Recent Advancement in Bio-precursor derived graphene quantum dots: Synthesis, Characterization and Toxicological Perspective.

Graphene quantum dots (GQDs), impressive materials with enormous future potential, are reviewed from their inception, including different precursors. Considering the increasing burden of industrial and ecological bio-waste, there is an urgency to develop techniques which will convert biowaste into active moieties of interest. Amongst the various materials explored, we selectively highlight the use of potential carbon containing bioprecursors (e.g. plant-based, amino acids, carbohydrates), and industrial waste and its conversion into GQDs with negligible use of chemicals. This review focuses on the effects of different processing parameters that affect the properties of GQDs, including the surface functionalization, paradigmatic characterization, toxicity and biocompatibility issues of bioprecursor derived GQDs. This review also examines current challenges and s the ongoing exploration of potential bioprecursors for ecofriendly GQD synthesis for future applications. This review sheds further light on the electronic and optical properties of GQDs along with the effects of doping on the same. This review may aid in future design approaches and applications of GQDs in the biomedical and materials design fields.

Graphene-based nanocomposites for sensitivity enhancement of surface plasmon resonance sensor for biological and chemical sensing: A review.

Surface plasmon resonance (SPR) offers exceptional advantages such as label-free, in-situ and real-time measurement ability that facilitates the study of molecular or chemical binding events. Besides, SPR lacks in the detection of various binding events, particularly involving low molecular weight molecules. This drawback ultimately resulted in the development of several sensitivity enhancement methodologies and their application in the various area. Among graphene materials, graphene-based nanocomposites stands out owing to its significant properties such as strong adsorption of molecules, signal amplification by optical, high carrier mobility, electronic bridging, ease of fabrication and therefore, have established as an important sensitivity enhancement substrate for SPR. Also, graphene-based nanocomposites could amplify the signal generated by plasmon material and increase the sensitivity of molecular detection up to femto to atto molar level. This review focuses on the current important developments made in the potential research avenue of SPR and fiber optics based SPR for chemical and biological sensing. Latest trends and challenges in engineering and applications of graphene-based nanocomposites enhanced sensors for detecting minute and low concentration biological and chemical analytes are reviewed comprehensively. This review may aid in futuristic designing approaches and application of grapheneous sensor platforms for sensitive plasmonic nano-sensors.

Preparation, Characterization and In Vivo Assessment of Repaglinide Nanosuspension for Oral Bioavailability Improvement.

AIMS AND BACKGROUND: The objective of the study was to improve the bioavailability of poorly soluble repaglinide (RPG) by preparing nanosuspension with poloxamer 188 using high pressure homogenization (HPH). The recent patents on nanocrystals (US20150337006A1) facilitated selection of drug and polymer. METHODS: Suspensions containing dissimilar sized particles were prepared by ultrasonication and HPH. The prepared aqueous suspensions were lyophilized and then characterized. Further, the dried aqueous suspensions were evaluated for drug content, solubility, in vitro dissolution, oral bioavailability study and stability study. RESULTS: RPG nanoparticles size, polydispersity index (PDI) and zeta potential were found to be 280.8 ± 15 nm, 0.279 ± 0.04 and - 25.81 ± 1.6mV, respectively. DSC and XRD results showed that RPG particles in aqueous suspensions were present in a crystalline state; however, RPG nanoparticles exhibited decreased lattice energy due to smaller particle size. Nanoparticles prepared by HPH exhibited significant improvements in solubility and dissolution rate. Oral bioavailability was found to be enhanced by 1.93 fold in comparison with that of plain RPG. The nanosuspension was found to be stable when stored at 5°C ± 3°C. CONCLUSION: The outcomes of the study revealed significant enhancement in dissolution rate and oral bioavailability of RPG due to size reduction to nano range by HPH.

ISATIN: New Hope Against Convulsion.

