Current Bioactive Compounds - Volume 13, Issue 2, 2017

Background: Alzheimer’s disease (AD) is a deteriorating neurodegenerative non-curable disease that affects millions worldwide. Current drugs have side effects that are significant. In AD, the betaamyloid precursor protein (β-APP), critical for normal neuron growth, survival and repair, is improperly cleaved by specific aspartic proteases creating fragments that form amyloid beta. These fragments aggregate outside neurons and create plaques which lead to destruction of neural signaling. The pathophysiology of AD is complex and there are many approaches to combating the disease. Many studies target PTB domain-containing proteins in order to inhibit binding to β-APP to prevent amyloid formation; whereas others target inhibition of specific aspartate proteases required for amyloid plaque formation. The role of GSK-3 is actively being studied as well as specific inhibitors to this target for AD. Methods: Initially a structural search was done in the Protein Data Bank (PDB) for all protein targets in the absence and presence of inhibitors and regulating molecules involved in AD. The structural criteria of the crystallographic data for this review of proteins associated with AD are the following: 1) A resolution of 3.0 angstroms or higher; 2) 3.5% redundancy in data; 3) Greater than 85% completeness; 4) Rfactor less than 24%; 5) Rfree below 28% and within 3% of Rfactor ; 6) 100% occupancy of inhibitor or regulator (if present). In addition, preliminary characterization (sizing) of nanoparticles with fluorescent spectroscopy and dynamic light scattering is reported. Results: Structural examples analyzed include Presenilin Homologue (PSH) protein and Mint1 which are important for the regulation of β-APP. Mint1 and Presenilin are examples analyzed of the phosphotyrosine- binding (PTB) domain. Recent studies of the inhibition of the aspartic protease BACE1 that is known to cleave β-APP to β-amyloid essential to forming β-amyloid plaques is reviewed. A structural analysis of BACE1/inhibitor complexes is provided with suggested modifications to increase bioavailability of inhibitors. Finally, a novel technique utilizing nanoparticles to destroy β-amyloid plaques is introduced as a possible future therapy for AD. Preliminary characterization and analysis of nanoparticle sizes to deliver GSK-3 inhibitors is presented. Conclusion: These structure-based examples discussed confirm a high level of complexity involved in regulating β-APP that presents a formidable challenge as a target for drug development to block β- amyloid plaque formation (β-APP cleavage) in AD. A more direct approach to combat AD is the inhibition of the aspartic protease BACE1. In addition the role of GSK-3 in AD introduces a new level of complexity in the pathophysiology of AD. Taken together, the current focus of many studies is now on drug delivery to these known targets via nanoparticles and microspheres.

Oxidative injury or cellular damage developing from free radicals or reactive oxygen species (ROS) seems to be the basic mechanism involved in the etiology of different ailments such as neurodegenerative, cardiovascular, inflammatory and other chronic diseases. The data proposes that ROS of any origin can be quench using natural scavengers contained by our daily foods and medicinal plants. In this context, the search of novel antioxidant compounds from natural sources has been increased. The alkaloids consist of most abundant naturally occurring group of secondary metabolites in plant-kingdom. Their different biological activities such as cardiovascular, anti-ulcer, antispasmodic, antirheumatic, antiinflammatory, antinociceptive and antibacterial have been ascribed to different compounds belonging to this chemical group. Moreover, the broad range of biological activities makes many alkaloids prominent starting point for chemical medicinal chemistry. The literature reviewed in this article, summarized by an informative and easy-to-understand table, will focus on the advances in antioxidant potential of natural alkaloids, paving the way for new pharmaceutical and/or pharmacological studies.

