Search

A combination of Ofloxacin, Tinidazole, Terbinafine hydrochloride, and Clobetasol propionate is used for treatment, control, prevention, and improvement of bacterial and fungal skin infections. Two...

Background: Human GPR40 receptor, also known as free fatty-acid receptor 1, is a Gprotein- coupled receptor that binds long chain free fatty acids to enhance glucose-dependent insulin secretion. In order to improve the resistance and efficacy, computational tools were applied to a series of 3-aryl-3-ethoxypropanoic acid derivatives. A relationship between the structure and biological activity of these compounds, was derived using a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using CoMFA, CoMSIA and two-dimensional QSAR study using HQSAR methods. Methods: Building the 3D-QSAR models, CoMFA, CoMSIA and HQSAR were performed using Sybyl-X software. The ratio of training to test set was kept 70:30. For the generation of 3D-QSAR model three different alignments were used namely, distill, pharmacophore and docking based alignments. Molecular docking studies were carried out on designed molecules using the same software. Results: Among all the three methods used, Distill alignment was found to be reliable and predictive with good statistical results. The results obtained from CoMFA analysis q2, r2cv and r2 pred were 0.693, 0.69 and 0.992 respectively and in CoMSIA analysis q2, r2cv and r2pred were 0.668, 0.648 and 0.990. Contour maps of CoMFA (lipophilic and electrostatic), CoMSIA (lipophilic, electrostatic, hydrophobic, and donor) and HQSAR (positive & negative contribution) provided significant insights i.e. favoured and disfavoured regions or positive & negative contributing fragments with R1 and R2 substitutions, which gave hints for the modifications required to design new molecules with improved biological activity. Conclusion: 3D-QSAR techniques were applied for the first time on the series 3-aryl-3- ethoxypropanoic acids. All the models (CoMFA, CoMSIA and HQSAR) were found to be satisfactory according to the statistical parameters. Therefore such a methodology, whereby maximum structural information (from ligand and biological target) is explored, gives maximum insights into the plausible protein-ligand interactions and is more likely to provide potential lead candidates has been exemplified from this study.

The temperature and magnetic field dependent oscillatory magneto-resistance of a compressively strained La0.3Pr0.4Ca0.3MnO3 thin film was measured for various post annealing conditions (i.e., Argon/Air) in order to study the effects of hole concentration on the magnitude of the negative AMR below the crossover temperature T*. It was found that Ar and Air annealing have adverse effects on the negative AMR below T*. Interestingly, annealing driven hole doping and A-site Pr doping show similar effects on the negative AMR of these films. The mechanism responsible for these changes is discussed.

Lutein (LUT), is one of the most important carotenoids having prominent antioxidant activity. However, its use is limited due to poor solubility and instability under adverse conditions. LUT was microencapsulated with soluble polymers using spray drying to improve its solubility and bioavailability. Maltodextrin (polysaccharide base) and copovidone (polyvinyl pyrrolidone vinyl acetate based copolymer) were evaluated as hydrophilic carriers for encapsulation of LUT. Design of Experiments (DOE) was utilized and microencapsulation process was optimized using full factorial design. Copovidone proved to be better carrier compared to maltodextrin and showed enhanced dissolution and antioxidant characteristics of LUT. Microencapsulated LUT powder was characterized by dissolution study, DSC, XRD and SEM. This study can be used as a guideline for optimization of microencapsulation of similar bio-actives with hydrophilic carriers to improve solubility and subsequent bioavailability.

Circulating levels of TNF-αand the adhesion molecules L-Selectin and VCAM-1 as well as their expression in the primary tumors of patients with benign thyroid diseases and papillary thyroid carcinoma (PTC) have been determined in this study. The serum levels of TNF-α, L-Selectin, and VCAM-1 were significantly higher in patients with both benign thyroid diseases and PTC as compared to the healthy individuals. However, the levels of only TNF-αand L-Selectin, and not VCAM-1, were significantly higher in patients with PTC in comparison to those observed in patients with benign thyroid diseases. Further the expression of TNF-αand L-Selectin was also significantly higher in the primary tumors of PTC patients, relative to the benign thyroid diseases. The expression of L-Selectin and VCAM-1 significantly correlated with aggressive tumor behavior. In PTC patients, the circulating TNF-αlevels significantly positively correlated with the levels of L-Selectin, while TNF-αimmunoreactivity was significantly associated with VCAM-1 expression. Serum TNF-αwas found to be a significant prognosticator for OS in PTC patients. Overall the results signify that the interaction between TNF-αand the adhesion molecules may have a role in thyroid carcinogenesis and understanding this complexity may offer potential therapeutic targets for better management of thyroid cancer.

