Nanotechnology-based approaches applied to nutraceuticals.

Nutraceuticals and food industries are opening to a tremendously upcoming technology in the field of "Nano science". A new prospect has been defined by nanotechnology by conferring modified properties of nanomaterials and its application in the development of nanoformulations, nutritional supplements and food industry. Nanomaterials reveal exclusive properties because of their small size and high surface/volume ratio; thus, they have a complete application in nutraceuticals and food sector. In the existent review article, we obligate to present a comprehensive outline of the application of nanomaterials in development of advanced nano-based nutraceuticals with enhanced bioavailability, solubility, improved encapsulation efficiency, increased stability, sustained and targeted drug delivery, protection against degradation and microbial contamination and with improved pharmacological activity. It also highlights the importance of nanomaterials as nanosensors/nano-bio sensors for encapsulating peptides, antibodies, enzymes, etc. and in the food packaging industry and its future application. Thus, the review aims to focus on the benefits and new dimensions provided by nanomaterials and nanotechnology in health sectors by improving treatment strategies and quality of life.

In silico designing, in vitro and in vivo evaluation of potential PPAR-γ agonists derived from aryl propionic acid scaffold.

Attributed to several side effects, especially on hepatic tissues and body weight, there is always an urge of innovation and upgrading in already existing medication being used in maintaining diabetic condition. Therefore, in the present work, forty-eight molecules derived from arylpropionic acid scaffold were synthesized and their evaluation against diabetes was carried out. The synthesis of these molecules attributed to excellent dock score displayed by all the structures performed against PPAR-γ receptor site. Subsequently, all the derivatives were primarily deduced for their antidiabetic potential by OGTT. The compounds that showed significant antidiabetic activity in OGT Test and also exhibited high dock scores were assessed further by in vitro PPAR transactivation assay to assure analogy between in vivo and in vitro studies. The antidiabetic activity of these active compounds was then evaluated on STZ induced diabetic model in vivo. The most active compounds were scrutinized for its effect on PPAR-γ gene expression and hepatotoxic effect. Finally, it was recapitulated that these derivatives can provide a new prospect towards the development of antidiabetic agents with fewer side effects.

Design, synthesis and biological evaluation of benzoxazolinone-containing 1,3,4-thiadiazoles as TNF-α inhibitors.

A library of nineteen benzoxazolinone-based 1,3,4-thiadiazoles has been synthesized and screened for their anti-inflammatory activity. The compound 1f exhibited a potent anti-inflammatory activity with an inhibition of 65.83% and 32.50% after 3 h and 5 h respectively. It also exhibited a significant in vitro (p < 0.01), TNF- α inhibitory activity with 51.44 % inhibition. The compound 1f showed hydrogen bonding with GLN 61 and interactions with TYR 119, TYR 151 and GLY 121. The histopathology report showed that none of the compounds caused gastric ulceration. The results from the in vivo & in vitro antiinflammatory activity along with In Silico studies exhibit that benzoxazolinone-based 1,3,4-thiadiazoles may be used in the future development of anti-inflammatory drugs.

Synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3ß inhibitors with in vivo antidepressant activity.

Recent findings of potential implications of glycogen synthase kinase-3ß (GSK-3ß) dysfunction in psychiatric disorders like depression, have increased focus for development of GSK-3ß inhibitors with possible anti-depressant activity. Keeping this in view, we synthesized a series of benzimidazole-linked-1,3,4-oxadiazole carboxamides and evaluated them for in vitro GSK-3ß inhibition. Active compounds were investigated for in vivo antidepressant activity in Wistar rats. Docking studies of active compounds have also been performed. Among nineteen compounds synthesized, compounds 7a, 7r, 7j, and 7d exhibited significant potency against GSK-3ß in sub-micromolar range with IC50 values of 0.13 µM, 0.14 µM, 0.20 µM, 0.22 µM respectively and significantly reduced immobility time (antidepressant-like activity) in rats compared to control group. Docking study showed key interactions of these compounds with GSK-3ß. These compounds may thus serve as valuable candidates for subsequent development of effective drugs against depression and related disorders.

Oxazolo[4,5-b]pyridine-Based Piperazinamides as GSK-3ß Inhibitors with Potential for Attenuating Inflammation and Suppression of Pro-Inflammatory Mediators.