Background: Despite considerable evidence showing the importance of the 1,4- dihydropyridines, there are very few review articles which provide full access to systematic literature. This review aims to provide synthetic strategy of 1,4-dihydropyridines and medicinal application of different substituted dihydropyridines to develop potent molecules. Methods: A detailed structured search of bibliographic databases was undertaken for peer reviewed research literature using a focused criteria and by different database searches like Pubmed, Scifinder, Elsevier and ACS search. Results: Sixty six papers were included in the review. Molecules containing dihydropyridine scaffold bind to the L-type calcium channel and act as a multifunctional lead molecule for the various cardiovascular activities like antihypertensive, antianginal, vasodilator and cardiac depressants. Apart from the CVS activities, antitubercular, anticonvulsant, antitumor, analgesic, anti-inflammatory, stress protection, antiulcer and antioxidant activities were also observed. The present review highlights the reactivity of DHPs (dihydropyridines) including various synthetic routes as well as specified structural activity features with corresponding pharmacological activities. Conclusion: The findings of this review confirm the significance of a 1,4-dihydropyridines as a privileged scaffold in medicinal chemistry. The major role of this scaffold is in the prevention or treatment of the various diseases. The DHPs are versatile molecules, which exhibit various pharmacological activities such as antimicrobial, antihypertensive, anti-HIV, anticancer, etc.

Background: Alzheimer's disease (AD) is a neurodegenerative and irreversible disease that inevitably progresses to the death. The usage of acetylcholinesterase (AChE) inhibitors has been effective in reducing the symptoms of this disease. This study aims to examine the compounds from the species of Amaryllidaceae family as a source for active compounds able to inhibit AChE and contribute to the treatment of AD. Methods: Molecular modeling was done with DFT/B3lyp/6-31G** method for the compounds: Galantamine, Assoanine, Oxoassoanine, Epinorgalatamine, Hidroxygalantamine and Sanguinine. Potential electrostatic maps and frontier orbital were calculated to investigate the likely sites of biological activity of the compounds. The Pearson correlation was performed between the calculated descriptors and the total energy to evaluate the descriptors that have better correlations. Similarly, correlation of the calculated descriptors was performed with the hydration energy. Predictions of pharmacokinetic and toxicological properties (mutagenicity and carcinogenicity) were obtained for the studied compounds. Results: The molecule with the highest GAP was epinorgalantamine, which indicates greater stability and lower reactivity than sanguinine that showed low stability and increased chemical reactivity. Sanguinine, galantamine and epinorgalantamine molecules showed good pharmacokinetic results. Epinorgalantamine and hidroxygalantamine did not exhibit mutagenicity. Conclusion: Epinorgalantamine showed the most satisfactory pharmacokinetic and toxicological results when compared to the parameters obtained from the other compounds investigated. However, more work is still required so that, in the future, the use of natural compounds can contribute to the treatment of patients with AD.

Background: Convulsion is a central neurological disorder and it occurs due to excess firing of the neurons. Globally, the number of patients suffering by convulsion is increasing day by day. There is a current need of discovery and development of new potential anticonvulsant agents. Methods: A series of novel pyrimidine derivatives (1a to 2e) were synthesized from benzaldehyde, ethylacetoacetate, thiourea or urea through single pot operation following Biginelli reaction and subsequently the products were modified by two steps reaction to obtain the pharmacophoric demanded molecules. The newly synthesized compounds were characterized by FTIR, 1H and 13C NMR, ESI-MS and elemental analyses. The anticonvulsant activity of all the title compounds was investigated against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) models and their neurotoxicity was also evaluated by rotarod method in albino mice. Results: Compounds 1a, 1b, 2a and 2b were found to be active as compared to phenytoin and carbamazepine as standards. Compound N`-(diphenylmethylene)-6-methyl-4-phenyl-2-thioxo-1, 2, 3, 4- tetrahydropyrimidine-5-carbohydrazide (1b) has emerged as a lead in this series with no neurotoxicity. Conclusion: Compound 1b can further be evaluated by the researchers to test its potency and toxicity for future pursuit.

Background: Essential oils extracted from plant materials are widely studied because of their fungicide and bactericide actions. However, these essential oils also contain compounds with antioxidant activity. Therefore, the antioxidant capacity of essential oils from spices, herbs and citrus was analyzed. Methods: We evaluated the antioxidant activity of the extracts of spices, herbs and citrus essential oils with the aid of in vitro techniques DPPH (2,2-diphenyl-1-picryl-hidrazila), ABTS (2,2`-azino-bis-3- ethylbenzthiazoline-6-sulphonic acid), FRAP (Ferric reducing ability power) and ORAC (Oxygen Radical Absorbance Capacity). For identification of the major compounds present in the essential oils gas chromatography- mass spectrometry (GC-MS) was used. Results: The clove and cinnamon essential oils showed high antioxidant capacity, particularly the essential oil extracted from clove leaves, which showed antioxidant capacity values of 1753.36 and 779.06 µmol TE/g in DPPH and ORAC assays, respectively. The nutmeg and oregano essential oils presented intermediate results. The identification of bioactive compounds was performed in these essential oils by gas chromatography-mass spectrometry. Eugenol and caryophyllene were the main compounds observed in the clove and cinnamon essential oils. The principal component analysis (PCA) confirmed the superiority of the clove and cinnamon essential oils. Conclusion: Therefore, the essential oils extracted from spices proved to be promising sources of antioxidants.

