Current Bioactive Compounds - Volume 12, Issue 4, 2016

Background: The most important investigations since the first publication on opiorphin, in 2006, are summarized in this review. Opiorphin is a human endogenous pentapeptide (Gln-Arg-Phe-Ser-Arg) which inhibits both the Neutral EndoPeptidase (NEP) and aminopeptidase N (AP-N), protecting enkephalins from degradation by these ectopeptidases, thus activating endogenous enkephalin-related opioid pathways. Objective: In this review we highlight the in vitro and in vivo effects of opiorphin. Results: We examine in detail the structure-activity relationship studies addressed in order to identify the amino acids of opiorphin sequence required to functional interactions with its targets and to design its metabolically stable analogs. The modulation of emotionalrelated behaviors and effects on smooth muscle motility including their resulting therapeutic implication are also analysed. In addition, the in vitro potency of opiorphin and its metabolically stable analogs on opioid receptor binding by enkephalin-related peptides are also summarized. Finally, quantitative or semiquantitative analytical methods of opiorphin on various biological samples are cited. Conclusion: The advantages and difficulties of therapeutic applications of opiorphin peptide and its synthetic derivatives are discussed.

Background: This review elaborates the updated synthetic approaches of a known group of dihydropyrimidinones/thiones and their reactions. Also an updated literature overview on the biologically active dihydropyrimidinone analogs is provided. Methods: The data written in this review was taken from the peer reviewed national and international literature and a deductive qualitative content analysis methodology was used to analyse the interventions and findings of included studies. Results: More than 100 papers were included in the review. For the synthesis of dihydropyrimidones/ thiones, all types of catalyst variants viz. acidic, basic, Lewis acids, ionic liquids, simple salts, nano-particles etc. have been used in the past few decades as evident by the patents and publications in the reputed international journals of organic chemistry. Also sonication and microwave irradiations have been reported for the time economy and rate enhancement of dihydropyrimidone/ thione synthesis. The focus of this review will be on recent pharmacological results of the dihydropyrimidinones/ thiones in the area of Anti-Cancer, Anti-malarial, Anti-hypertensive, Potassium channel antagonists, Anti-tubercular activity, Anti-HIV agents, Anti-bacterial, Anti-microbial, Anti-inflammatory and Anti-epileptics activities. Conclusion: The findings of this review include a large number of dihydropyrimidone/thione derivatives with a wide spectrum of biological activities which have been synthesized by making variation in all the three building blocks. In future novel dihydropyrimidines with important biological properties will undoubtedly be discovered using combining combinatorial synthesis, effective processes and optimal reaction conditions employing green catalysts, which should be designed to eliminate the use and generation of hazardous substances.

An HPLC-coulometric electrode array detection (CEAD) based method for the determination of protocatechuic acid, chlorogenic acid, rutin (quercetin-3-O-rutinoside), nicotiflorin (kaempferol-3-Orutinoside) and quercetin in elderberry juice was developed. Sample work up for the determination of phenolic acids included solid phase extraction (SPE). For the analysis of flavonoids, simple dilution and centrifugation steps were sufficient. The compounds were separated isocratically on the same reversed phase column using two different mobile phases to prevent long retention times and tailing of the aglycone peaks. The analytes were then detected at twelve coulometric cells. The current/voltage curves contributed to compound identification and to verification of the peak purity of the separated compounds. Additionally, LC-ESI-MS in the negative ion scan mode was applied for qualitative analysis. Quantification of the compounds was carried out by standard addition method. The content in elderberry juice varied between 785 mg/l for rutin and 2.8 mg/l for quercetin. The presented rapid and reliable method can be used to differentiate between elderberry juices of different origins. Coulometric electrode array detection was applied for the first time for the determination of these compounds in elderberry juice. Dedicated to em. O. Univ. Prof. Dr. Adolf Neckel on the occasion of his 90th birthday.

Functional beverage from fermented beet-root (Beta vulgaris) using a coculture of Lactobacillus acidophilus and Lactobacillus plantarum was investigated. The juice was fermented for 24 and 48 h and the samples were analyzed for their physio-chemical changes, cell viability and preservation efficiency. A pH drop was observed for four days in both 24 and 48 h fermented samples, after which the pH increased till the 26th day and thereafter remained constant. HPLC analysis confirmed the presence of greater amounts of organic acids in the 48 h fermented sample. HPLC analysis confirmed the presence of greater amounts of organic acids in the 48 h fermented sample than the 24 h fermented sample. The presence of kaempferol 3- Orutinoside might also be confirmed by HPLC. FTIR analysis showed the presence of aromatic amines in the fermented juice. Fermented juice showed a significant antibacterial activity against Listeria monocytogenes. Also, the 48 h fermented juice showed 64% cytotoxic activity against human liver cancer cells Hep G2.