BACKGROUND: Epilepsy is one in every of the foremost important chronic neurological disorders with high incidence worldwide. Several epileptic patients don't seem to be fully treated with currently available marketed medicines likewise so many drugs have shown unfavorable side effect and drug interaction. Therefore, there are continuing interests to seek out new anticonvulsant drugs. METHODS: Literature search was carried out to indentify isatin containing derivatives as anticonvulsant drugs. RESULTS: Common synthetic schemes were studied to design and develop isatin derives anticonvulsant agents. Various structural features essential for the design of isatin compounds were reported. Anticonvulsant activity is evaluated by different tests were identified and their results can be considered for the design of novel isatin derivatives as anticonvulsants. CONCLUSION: In outline, isatin has been proved to be an excellent hybrid building the molecule with interesting biological activities. Among the prospect of derivatizing the N1, C2 and C3 positions, along with substitution on the aromatic ring, the synthetic modification for isatin is almost endless. Despite the fact that isatin derivatives are well-studied compounds, new derivatives are continually being discovered on the basis of known AEDs, isatin has been fused with other bioactive drug fragments and subsequently investigated as hybrid/dual action drugs and selectively targeted against convulsion.

Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies.

Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED50 = 23.5 mg/kg, MES, mice, i.p.; ED50 = 32.6 mg/kg, scPTZ, mice, i.p.; ED50 = 45.2 mg/kg, 6-Hz, mice, i.p.; TD50 = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED50 = 26.1 mg/kg, MES, mice, i.p.; ED50 = 79.4 mg/kg, scPTZ, mice, i.p.; TD50 = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters.

Exploring Anti-inflammatory Potential of Thiazolidinone Derivatives of Benzenesulfonamide via Synthesis, Molecular Docking and Biological Evaluation.

BACKGROUND: The present study reports the synthesis and biological evaluation of thiazolidinone derivatives bearing benzenesulfonamide investigated for cyclooxygenase-2 (COX-2) inhibitory activity and in vivo anti-inflammatory activity. METHODS: The synthesis of 4-(4-oxo-2-substituted-1,3-thiazolidin-3-yl) benzenesulfonamide derivatives were carried out by conventional synthesis, involves the one-pot condensation reaction of sulfanilamide. The synthesized compounds were evaluated against COX-1 and human recombinant COX-2 by using colorimetric enzyme assay kit and in-vivo study was carried out by carageenan induced rat paw edema method. RESULTS: Five derivatives 3a, 3b, 3f, 3g, and 3j showed pronounced COX-2 percentage inhibition (55.76, 61.75, 46.54, 43.32, and 49.77% respectively). Structure activity relationship suggested that the compound with a 4-hydroxy group on phenyl ring leads to more selective inhibition of COX-2 than celecoxib, which is supported by molecular docking study. In silico ADME properties showed that compound 3a, 3b, 3f, 3g, and 3j complies Lipinski's rule of five and show no violation. Molecular docking study divulged the binding interactions of thiazolidinone derivatives into the active site of COX-2 and thereby helps to design the potent inhibitors. CONCLUSION: The overall studies inferred that compound 3b rendered it as a good leadcandidate for the further development of more potent anti-inflammatory agent.

Nanostructured lipid carriers as a potential vehicle for Carvedilol delivery: Application of factorial design approach.

Present invention relates to design of nanostructured lipid carriers (NLC) to augment oral bioavailability of Carvedilol (CAR). In this attempt, formulations of CAR-NLCs were prepared with glyceryl-monostearate (GMS) as a lipid, poloxamer 188 as a surfactant and tween 80 as a co-surfactant using high pressure homogenizer by 2(3) factorial design approach. Formed CAR-NLCs were assessed for various performance parameters. Accelerated stability studies demonstrated negligible change in particle size and entrapment efficiency, after storage at specified time up to 3 months. The promising findings in this investigation suggest the practicability of these systems for enhancement of bioavailability of drugs like CAR.

In silico exploration of c-KIT inhibitors by pharmaco-informatics methodology: pharmacophore modeling, 3D QSAR, docking studies, and virtual screening.