Background: Dipeptidyl Peptidase 4 (DPP 4) enzyme cleaves an incretin-based glucoregulatory hormone Glucagon Like Peptide -1 from N-terminal where penultimate amino acid is either alanine or proline. Several DPP 4 inhibitors, “gliptins”, are approved for the management of Type 2 Diabetes or are under clinical trial. In the present study, combined pharmacophore and docking-based virtual screening protocol were used for the identification of new hits from the Specs Database, which would inhibit DPP 4. Methods: The entire computational studies were performed using the Discovery Studio v. 4.1 software package, Pipeline Pilot v. 9.2 (Accelrys Inc.) and FRED v. 2.2.5 (OpenEye Scientific Software). Common feature pharmacophore model was generated from known DPP 4 inhibitors and validated by Receiver Operating curve analysis and GH-scoring method. Database search of Specs commercial database was performed using validated pharmacophore. Hits obtained from pharmacophore search were further docked into the binding site of DPP 4. Based on the analysis of docked poses of hits, 10 compounds were selected for in- vitro DPP 4 enzyme inhibition assay. Results: Based on docking studies, virtual hits were predicted to form interaction with essential amino acid residues of DPP 4 and have an almost similar binding orientation as that of the reference molecule. Three compounds having Specs database ID- AN-465/42837213, AP-064/42049348 and AN- 465/43369427 were found to inhibit DPP 4 enzyme moderately. Conclusion: The present study demonstrates a successful utilization of in-silico tools in the identification of new DPP 4 inhibitor, which can serve as a starting point for the development of novel DPP 4 inhibitors.

Lutein (LUT) is one of the most important carotenoid and; the most prominent being its antioxidant activity. However, its use is limited due to poor solubility and instability under adverse conditions. An attempt is made to increase the solubility and hence bioavailability of LUT using various cyclodextrins viz., betacyclodextrin (βCD), hydroxypropyl betacyclodextrin (HP-βCD) and methyl betacyclodextrin (M-βCD). Physical mixtures and spray dried inclusion complexes were prepared and characterized using spectroscopic techniques, DSC and XRD studies. From the phase solubility and dissolution studies it was found that, M-βCD significantly improved the solubility of LUT. These complexes were further subjected to in vitro anti-proliferative activity in order to validate results obtained from solubility studies. The biological results were in congruence with the results of solubility studies. Spray dried complex of LUT:M-βCD showed significant percent growth inhibition as compared to other two complexes and LUT alone. Molecular modeling studies established the host–guest stoichiometry with the lowest energy to be 2:1, with the two hexatomic rings of a LUT molecule occupying the two M-βCD cavities. The present study forms the basis for the development of oral formulations of LUT with significantly improved solubility and bioavailability.

Astaxanthin (AXT) is a carotenoid which gained a lot of importance as a nutritional ingredient in Nutraceuticals and as a food additive. However this bioactive failed to gather absolute significance due to poor aqueous solubility. This study explores the improved dissolution rate of AXT by its complexation with methyl betacyclodextrin (M-βCD) using spray drying technique which is very much scalable and accepted in industry. The experimental methodology undertaken proved that at 1.0 molar concentration of M-βCD, the solubility of AXT was 0.012 mM, representing a 54-fold enhancement over baseline solubility (

Glycogen synthase kinase-3? (GSK-3?) is an important class of therapeutic drug target currently receiving wide attention. In our computational approach, shape-based similarity search was used to screen the SPECS database, based on the shape of Tideglusib molecule; a known GSK-3? inhibitor. The resulting virtual hits were applied for docking studies on the known binding pockets of GSK-3?. A novel compound [7,10-dioxo-4,5-dihydro-7H,10H-pyrano[3,2,1-ij]quinolin-8-yl acetate] proposed from docking results in the substrate site of GSK-3? was found to have inhibitory activity (IC50) above 100?M concentration in ADP-GloTM Kinase assay. This communication aims to put forward in identifying newer hit on GSK-3? target via virtual screening approach.

Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase, which is associated with the pathophysiology of several diseases such as diabetes, cancer, psychiatric and neurodegenerative diseases. Tideglusib is a potent, selective, and irreversible GSK-3 inhibitor that has been investigated in phase II clinical trials for the treatment of progressive supranuclear palsy and Alzheimer's disease. In the present study, we performed pharmacophore feature-based virtual screening for identifying potent targetspecific GSK-3 inhibitors. We found 64 compounds that show better GSK-3 binding potentials compared with those of Tideglusib. We further validated the obtained binding potentials by performing 20-ns molecular dynamics simulations for GSK-3 complexed with Tideglusib and with the best compound found via virtual screening in this study. Several interesting molecular-level interactions were identified, including a covalent interaction with Cys199 residue at the entrance of the GSK-3 active site. These findings are expected to play a crucial role in the binding of target-specific GSK-3 inhibitors.

Background: Gentamicin is a commonly used antibiotic for the treatment of Gram-negative infections, but nephrotoxicity limits its use. Cyperus scariosus Linn. (CS) has been found to have antioxidant properties in vitro. Objectives: The aim of this study was to evaluate the nephroprotective effects of CS in gentamicin-induced acute kidney injury (AKI). Methods: The animals were divided into nine groups. AKI was produced with a 100 mg/kg intraperitoneal (i.p.) injection of gentamicin for 7 days. Next, α-lipoic acid 100 mg/kg i.p. served as the active control, while the test drug (CS) was given in two doses (150 mg/kg and 250 mg/kg orally) for 10 days. Distilled water, 1 ml/day orally for 7 days, served as the vehicle control. The protective and curative effects, respectively, were assessed by the administration of CS before and after the induction of AKI. The effects of CS on AKI were assessed by serological and histopathological parameters. Results: Serum creatinine was significantly increased (P < 0.05) while 24 hours urine output, urine creatinine, and serum protein were significantly decreased (P < 0.05) in rats treated with gentamicin as compared to the control group. As the active control, α-lipoic acid showed nephroprotective effects on the urinary, serological, and histopathological parameters. C. scariosus Linn., as a preventive and curative therapy, restored urine output and altered the serological parameters non-significantly compared to the disease-control group. It also preserved the normal kidney architecture, as evidenced by histopathological parameters. Conclusions: In our study, hydroalcoholic extract of Cyperus scariosus Linn. offered nephroprotection in the form of AKI prevention and for the treatment of established AKI.

Background Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF-7 and MDA-MB-231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results We found that the resistant cell lines showed 7–100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2071-1) contains supplementary material, which is available to authorized users.

Impurity profiling includes a description of the identified and unidentified impurities present in new drug substances or drug products. Isolation and elucidation of the structures of degradation products are typically collaborative research involving knowledge of analytical, organic and physical chemistry with spectroscopic information. Stability testing guidelines issued by International Conference on Harmonization (ICH) require the reporting, identification and characterization of degradation products (DPs). The alkaline degradant was detected by high performance liquid chromatography (HPLC) at relative retention time (RRT) of 1.48 with respect to Ezetimibe. This degradant was isolated by preparative HPLC. Purity of the isolated solid was found to be more than 99%. Structure of alkaline degradant was confirmed by LC-MS, 1 H and 13 C NMR and IR spectroscopy. On the basis of spectral data, the structure of the degradant was confirmed as 5-(4-fluorophenyl)-2-((4-fluorophenyl amino)-(4-hydroxyphenyl)methyl)-pent-4-enoic acid. An understanding of the parts of the molecule that are susceptible to degradation can help in the design of more stable analogs. Determining the structures of the major degradation products can reveal whether or not a known carcinogen or toxic compound is or might possibly be formed.

This work presents the isolation and characterization of the alkaline degradant of Ezetimibe. Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, was subjected to alkaline degradation. Ezetimibe was reacted with 0.1M methanolic sodium hydroxide solution for 10min at 80°C to yield alkaline degradant to an extent of 90% of initial amount of the drug taken. This degradant was detected by high performance liquid chromatography (HPLC) at relative retention time (RRT) of 1.48 with respect to Ezetimibe. HPLC method involved an isocratic elution on a Waters Symmetry C(8) 150mm×4.6mm, 5μm column using ammonium acetate buffer (pH 4.5, 50mM) - acetonitrile (50:50, v/v) as the mobile phase at a flow rate of 1.0mL/min and UV detection at 242nm. The degradant was isolated by preparative HPLC. Purity of the isolated solid was found to be more than 99%. Structure of alkaline degradant was confirmed by LC-MS, (1)H and (13)C NMR and IR spectroscopy. On the basis of spectral data, the structure of the degradant was confirmed as 5-(4-fluorophenyl)-2-[(4-fluorophenyl amino)-(4-hydroxyphenyl)methyl]-pent-4-enoic acid. The route for the formation of this degradant is also proposed. Determining the structures of degradation products arouse during stress testing can be useful for preclinical discovery efforts.