Background: Antioxidant and Anti-LOX properties of plant species are important in the selection of plants for their medicinal and phytochemical assessment. This study aims at comparing antioxidant and anti-LOX properties of ethanolic extracts from different plant parts (leaf and stem) at different phenological stages (mature and immature) of the rare Acridocarpus orientalis. Methods: Fresh A. orientalis samples were collected from around Al-Ain city in the United Arab Emirates (UAE). Aerial parts of A. orientalis (10 g) were extracted with 70% (v/v) aqueous ethanol (200 mL). DPPH scavenging activity, ABTS radical cation decolorization assay, Ferric reducing-antioxidant power (FRAP) assay, and β-carotene bleaching assay were used for antioxidant activity assessment. LOX inhibitory assay was also used to investigate anti-inflammatory potentials of A. orientalis. Results: The DPPH scavenging activities, ABTS decolorization, FRAP and β-Carotene bleaching potentials of immature leaves were higher than extracts from other parts of the plant under investigation. This study also reported 91% improvement in the ABTS absorption when comparing C0 (control) to C10 (10 µg extract concentration), in immature leaf extracts. Considerable differences in the FRAP potentials of leaves vs stems was revealed in this investigation. β-Carotene bleaching potentials in the leaves were also comparatively higher than in the stems. Additionally, immature leaves had more anti-LOX potential than other parts of the plant at different phenological stages. Conclusion: A. orientalis presents considerable antioxidant as well as anti-inflammatory activities and therefore may be a good candidate for hepato-protective effects. The present investigation is the first component of an in-vivo assessment of the hepato-protective potentials of A. orientalis in the experimental animals.

Background: Capsaicinoids content of peppers is one of the major parameters that determine its commercial and nutritional values. Despite their properties and application in the food industry, capsaicinoid compounds have been widely studied in the pharmaceutical area due to their therapeutic activities such as antioxidant, antimicrobial, antitumor, antiobesity, anti-inflammatory and analgesic effects. Methods: Capsacin bioactivity prediction step was made with PharmMapper, SwissTargetPredicition and PASS online servers. After, docking simulations were performed for capsaicin and acetylcholinesterase with GOLD suite 4.12 inside a sphere of 17 Å centered at CZ atom of Phe331, where the 5 top-ranked poses were selected using the Chemscore function and a population size of 100, selection pressure of 1.1, 100,000 operations, number of islands of 5, niche size of 2, crossover frequency of 95, mutation frequency of 95 and migration frequency of 10. Results: The bioactivity prediction data of capasaicin revealed a wide range of potential activities in humans, specially the interference in enzymes involved in metabolic reactions, anti-inflammatory and antineoplastic propensity, pain control and action on cholinergic transmission. Docking simulations with acetylcholinesterase showed that capsaicin may reach the enzyme peripheral anionic site, being a candidate capable of possibly avoiding the amyloid assembly step in Alzheimer’s disease. Conclusion: The natural product capsaicin, extracted from chili peppers, presents a wide bioactivity spectrum. It is already used in clinical practice due to its potential benefits as an analgesic drug. The hypothesis of capsaicin acting as a neuroprotective agent against alzheimer’s disease seems to be logical once some bioactivity prediction tools reveal the possible action on mechanisms important for actual drugs, specially the inhibition of acetylcholinesterase. Capsaicin has a chemical structure able to reach the peripheral anionic site of the enzyme, being a potential candidate to influence amyloid deposition and induce a disease-modifying effect against Alzhemier’s disease.