c-KIT is a component of the platelet-derived growth factor receptor family, classified as type-III receptor tyrosine kinase. c-KIT has been reported to be involved in, small cell lung cancer, other malignant human cancers, and inflammatory and autoimmune diseases associated with mast cells. Available c-KIT inhibitors suffer from tribulations of growing resistance or cardiac toxicity. A combined in silico pharmacophore and structure-based virtual screening was performed to identify novel potential c-KIT inhibitors. In the present study, five molecules from the ZINC database were retrieved as new potential c-KIT inhibitors, using Schrödinger's Maestro 9.0 molecular modeling suite. An atom-featured 3D QSAR model was built using previously reported c-KIT inhibitors containing the indolin-2-one scaffold. The developed 3D QSAR model ADHRR.24 was found to be significant (R2 = 0.9378, Q2 = 0.7832) and instituted to be sufficiently robust with good predictive accuracy, as confirmed through external validation approaches, Y-randomization and GH approach [GH score 0.84 and Enrichment factor (E) 4.964]. The present QSAR model was further validated for the OECD principle 3, in that the applicability domain was calculated using a "standardization approach." Molecular docking of the QSAR dataset molecules and final ZINC hits were performed on the c-KIT receptor (PDB ID: 3G0E). Docking interactions were in agreement with the developed 3D QSAR model. Model ADHRR.24 was explored for ligand-based virtual screening followed by in silico ADME prediction studies. Five molecules from the ZINC database were obtained as potential c-KIT inhibitors with high in -silico predicted activity and strong key binding interactions with the c-KIT receptor.

Synthesis, biological evaluation and docking study of maleimide derivatives bearing benzenesulfonamide as selective COX-2 inhibitors and anti-inflammatory agents.

A series of maleimide analogs bearing benzenesulfonamide were synthesized (4a-r). The anti-inflammatory activity of synthesized derivatives was evaluated using carrageenan induced rat paw edema model. COX-1 and COX-2 potency was evaluated through in vitro cyclooxygenase assays. The results revealed that, compounds 4a, 4h, 4 j, 4 k and 4r had potent COX-2 percentage inhibition as well as in vivo anti-inflammatory activity. The potent compound 4 j was docked into the COX-2 active site to determine the probable binding model. The results of in vivo and in vitro studies demonstrate that phenyl ring with electron withdrawing groups on maleimide ring would generate more potent anti-inflammatory agents. Thus, these compounds can serve as potential leads for further anti-inflammatory studies.

Recent advancement in discovery and development of natural product combretastatin-inspired anticancer agents.

The natural stilbenoids combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent antitubulin agents demonstrating antimitotic activity as well as tumor vascular disruption property. Due to structural simplicity and potent cytotoxicity of CA4 and CA1, they are considered as promising leads for the development of potent anticancer agents. In fact, scientific fraternity is motivated to synthesize several derivatives of CA4 and CA1 as novel therapeutic agents. In the literature, several studies have been carried out to evaluate the medicinal chemistry, pharmacology and structure-activity relationships (SAR) of a variety of modified combretastatin derivatives. The present report aimed at comprehensively revising the recent advancements (2006-2014) in the medicinal chemistry and SAR of diversified combretastatin analogues. The published data concerning new combretastatin A-4 analogues as antimitotic anticancer agents are presented and SAR is reviewed and discussed.

Synthesis, Biological Activity, and Docking Study of Novel Isatin Coupled Thiazolidin-4-one Derivatives as Anticonvulsants.

A series of 2-(substituted-phenyl)-3-(2-oxoindolin-3-ylidene)amino)-thiazolidin-4-one derivatives were designed and synthesized under microwave irradiation, using an eco-friendly, efficient, microwave-assisted synthetic protocol that involves cyclocondensation of 3-substituted benzylidine-hydrazono-indolin-2-one 3a-j with thioglycolic acid in dimethyl formamide (DMF) as solvent and anhydrous zinc chloride as a catalyst, keeping in view the structural requirement of the pharmacophore. The intermediate compounds 3a-j were obtained by condensation of the hydrazone of indoline-2,3-dione with aromatic aldehydes. The synthesized derivatives were evaluated for CNS depressant activity and anticonvulsant activity in mice using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) induced seizure tests. All the derivatives showed good CNS depressant activity and showed protection in the MES test, indicative of their ability to inhibit the seizure spread. A histopathological study was performed to evaluate liver toxicity caused by the synthesized compounds. The compounds were nontoxic. A computational study was performed, in which log P values were calculated experimentally. Virtual screening was performed by molecular docking of the designed compounds into the ATP binding sites of the NMDA and AMPA receptors, to predict if these compounds have analogous binding modes.

Synthesis and in vitro Evaluation of Polymeric Prodrug of Ibuprofen with Amino Acid Spacer.