Astaxanthin (3, 3′-dihydroxy-β, β-carotene-4, 4′-dione; AST) belongs to class of xanthophylls and is very effective antioxidant. It has very poor aqueous solubility resulting in lower bioavailability which presents major concerns in product development for oral use. AST was microencapsulated with soluble polymers using spray drying to improve its solubility and bioavailability. Quality by Design (QbD), a widely used approach for prediction of quality for desired specifications and effects was applied Design of Experiments (DOE), a useful component of QbD was utilized to understand the effect of variables and their interactions. Different formulation variables like ratio of hydrophilic carriers, concentration of solubilizers and homogenizer speed were challenged in the experimental design during the process of microencapsulation. The optimized formulation showed consistent release rate and characterization was done by DSC, XRD and SEM study. Percent cell growth inhibition was increased in optimized formulation as compared to plain AST. This QbD study can form a basis for further development of poorly water soluble AST formulation by oral route with improved bioavailability on larger scale.

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.

Imidazole heterocycles containing oxygen or sulfur heteroatoms are of considerable pharmaceutical interest. Many synthetic strategies for imidazolidine-2-thione and imidazole-2-thione derivatives were developed in the past years. They have been well documented by a steadily increasing number of publications and patents. Substituted imidazolidine-2-thiones and imidazole-2-thiones display remarkable biological activities. For instance, imidazole-2-thione has been reported to exhibit antimicrobial, antifungal, antithyroid, antioxidant, cardiotonic, antihypertensive, Dopamine beta-Hydroxylase (DBH) inhibitory and anti-HIV properties. Imidazolidine-2-thione derivatives have been reported to exhibit antimicrobial activity, anti-HIV activity, antifungal activity and so forth. The main purpose of this review is to present a survey of the literature on the different methods of synthesis and reactions involving imidazolidine-2-thione and imidazole-2-thione during the last few decades. This article summarizes an efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 3,5-disubstituted-thiohydantoin, also reported previously. Synthesis of metal complexes of imidazolidine-2-thione and its derivatives were reported as antimicrobial agents also discussed in the article. Some of the chiral imidazolidine-2-thione N-and C-nucleoside were reported as precursors for the synthesis of azidonucleosides and fluoronucleosides known for their anti-AIDS activity. Metal complexes of heterocyclic thione ligands were reported to possess antifungal activity. Imidazolidine-2-thione and imidazole-2-thione derivatives have found applications in diverse therapeutic areas. Imidazolidine-2-thiones are also used as a chiral auxiliary and ligand for asymmetric catalysis.

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.

Imidazole heterocycles containing oxygen or sulfur heteroatoms are of considerable pharmaceutical interest. Many synthetic strategies for imidazolidine-2-thione and imidazole-2-thione derivatives were developed in the past years. They have been well documented by a steadily increasing number of publications and patents. Substituted imidazolidine-2-thiones and imidazole-2-thiones display remarkable biological activities. For instance, imidazole-2-thione has been reported to exhibit antimicrobial, antifungal, antithyroid, antioxidant, cardiotonic, antihypertensive, Dopamine beta-Hydroxylase (DBH) inhibitory and anti-HIV properties. Imidazolidine-2-thione derivatives have been reported to exhibit antimicrobial activity, anti-HIV activity, antifungal activity and so forth. The main purpose of this review is to present a survey of the literature on the different methods of synthesis and reactions involving imidazolidine-2-thione and imidazole-2-thione during the last few decades. This article summarizes an efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 3,5-disubstituted-thiohydantoin, also reported previously. Synthesis of metal complexes of imidazolidine-2-thione and its derivatives were reported as antimicrobial agents also discussed in the article. Some of the chiral imidazolidine-2-thione N-and C-nucleoside were reported as precursors for the synthesis of azidonucleosides and fluoronucleosides known for their anti-AIDS activity. Metal complexes of heterocyclic thione ligands were reported to possess antifungal activity. Imidazolidine-2-thione and imidazole-2-thione derivatives have found applications in diverse therapeutic areas. Imidazolidine-2-thiones are also used as a chiral auxiliary and ligand for asymmetric catalysis.