Recent studies reveal that glycogen synthase kinase-3ß (GSK-3ß) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro GSK-3ß inhibitory and in vivo anti-inflammatory activity. The compounds 7d, 7e, 7g, and 7c displayed the best GSK-3ß inhibitory activity among all the synthesized compounds, with corresponding IC50 values of 0.34, 0.39, 0.47, and 0.53 µM. Among the compounds 7d, 7e, 7g, and 7c examined for in vivo anti-inflammatory activity in the rat paw edema model, compound 7d exhibited maximum inhibition, reducing the paw volume by 62.79 and 65.91% at 3 and 5 h post-carrageenan administration, respectively, in comparison to indomethacin (76.74% at 3 h and 79.54% at 5 h after carrageenan administration). Furthermore, these compounds (7d, 7e, 7g, and 7c) were also found to substantially inhibit pro-inflammatory mediators, i.e., TNF-α, IL-1ß, and IL-6, ex vivo in comparison to indomethacin and did not pose any gastric ulceration risk, indicating the potential of this oxazolopyridine scaffold for the development of GSK-3ß inhibitors and their application as anti-inflammatory agents.

Novel 2,4-dichlorophenoxy acetic acid substituted thiazolidin-4-ones as anti-inflammatory agents: Design, synthesis and biological screening.

A library of fourteen 2-imino-4-thiazolidinone derivatives (1a-1n) has been synthesized and evaluated for in vivo anti-inflammatory activity and effect on ex-vivo COX-2 and TNF-α expression. Compounds 1k (5-(2,4-dichloro-phenooxy)-acetic acid (3-benzyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) and 1m (5-(2,4-dichloro-phenooxy)-acetic acid (3-cyclohexyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) exhibited in vivo inhibition of 81.14% and 78.80% respectively after 5h in comparison to indomethacin which showed 76.36% inhibition of inflammation without causing any damage to the stomach. Compound 1k showed a reduction of 68.32% in the level of COX-2 as compared to the indomethacin which exhibited 66.23% inhibition of COX-2. The selectivity index of compound 1k was found to be 29.00 in comparison to indomethacin showing selectivity index of 0.476. Compounds 1k and 1m were also found to significantly suppress TNF-α concentration to 70.10% and 68.43% in comparison to indomethacin which exhibited 66.45% suppression.

Natural and synthetic bioactive inhibitors of glycogen synthase kinase.

Glycogen synthase kinase-3 is a multi-functional serine-threonine kinase and is involved in diverse physiological processes, including metabolism, cell cycle, and gene expression by regulating a wide variety of known substrates like glycogen synthase, tau-protein and ß-catenin. Aberrant GSK-3 has been involved in diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. In this review, we present an overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation. In addition, a detailed description of the small molecule inhibitors of GSK-3 with different mode of action discovered or specifically developed for GSK-3 has been presented. Furthermore, some clues for the future optimization of these promising molecules to develop specific drugs inhibiting GSK-3, for the treatment of associated disease conditions have also been discussed.

Synthesis of pyrimidin-4-one-1,2,3-triazole conjugates as glycogen synthase kinase-3ß inhibitors with anti-depressant activity.

GSK-3 specific inhibitors are promising candidates for the treatment of devastating pathologies such as diabetes, neurodegenerative diseases and cancers. We have synthesized a library of pyrimidin-4-one-1,2,3-triazole conjugates using click-chemistry approach and evaluated them as glycogen synthase kinase-3ß inhibitors. Compounds 3g, 3j, 3n and 3r were found to be most potent among the eighteen pyrimidin-4-one-1,2,3-triazole conjugates synthesized and they were further evaluated for their in vivo anti-depressant activity. Compound 3n (2-((1-(3,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-methyl-6-phenylpyrimidin-4(3H)-one) exhibited the most potent inhibitory activity against GSK-3ß with IC50 value of 82nM and was also found to exhibit significant antidepressant activity at 50mg/kg, when compared with fluoxetine, a known antidepressant drug. The molecular docking studies were performed to elucidate the binding modes of the compounds with the GSK-3ß target and two crucial interactions namely, hydrogen bond formation with Val 135 and Lys 183 residues in the active site of GSK-3ß were observed.

Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3ß inhibitors with anti-depressant activity.

A series of benzimidazole based thiadiazole and carbohydrazide conjugates have been synthesized and evaluated for inhibition of glycogen synthase kinase-3ß and anti-depressant effect. Compounds 4f, 4j, 5b, 5g and 5i were found to be the most potent inhibitors of GSK-3ß in vitro amongst the twenty-five benzimidazole based thiadiazole and carbohydrazide conjugates synthesized. Compound 5i was also found to exhibit significant antidepressant activity in vivo at 50mg/kg, when compared to fluoxetine, a known antidepressant drug. The molecular docking studies revealed multiple hydrogen bond interactions by the synthesized compounds with various amino acid residues, viz, ASP-133, LYS-183, PRO-136, VAL-135, TYR-134, or LYS-60 at the GSK-3ß receptor site.

Synthesis and immunopotentiating activity of novel isoxazoline functionalized coumarins.

A novel series (13) of isoxazoline functionalized coumarins was synthesized through 1,3-dipolar cyclization of nitrile oxides with Allylated coumarins. Synthesis of effective and target selective immunostimulators through conjugation of diversely substituted isoxazolines and 7-hydroxycoumarins is the focus of the present article. The proposed synthetic scheme was observed to be highly regiospecific yielding attempted conjugates in good yield (>90%). Kinetic resolution of the racemates was carried out by employing lipase B from Candida antarctica (CALB). The synthesized compounds were screened in vitro and in vivo for their biological activities viz. toxicity and impact on splenocyte proliferation (T- and B-cell proliferation), antibody production (HA titre), delayed-type hypersensitivity reaction (DTH), T-cell subtypes (CD4 and CD8), cytokine production (IL-2, IFN-γ, and IL-4) and NO (macrophage) production. Our results establish that isoxazoline functionalized coumarins exhibit excellent immune potentiating activity especially compounds 2, 4 and 8 whose activity is more than that of Levimasole as standard. The structure activity relations are explained in light of the structural/functional aspects of tested compounds. To the best of our knowledge the presented work is first of its kind and is presaged to prove very useful for the design and synthesis of bis-heterocycle based novel, therapeutically selective and effective immunopotentiators.

Novel Piperine Derivatives with Antidiabetic Effect as PPAR-γ Agonists.

Piperine is an alkaloid responsible for the pungency of black pepper. In this study, piperine isolated from Piper nigrum L. was hydrolyzed under basic condition to obtain piperic acid and was used as precursor to carry out the synthesis of twenty piperine derivatives containing benzothiazole moiety. All the benzothiazole derivatives were evaluated for their antidiabetic potential by OGT test followed by assessment of active derivatives on STZ-induced diabetic model. It was observed that nine of twenty novel piperine analogues (5b, 6a-h), showed significantly higher antidiabetic activity in comparison with rosiglitazone (standard). Furthermore, these active derivatives were evaluated for their action as PPAR-γ agonists demonstrating their mechanism of action. The effects on body weight, lipid peroxidation, and hepatotoxicity after administration with active derivatives were also studied to further establish these derivatives as lead molecules for treatment of diabetes with lesser side-effects.

Synthesis and tyrosinase inhibition activity of trans-stilbene derivatives.

Synthesis of a focussed library of trans-stilbene compounds through Wittig and other base catalysed condensation reactions is presented. The synthesized stilbenes were screened for their inhibitory potential against murine tyrosinase activity to explore the structure activity relationship (SAR). Presence of electron withdrawing group (-CN) at the double bond and hydroxyl group or halogen atom especially at para-position on the aromatic rings was found to significantly elevate the inhibitory activity. Among all the compounds screened, compounds 2, 6, 8, 10, 11, 15 and 21 were found to exhibit appreciable inhibitory activity. Compound 21 ((E)-2,3-bis(4-Hydroxyphenyl)acryonitrile) was found to be the most active with an IC50 value of 5.06 µM which is less than half of the value 10.78 µM observed for resveratrol (common standard used in murine tyrosinase activity studies) under similar conditions. The results obtained from the present study reveal structural/functional group sensitivity for the tyrosinase inhibitory activity of stilbenoid moieties and are expected to be very helpful for the design and synthesis of novel, selective and effective tyrosinase inhibitors.

