nausea vomiting (CINV), radiation-induced NV, postoperative NV as well as off-labeled drugs used in pregnancy. For the quantitative determination of ondansetron in bulk and pharmaceutical dosage form, a simple reversed-phase HPLC method was successfully developed and validated. Nucleodur 100 – 10 C18 column (216 mm, 4.6 mm, and 5 μm) was used. The solvent system was methanol: water: acetonitrile (80:15:5, v/v/v), whose pH was adjusted to 2.8 by using a few drops of ortho-phosphoric acid, delivered at a flow rate of 1ml/min. Eluents were detected at a wavelength of 308 nm. The proposed method was found to be specific, sensitive and linear (R² > 0.9999) within a desired range of 0.15 – 5 μg/ml, accurate (99.61 – 100.23%), precise (0.004 – 0.2%), and showed good robustness and ruggedness. The limit of detection and quantification was 0.27 μg/ml and 0.8 μg/ml, respectively. A statistically paired sample t-test for the analysis of precision was employed. The proposed method was applied to different marketed formulations.

Raspberry ketone (RK) is an active constituent obtained from Rubus idaeus (Rosaceae), which has been traditionally used against diabetes, hypertension, etc. The objective of this study was to assess the cardioprotective effect of RK against isoproterenol (ISO)-induced cardiac hypertrophy in Wistar rats. Rats were arbitrarily divided into six groups and were treated daily with raspberry ketone (100 and 200 mg/kg), fenofibrate (80 mg/kg) and propranolol (10 mg/kg) along with ISO (3 mg/kg, subcutaneously) for 28 days. Twenty-four hours after the last dose administration, serum and heart tissue samples from the animals were taken and their hemodynamic (blood pressure, heart rate], biochemical (CK-MB, LDH, troponin-T, PPAR-α, apolipoprotein C III, c-reactive protein, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein, malondialdehyde, reduced glutathione, superoxide dismutase, catalase, Na⁺-K⁺-ATPase, total antioxidant capacity, and nitric oxide), histopathological, and immunohistochemical (caspase-3, nuclear factor-κB, tumor necrosis factor-α) analysis was performed along with gravimetric analysis. Administration of ISO significantly altered the cardiac integrity and physiology and these changes were significantly averted by the administration of RK (100 and 200 mg/kg). These results were also found to be comparable with those of the standard drugs, fenofibrate and propranolol. The assessment of cardiac morphology by histopathological and immunohistochemical analysis further validated these results. This study thus demonstrated that RK at doses of 100 and 200 mg/kg showed a dose-dependent decrease in inflammation, oxidative stress, and dyslipidemia against ISO-induced cardiac hypertrophy in Wistar rats, which could be due to agonistic action of RK at PPAR-α receptor subtype.

The effect of thioctic acid (TA), 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride (emoxypine), and their ester derivative (2-ethyl-6-methylpyridinol-3-yl-thiooctanoate, thioxypine) on the behavior of rats in an elevated plus maze (EPM) was studied. Intraperitoneal administration (three times) of TA, emoxypine, and their equimolar mixture in single doses of 36.25, 72.5, and 145 μmol/kg enhanced individual manifestations of anxious behavior in the EPM but did not cause full-blown anxiogenic effects. Similar pro-anxiogenic effects were observed when TA was administered in a dose of 36.25 μmol/kg and emoxypine in doses of 72.5 and 145 μmol/kg. The equimolar mixture of the non-esterified components of thioxypine had a pro-anxiogenic effect in doses of 36.25 and 72.5 μmol/kg. Combination of TA and 2-ethyl-6-methyl-3-hydroxypyridine into the ester potentiated their pro-anxiogenic activity, which manifested as an extensive anxiogenic effect of thioxypine when administered three times in a dose of 145 μmol/kg.