Gymnema sylvestre R.Br. is an important medicinal plant traditionally used as an antidiabetic agent. Excessive use of the plant has resulted in its mass depletion from the natural habitat. In the present work, flavonoids were identified from the plant parts and callus culture. Different colored callus was obtained using various concentrations of hormones. The flavonoids (quercetin and kaempferol) were identified using chromatographic and spectral studies. Total flavonoid content was found to be more in aerial parts as compared to the callus tissue. However, antioxidant potential, in terms of DPPH scavenging activity, was more in callus as compared to the leaves.

Strawberry fruits have a high antioxidant capacity that it is associated with the content of polyphenolic compounds and, specifically, anthocyanins. A potential source of these compounds is the strawberry pulp processing industry, which produces a large quantity of agro-industrial waste in its production chain. The anthocyanins were extracted using ethanol acidified with hydrochloric, tartaric, citric, lactic, and phosphoric acids, and based on complete experimental design; they were evaluated as the amount of solvent (20 to 50 mL). The number of extractions (1 to 5) and the time (10 to 30 minutes) can affect the yield of the extracts of pelargonidin 3-glucoside from the residue of strawberry pulp processing. The best conditions were as follows: 20 mL of solvent, four extractions and 12 minutes using ethanol acidified with 1% hydrochloric acid, where 703.45 μg/ g of pelargonidin 3-glucoside was found, representing 98% extraction.

Background: Searching for well-organized organic synthesis approach that can be authenticated for the rapid generation of complex organic molecules from simple and readily accessible starting materials are in a vogue in the recent epochs. Recently, the developments of green protocols which are environmentally benign and without pollution have received substantial levels of consideration, owing to the increasing tendency of the chemical industry towards green synthetic methods. Multi-component reactions (MCRs) are one of the powerful tools. MCRs is influenced by microwave under solvent free condition as a powerful green alternative to the conventional synthesis. 4H-Pyrans derivative is essential building block in organic synthesis as well as in medicinal chemistry. Our aim is to find out the best environmental friendly catalytic system for the synthesis of pyranopyrazoles and carrying out organic reactions under solvent free condition Synthesis of new and desired compounds have an endless demand. The present work shows one-pot, four-component, an efficient and solvent free synthesis of pyrano[2,3-c]pyrazole derivatives which have been accomplished by the cyclization reaction with excellent yields, using ZnOCl2 as a prompt catalyst. All the derivatives have been characterized by elemental analysis and various spectroscopic methods. All the final scaffolds have been subjected to in vitro antibacterial screening. Methods: A mixture of aldehyde derivatives (1a-1g) 0.50 g (4.7116 mmol), malononitrile 2 0.31 g (0.299 g/ml) (4.1116 mmol), ethyl acetoacetate 3 0.61 g (4.7116 mmol) and 2, 4-dinitrophenyl hydrazine 4 (4.7116 mmol) were placed into 25 ml flat-bottomed flask in the presence of the catalyst, ZnOCl2 (10 mol %). The reaction mixture was heated at 60°C for 15- 45 min. The progress of the reaction was monitored by TLC. After consumption of starting materials, the mixture was poured into cold water and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and evaporated under reduced pressure. The aqueous layer was filtered to reuse and washed with methanol for two to three times to remove the strains. The isolated compounds (5a-5g) were then dried and subjected to column chromatography using 20% (v/v) Ethyl acetate: hexane mixture as an eluent with 90-96% yield of product. The catalyst was reused up to three cycles with a slight decrease of catalytic activity. Results: First we performed four-component cyclization reaction between aldehyde derivative, malononitrile, ethyl acetoacetate and 2, 4-dinitrophenyl hydrazine as a model reaction to attaining the optimal reaction conditions. Results showed that the reaction proceeds in the presence of ZnOCl2 was better with yield and time as compared to all catalysts of the series. After getting optimal condition, we synthesized 5a-5g compounds by using ZnOCl2 as a catalyst. Antibacterial activity of synthesized compound was carried out on Nutrient-agar plates by well–diffusion assay against test culture. Compounds 5f, 5d, and 5b showed good activity to standard drug against Enterobacter aerogens, Escherichia coli, Bacillus cereus and Micrococcus luteus Gram positive bacteria, respectively. Conclusion: In summary, we have developed an efficient method for the one-pot synthesis of various pyrano[2,3-c]- pyrazole derivatives by using ZnOCl2 as prompt catalyst. This protocol is very simple from the experimental point of view. We used a green and recyclable catalyst, high yield of products with high purity, avoiding the use of hazardous organic solvents, novelty and the simple work up, and there was not any requirement of anhydrous conditions, thus making the present method a valuable contribution in accord with green chemistry principles. The antibacterial and antioxidant activities of the synthesized compounds, were evaluated in vitro. The antibacterial data revealed that the all synthesized compounds proved to be active against the test organism, two gram negative and two gram positive reference strains as compared to standard drugs.