Recent trends in electrospinning of polymer nanofibers and their applications in ultra thin layer chromatography.

Fabrication of polymer derived electrospun nanofibers by electrospinning as chromatographic sorbent bed for ultra-thin layer chromatography (UTLC) is a very demanding topic in analytical chemistry. This review presents an overview of recent development in the fabrication of polymer derived electrospun nanofibers and their applications to design UTLC plates as stationary phases for on-plate identification and separation of analytes from their mixture solutions. It has been reported that electrospun fiber based stationary phases in UTLC have enhanced separation efficiency to provide separation of analyte mixture in a shorter development time than those of traditional particle-based TLC stationary phases. In addition, electrospun UTLC is cost effective and can be modified for obtaining different surface selectivities by changing the polymer materials to electrospun devices. Electrospun UTLC plates are not available commercially till date and efforts are being rendered for their commercialization. The morphology and diameter of electrospun nanofibers are highly dependent on several parameters such as type of polymer, polymer molecular weight, solvent, viscosity, conductivity, surface tension, applied voltage, collector distance and flow rate of the polymer solution during electrospinning process. Among the aforementioned parameters, solution viscosity is an important parameter which is mainly influenced by polymer concentration. This review provides evidence for the fabrication of UTLC plates containing electrospun polymer nanofibers. Furthermore, the future prospects related to electrospinning and its application in obtaining of different types of electrospun nanofibers are discussed. The present communication is aimed to review the work which appeared during 2009-2014 on the application of polymer derived electrospun nanofibers in ultra thin layer chromatography.

Synthesis of Novel Oxazolo[4,5-b]pyridine-2-one based 1,2,3-triazoles as Glycogen Synthase Kinase-3ß Inhibitors with Anti-inflammatory Potential.

A novel series of oxazolo[4,5-b]pyridine-2-one based 1,2,3-triazoles has been synthesized by click chemistry approach and evaluated for in vitro GSK-3ß inhibitory activity. Compound 4g showed maximum inhibition with IC50 value of 0.19 µm. Keeping in view the effect of GSK-3ß inhibition on inflammation, compounds 4g, 4d, 4f, 4i, 4n and 4q exhibiting significant GSK-3ß inhibition were examined for in vivo anti-inflammatory activity in rat paw edema model. The compounds 4g, 4d, 4f and 4i showed pronounced in vivo anti-inflammatory activity (76.36, 74.54, 72.72 and 70.90%, respectively, after 5h post-carrageenan administration) and were further found to inhibit the pro-inflammatory mediators, viz. NO, TNF-α, IL-1ß, and IL-6 substantially in comparison with indomethacin, an anti-inflammatory drug as well as SB216763, a GSK-3ß inhibitor, reported to exert a similar effect. Histopathology studies confirmed the tolerance of gastric mucosa to these compounds.

Synthesis of Novel Pyrimidin-4-One Bearing Piperazine Ring-Based Amides as Glycogen Synthase Kinase-3ß Inhibitors with Antidepressant Activity.

Novel pyrimidin-4-one derivatives have been synthesized using EDC coupling and evaluated as glycogen synthase kinase-3ß (GSK-3ß) inhibitors. Among all the synthesized compounds, compound 5 (3-methyl-6-phenyl-2-(piperazin-1-yl)-3,4-dihydropyrimidin-4-one) exhibited the most potent inhibitory activity against GSK-3ß with IC50 value of 74 nm. The molecular docking studies were performed to elucidate the binding modes of the compounds with the target, and a crucial interaction involving hydrogen bond formation with Val-135 to the active site of GSK-3ß was observed. Furthermore, the synthesized compounds were subjected to in vivo evaluation of their antidepressant activity, and compound 5 showing highest inhibition of GSK-3ß was also found to significantly reduce the duration of immobility at 50 mg/kg, when compared with fluoxetine, a known antidepressant drug. The results of our study suggest that compound 5 may serve as a valuable template for the design and development of inhibitors of GSK-3ß with antidepressant activity.

Antidiabetic effect of novel benzenesulfonylureas as PPAR-γ agonists and their anticancer effect.