The present work is an agreement with simple and efficient method of improving the therapeutic efficacy of ibuprofen by masking its acidic moiety. It aims to reduce gastrointestinal side effects by controlling the rate, duration and site of release. This is achieved by synthesis and evaluation of polymeric prodrug of ibuprofen with natural polymer sodium alginate. The synthesis was supported by N-protected serine as spacer due to chemical incompatibility of drug and polymer. Synthesized prodrug was characterized for confirmation of said structures. The in-vitro dissolution profile of ibuprofen-alginate prodrug showed that the release of the drug is significantly higher in case of pH 7.2 buffer as compared to ibuprofen, which might be due to ester group adjacent to drug get hydrolyzed. The hydrolysis was found to be with faster rate in alkaline media than that of in acidic media.

Animal models for Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disease with major impacts on patients' lives and on society as a whole. It is one of the most common neurodegenerative diseases in the world, second only to Alzheimer's disease. Low levels of production of dopamine (DA) are associated with PD. This is caused by a progressive loss of neurons in the midbrain's substantia nigra, resulting in changes in neural conduction within the nigrostriatum. Research into PD has been going on since 1960, still there is no cure although the symptoms can be effectively controlled and the severity of the affliction can be reduced. The main obstacle in the development of neuroprotective therapy is a limited understanding of the key molecular events that provoke neurodegeneration. A misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are the critical factors in the pathogenesis of PD. Neurotoxic models (particularly 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine) have been very useful in elucidating the molecular cascade of cell death in dopaminergic neurons. They are also of use in efforts to limit the progression of the disease and to prevent the long-term functional and pathological outcome in PD. The establishment of animal and cellular models of mutations in LRRK2 and α-synuclein, and mutations in parkin, DJ-1 and PINK1, has been of use in elucidating the molecular mechanisms of this disorder, and research using these models is providing new ideas about the pathogenesis of PD. Several researchers are synthesizing and screening novel derivatives for their antiparkinsonian potential using different animal models. In this work we describe different animal models used in assessing the antiparkinson activity of novel therapeutic treatments.

Quinazolines: new horizons in anticonvulsant therapy.

The search for novel anticonvulsants with more selectivity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. The potency and selectivity in the pharmacological response of quinazolines as anticonvulsant have attracted the attention of many researchers to explore this framework for its potential. It is, therefore, topic of interest to study development of new synthetic strategies and their anticonvulsant potential based on the most recent knowledge emerging from the latest research. This review reports current progress in the area of new biologically active quinazoline scaffold as potent anticonvulsant. It is a sincere attempt to compile the synthetic and design aspects of quinazoline derivatives with significant anticonvulsant action. This structural class of compound can prove to be useful for the design and development of potent anticonvulsant agents.

Graphene oxide based magnetic nanocomposites for efficient treatment of breast cancer.

The present work reports a simple one step synthesis of nanoscale graphene oxide magnetic composites (GO-IO) using ferrofluid (GO-IOF). The obtained GO-IO were compared with GO-IO obtained from in situ (GO-IOI) methods. Anastrozole (ANS) was loaded on the GO-IOI and GO-IOF via simple stirring method to form GO-IOA and GO-IOFA respectively. These GO-IO prepared by two techniques were characterized using spectroscopic techniques and vibrating sample magnetometer (VSM) analysis. Particle size and potential were measured using Malvern Zetasizer. Scanning electron microscopy (SEM) was used for studying the surface morphology of GO-IO, and in addition to this elemental analysis was also performed for confirming the presence of iron. The cell viability assay was carried out using the MCF-7 cell line. It revealed that GO-IOFA had reasonably high cytotoxicity (49.7%) compared to GO (13.1%), ANS (16.6), GO-IOI (13%), GO-IOF (13.6) and GO-IOIA (18.34%). Both, GO-IOIA and GO-IOFA showed improved cytotoxicity when compared with pure ANS. GO-IOF were found to exhibit superior magnetic activity due to higher iron content along with smaller particle size and higher loading efficiency compared to GO-IOI. The overall effect suggests that GO-IO can be utilized as efficient carriers for the loading of chemotherapeutic agents.

A comprehensive review on synthesis and designing aspects of coumarin derivatives as monoamine oxidase inhibitors for depression and Alzheimer's disease.