Pharmaceutical companies have made major investments in high- throughput technologies for genomic and proteomic research, combinatorial chemistry and biological screening in order to identify more potential drug candidates at a faster pace. However, synthesis and lead compound optimisation remain the bottlenecks in the drug discovery process. Developing chemical compounds with the desired biological properties is time-consuming and expensive. Consequently, increasing interest is being directed towards technologies that allow more rapid synthesis and screening of chemical substances to identify compounds with functional qualities. Microwave heating is a process within a family of electroheat techniques, such as induction, radio frequency, direct resistance or infra-red heating, all of which utilise specific parts of the electromagnetic spectrum. These processes supplement, and in specific cases totally replace, conventional heating or drying systems used in industry. There is hardly any reaction type or name reaction that has not yet been tested in the microwave field. This is because some conventional systems are very bulky, not easy to operate, can pollute the environment due to harmful omissions and above all can be very inefficient. The major advantages of using microwaves are rapid heat transfer, volumetric and selective heating, compactness of equipment, speed of switching on and off and pollution-free environment as there are no products of combustion. Microwave leakage can certainly be kept well below government recommended levels. It has long been established that a dielectric material can be processed with energy in the form of high-frequency electromagnetic waves. The present review article describes the mechanism of microwave heating and comparison of the conventional and microwave assisted organic synthesis to improve the synthesis of the organic molecules.

1H NMR spectroscopy at 360 MHz has been used to study the interactions between the calmodulin function inhibitor calmidazolium (R24571) and (i) calmodulin (CaM) and (ii) skeletal muscle troponin C (sTnC). One equivalent of racemic calmidazolium binds tightly to CaM and perturbs a number of protein signals, corresponding to residues in both dicalcium-binding domains, in a manner characteristic of slow exchange. Calmidazolium binds with lower affinity to sTnC but still induces widespread perturbations in both domains. Extensive spectral overlap precludes definite assignment of intermolecular nuclear Overhauser effect (NOEs) although intraprotein NOEs do indicate the nature of some drug-induced conformational changes. Relaxation enhancements induced by two spin-labeled calmidazolium analogues demonstrate that several methionine residues of CaM, significantly immobilized by calmidazolium binding, are in fact located at or near its binding sites. These and other residue-specific broadening effects have enabled low resolution models to be constructed of the predominantly hydrophobic drug-binding sites on each domain of CaM. The hydrophobic portions of calmidazolium itself, and its analogues, contact side chains of Ala-15, Leu-18, Phe-19, Val-35, Met-36, Leu-37, Leu-39, Met-51, Met-71, Met-72, and Met-76 in the N-terminal domain of calmodulin, and Ala-88, Val-91, Phe-92, Val-108, Met-109, Leu-112, Phe-141, and Met-145 in its C-terminal domain. The model, and an analogous one of sTnC, can be used to rationalize drug-induced changes in intraprotein NOEs. Issues pertaining to the possible simultaneous binding of calmidazolium to both globular domains of the proteins are discussed in terms of the experimental results and the overall structures of each protein.

The entire proton NMR spectrum of the aminoglycoside antibiotic neomycin B has been assigned at physiological pH by a combination of two-dimensional J-resolved and J-correlated and nuclear Overhauser enhancement difference spectroscopy. Unambiguous assignment of all four ring systems is possible without recourse to model or derivative compounds by observing nuclear Overhauser enhancements between as well as within rings. The subsequent assignment of the carbon 13 spectrum is simply achieved using two-dimensional heteronuclear J-correlated techniques. The proton NMR spectrum of a sonicated aqueous dispersion of the intracellular second messenger precursor phosphatidylinositol 4,5-bisphosphate is reported for the first time. The spectrum is consistent with a high degree of side chain unsaturation and a conformation for the myo-inositol head group, which appears highly mobile, in which all bulky substituents are equatorial (except the 2-hydroxyl). Addition of aliquots of phosphatidylinositol 4,5-bisphosphate to an aqueous buffered solution of neomycin B induces complex changes in the whole spectrum of the latter, including downfield shifts of differential magnitude for several well-resolved signals, viz. the anomerics, and the pair of methylene protons of the substituted cyclohexane. The complexation kinetics are fast on the NMR time scale at 25 degrees C. The binding results are discussed in terms of a tentative complexation geometry.