Twenty one pyrazoline containing benzenesulfonylureas were synthesized and docked against PPAR-γ target. All the compounds were first screened for their antidiabetic potential by oral glucose tolerance test and then six active compounds were assessed on STZ diabetic model. It was found that five compounds showed significantly high antidiabetic activity in comparison to glibenclamide as well as rosiglitazone (standard drugs). The active compounds were evaluated for their effect on body weight since weight management is one of the main concerns associated with sulfonylureas. Finally, the most active compound 6f was shown to elevate PPAR-γ gene expression. The synthesized compounds were also screened for anticancer activity by National Cancer Institute. Five compounds (5i, 6e, 6g, 6i and 6j) were selected at one dose level and showed potency against cancers.

Design, Synthesis, and Biological Evaluation of Thiazolidine-2,4-dione Conjugates as PPAR-γ Agonists.

A library of synthesized conjugates of phenoxy acetic acid and thiazolidinedione 5a-m showed potent peroxisome proliferator activated receptor-γ (PPAR-γ) transactivation as well as significant blood glucose lowering effect comparable to the standard drugs pioglitazone and rosiglitazone. Most of the compounds showed higher docking scores than the standard drug rosiglitazone in the molecular docking study. Compounds 5l and 5m exhibited PPAR-γ transactivation of 54.21 and 55.41%, respectively, in comparison to the standard drugs pioglitazone and rosiglitazone, which showed 65.94 and 82.21% activation, respectively. Compounds 5l and 5m significantly lowered the blood glucose level of STZ-induced diabetic rats. Compounds 5l and 5m lowered the AST, ALT, and ALP levels more than the standard drug pioglitazone. PPAR-γ gene expression was significantly increased by compound 5m (2.00-fold) in comparison to the standard drugs pioglitazone (1.5-fold) and rosiglitazone (1.0-fold). Compounds 5l and 5m did not cause any damage to the liver and could be considered as promising candidates for the development of new antidiabetic agents.

Synthesis, biological evaluation and molecular docking of some substituted pyrazolines and isoxazolines as potential antimicrobial agents.

A series of substituted pyrazolines (2a-e, 3a-h and 6a-c) and isoxazolines (4a-e) were synthesized and their structures were established on the basis of IR, (1)H NMR, (13)C NMR and mass spectra. All the synthesized compounds were tested against two bacterial and four fungal strains and found to exhibit moderate to potent antifungal activity. Compounds 2b, 4c, 4d and 6a-c exhibited significant activity against all tested fungal strains. MIC values of all the active compounds were comparable with standard drug fluconazole. The results of the in silico molecular docking study supported the antifungal activity of the synthesized compounds.

Ameliorative effects of Trichosanthes dioica Extract in suppressing inflammatory mediators and attenuating oxidative stress.

The present study aimed to investigate the anti-inflammatory activity of the ethanolic extract of the aerial parts of Trichosanthes dioica and its successive fractions. The effect on oxidative stress involved in the pathogenesis of inflammation was evaluated. The ethanolic extract and its successive fractions were administered at a dose of 150 and 300 mg/kg b. w. for testing their anti-inflammatory activity by a carrageenan-induced edema model. The results showed that the ethyl acetate fraction exhibited significant potency against inflammation. Pertaining to mechanistic insight, the anti-inflammatory effect might be attributed to the attenuation in tumor necrosis factor-α level (ELISA assay) and reduced expression of cyclooxygenase-2 and nuclear transcription factor-κB (immunohistochemistry). The alleviation in oxidative stress has been pertinent to the elevation in the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione) by active fractions. Furthermore, the ulcerogenic effect was insignificant even at a three times higher dose. Finally, it was concluded that the ethyl acetate fraction which showed significant biological potential against inflammation and oxidative stress could be viewed as a source of effective treatment.

1,3,4-Thiadiazoles: a potent multi targeted pharmacological scaffold.

Despite a significant work on thiadiazoles, continuous efforts are still being made to identify novel heterocyclic compounds with potent biological activities. This review may help the medicinal chemists to develop new leads possessing 1,3,4-thiadiazole nucleus with higher efficacy and reduced side effects. This review throws light on the detailed synthetic approaches which have been used for the synthesis of thiadiazoles. This has been followed by the in depth analysis of the thiadiazoles with respect to their medicinal significance.