Monoamine oxidase (MAO) enzyme inhibition is a crucial target for the management of depression and Alzheimer disease and inhibitors of MAO are the most important drugs for their management. Coumarins are a large family of compounds, of natural and synthetic origin, that exhibit a variety of pharmacological activities, including MAO inhibition. The current review highlights the design and synthetic methods of coumarin derivatives as well as coumarins obtained from plant source as MAO inhibitors for treatment of depression and Alzheimer disease with salient finding related to structure-activity relationship. The aim of present review is to find out natural as well as synthetic coumarins as MAO inhibitors.

Stimuli-sensitive layer-by-layer (LbL) self-assembly systems: targeting and biosensory applications.

Stimuli-sensitive layer-by-layer (LbL) self-assembly systems have generated much interest among researchers worldwide due to the simplicity of the process by which they are produced and their numerous applications in drug delivery. LbL self-assembly systems involve simple alternative adsorption of oppositely charged polyelectrolytes on core materials and are thus considered to be promising tools for drug delivery and biosensing. Here, we discuss the latest findings from research into LbL systems, with special emphasis on drug delivery systems. This review highlights various stimuli-responsive LbL systems and their targeting and biosensory applications. For the convenience of readers, these stimuli-responsive LbL systems are classified as exogenous stimuli-responsive LbL systems and endogenous stimuli-responsive LbL systems.

Design and statistical optimization of osmotically driven capsule based on push-pull technology.

In present investigation attempt was made to develop and statistically optimize osmotically active capsule tailor made from the concept of bilayer (push-pull) osmotic tablet technology. The capsule was comprised of active (drug) and push (osmogen) layer. Active layer was compressed in form of tablet by mixing known amount of drug and formulation excipients. Similarly push layer was made by compressing Mannitol with formulation excipients. Finally, both layers were packed in hard gelatin capsule having small aperture at top and coated with semipermeable membrane to form osmotically active capsule. Formulated and optimized capsules were characterized for Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetric (DSC), scanning electron microscopy, In-vitro drug release study and Release models and kinetics. Statistically optimized formulation showed good correlation between predicted and experimented results, which further confirms the practicability and validity of the model.

Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol.

The present works deals with simple and efficient method of improving therapeutic efficacy of racemic ibuprofen by retarding gastrointestinal side effects through masking of carboxylic group chemically. This is achieved by synthesis and evaluation of ester derivatives of ibuprofen as mutual prodrugs with naturally occurring phenolic and alcoholic compounds. Promoieties like menthol; thymol and eugenol were selected with the aim of getting synergistic effect as these are natural analgesic having traditional medicinal values. Prodrugs are found to be highly lipophilic as compared to parent drug. All the prodrugs are found to be highly stable at acidic pH while undergoes hydrolysis at neutral and alkaline pH as indicated by their t(1/2) values. Synthesized prodrugs derivatives show increased anti-inflammatory activity that might be attributed to synergistic effect as ibuprofen conjugates to natural analgesics. Ulcer index shows much reduction in gastric ulceration compared to ibuprofen concluding the successful masking of acidic group.

Simultaneous determination of diclofenac potassium and drotaverine hydrochloride in human plasma using reversed-phase high-performance liquid chromatography.

A simple high-performance liquid chromatographic method with ultraviolet detection is proposed for the estimation of diclofenac potassium and drotaverine hydrochloride in human plasma. Liquid-liquid extraction was carried out with a mixture of dichloromethane-isopropyl alcohol (80:20, v/v). Chromatographic separation of the analytes and internal standard was achieved on an analytical 250 × 4.6 mm i.d. reversed-phase Thermo BDS Hypersil C8 (5 µm particle size) column using a mobile phase of acetonitrile-0.02M ammonium acetate buffer (53:47, v/v) at pH 3.5. The run time was less than 15 min. Column eluate was monitored at 230 nm. The linearity over the concentration ranges of 25-1500 ng/mL and 32-960 ng/mL was obtained for diclofenac potassium and drotaverine hydrochloride, respectively. The limit of quantification was 25 and 32 ng/mL for diclofenac potassium and drotaverine hydrochloride, respectively. Recoveries of diclofenac potassium and drotaverine hydrochloride from plasma were 97.45% and 98.27%, respectively.