Background: In the expanding field of anticancer drugs, HDAC inhibitors are playing an increasingly important role. To date, four/five HDAC inhibitors have been approved by FDA. All these compounds fit the widely accepted HDAC inhibitors pharmacophore model characterized by a cap group, a linker chain and a zinc binding group (ZBG), able to bind the Zn2+ ion in a pocket of the HDAC active site. Romidepsin, a natural compound, is the only thiol derivative. We have selected a new class of synthetic HDAC inhibitors, the thio-ω(lactam-carboxamide) derivatives, with ST7612AA1 as drug candidate, pan-inhibitor active in the range of single- to twodigit nanomolar concentrations. Preliminary results of a synthetic optimization attempt towards a fast scale-up process are here proposed. Methods: in the four steps of synthesis, from unsaturated amino acid intermediate to the final product, we explored different synthetic conditions in order to have a transferable process for a scale-up synthetic laboratory. Results: In the first step, isobutyl chloroformate was used and, after a simple work up with 1M HCl, 2 (96% yield) was obtained as a white solid, which was used directly in the next step. For thioacetic acid addition to the double bond of intermediate 2, two different routes were possible, with addition reaction in the first (D’) or last step (D). Reactions of 2 to give 5 or of 4 to give ST7612AA1 were both performed in dioxane. Reactions were fast and did not need the usually advised radical quenching with cyclohexene. The corresponding products were obtained in good yields (step D’, 89%; step D, 81%) after a flash chromatography. Conclusion: ST7612AA1, a thiol derivative prodrug of ST7464AA1, is the first of a new generation of HDAC inhibitors, very potent, orally administered, and well tolerated. Here, we have identified a synthetic route, competitive, versatile and easily transferable to industrial processes.

Background: A quantitative and reliable relationship between in vitro drug release and in vivo absorption is desirable for rational development and optimization of extended release (ER) dosage forms. This article describes the development and validation of an in vitro - in vivo correlation (IVIVC) for ER tablets of Lamotrigine. Methods: Two prototype extended release tablets of lamotrigine were formulated. Predictive in vitro dissolution method with changing pH of media from acidic to basic condition in Dissolution Apparatus Type II (United State Pharmacopoeia) was developed and the two formulations were evaluated to obtain in vitro data for the development of IVIVC. The in vivo dataset for development of IVIVC (plasma concentration data) was obtained from the two arms of a three-way, crossover study in 12 healthy volunteers after administration of the developed ER tablets. The third arm was a reference formulation for external validation. Results: An in-house mean plasma concentration data of an immediate release formulation was used to compute the in vivo weighting function. The fraction of drug absorbed was computed using numerical deconvolution and a linear correlation model was developed between fraction absorbed and fraction dissolved from the two formulations. Internal and external validation of the developed model was carried out based on prediction error of pharmacokinetic parameter estimates. Conclusion: Prediction error was less than 10% for both internal and external validations, demonstrating the validity of the developed model. Hence, the model can be used for comparison and selection of formulations for pivotal bioequivalence study.

Background: Salvia species are used traditionally for treatment of many disorders all around the world. Salvia santolinifolia is a medicinal plant, traditionally used for treatment of inflammation, hypercholesterolemia, hemorrhoids and diarrhea. Methods: In this study, antibacterial, antioxidant, toxicity, acetylcholinesterase and μ- glucosidase inhibitory activities of several extracts of S. santolinifolia were evaluated. Total phenol and flavonoid contents of the extracts were also determined. Results: The MeOH extract showed high antioxidant activity in DPPH scavenging and ferric reducing power assays. All samples exhibited high acetylcholinesterase (IC50 = 42-89 μg/ml) and μ-glucosidase inhibitory activities (IC50 = 24-174 μg/ml). The MeOH extract showed great antibacterial and antifungal activities especially against Bacillus cereus and Candida albicans with MIC values from 10 to 200 μg/ml. Conclusion: Our findings indicated that S. santolinifolia is a rich source of natural compounds with strong antimicrobial, antidiabetic and anti-Alzheimer activities. This plant has great potential for several applications as pharmaceuticals and functional foods.