Background: In this research, we investigated which bioactive substances are found in Hibiscus tiliaceus and whether they might make this plant a suitable additive to ruminant feed. The substances investigated include saponin, fumaric acid, and flavonoids. It is possible that these additives could minimise methane emission, and improve the growth performance of indigenous cattle. Methods: We evaluated the nutrient contents of extracts of H. tiliaceus, including crude protein, crude fibre, amino acids, fumaric acid, and active compounds. We extracted large and small leaves and small flowers from H. tiliaceus using various types and concentrations of solvents. The solvents used were water, ethanol, ethyl acetate, and ethyl ether. Results: We found more flavonoids and phenols in samples extracted with ethyl acetate than with the other solvents. In the case of the ethyl acetate solvent, the highest concentrations of both flavonoids and phenols were found in the small leaves rather than the large leaves. The fumaric acid content was higher in the small leaves than in the flower (48.18 vs. 35.47 ppm). The saponin content of the small leaves when dissolved in ethyl acetate and ethyl ether was higher than when water or ethanol were used as the solvent (24.6 and 32.0% vs. 3.0 and 1.2%, respectively). In the case of the small flowers, the highest saponin concentration was found in the extracts in water and ethanol (15.0 and 8.05% vs. 0.14 and 5.5%). We found higher concentrations of amino acids, protein, and low crude fibre in the small leaves. The fumaric acid content of the small leaves was higher than that of the small flowers. There were 24 organic compounds in the aqueous extracts of leaves. These mainly consisted of fatty acids and ester (31%), nitrogenous compounds (18.28%), and quinoline (23%). Conclusion: The leaves and flowers of small varieties of H. tiliaceus can potentially be used as feed additives to manipulate rumen conditions, improve feed efficiency, and reduce methane emissions.

Background: Many species of the genus Vitex from the Verbenaceae family are used in traditional medicine for the treatment of various medical conditions such as depression, venereal diseases, malaria, asthma, allergy, wounds, skin diseases, snake bite and body pains. One of them, Vitex agnuscastus L. has been used to treat pain, swelling, inflammation, headaches, rheumatism, and sexual dysfunction. Methods: The analgesic and anti-inflammaotry effects of essential oil extracts from Vitex agnus-castus L were evaluated employing various standard experimental test models. Acetic acid was used to induce writhes in mice and inflammation of paw edema. The analgesic activity of seeds essential oil at a dose of 150mg / kg gave a percentage of inhibition very near to diclofenac (40.13% and 40.41%, respectively). The essential oils show an anti-inflammatory activity in the test of the edema. Results: The evaluation of the percentage of inhibition indicates that the essential oil of Vitex agnuscastus L. seeds possess anti-inflammatory activity (150 mg/kg) nearby and sometimes better -during the time-than diclofenac (61,04% - 50% at 30 min; 62,04% - 83,33% at 60 min and 91,05% - 90,91% at 120 min, respectively). Conclusion: The results of this research indicated that Vitex agnus-castus L. essential oil of seeds remarkably inhibited inflammation and could explain the traditional usage of this plant.

Background: The rhizome of Oni-dokoro (a wild yam, Dioscorea tokoro) has extremely bitter taste and is not generally regarded edible; however, in northern part of Japan, such as Iwate and a part of Aomori, it is used as health promoting food. To clarify the reason, we examined the biologically active compounds in the rhizome collected at Iwate and compared them from the other area in literature. Methods: The acetonitrile extract from northern part of Japan was purified by bioassay-guided separation using antiproliferative activity to human leukemia HL-60 cell, and protodioscin (PD) was isolated and identified by instrumental analyses as the major active compound. Results: PD known as a saponin with four sugar moieties, an inhibitor for platelet aggregation, and a low density lipoprotein (LPL) lowering agent, displayed strong growth inhibitory effect to HL-60. The literature search suggested that the rhizome from other area contained dioscin and other saponins with three sugar moieties as their major component. We assume that the edible and health promoting effect of the rhizome in the particular area is partially derived from these different components. Conclusion: We were interested in the differences of utilization in the rhizome of wild yam Dioscorea tokoro, and examined the chemical composition in the rhizome to find protodioscin as antiproliferative compound to HL-60. In the report from other area, the rhizome exhibited dioscin as the major compound. Our study indicated that the protodioscin/dioscin composition varied regionally, although the reason still needs to be investigated.