Structural insight for imidazopyridazines as malarial kinase PfPK7 inhibitors using QSAR techniques.

With a view to the rational design of a selected series of 35 imidazopyridazine derivatives, 2D and 3D QSAR models have been developed for the prediction of antimalarial activity. The statistically best 2D QSAR model having r(2) = 0.9242 and q(2) = 0.8691 with pred_r(2) = 0.9206 was developed by SW-MLR and best 3D QSAR model having q(2) = 0.8607 with pred_r(2) = 0.8332 was developed by k-nearest neighbor molecular field analysis (kNN-MFA). Molecular docking study was also carried out to better understand of the interactions between PfPK7 enzyme target (pdb: 2pnm) and inhibitors in this series. The docking study suggests that these PfPK7 inhibitors interact with Met120, Lys55, Tyr117, Asp123, Leu179, Leu34, Asn35, Ala53, Glu88, Leu101, Tyr119, Ser124, Ser189 and Asp190 amino acid residues of protein PfPK7. Both QSAR and docking studies of such derivatives provide guidance for further lead optimization and designing of more potent PfPK7 inhibitors.

Exploring pharmacological significance of chalcone scaffold: a review.

Chalcones (1,3-diaryl-2-propen-1-ones) and their heterocyclic analogues, belong to the flavonoid family, which possess a number of interesting biological properties such as antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and anti-inflammatory activities. Several pure chalcones have been approved for clinical use or tested in humans. Clinical trials have shown that these compounds reached reasonable plasma concentration and are well-tolerated. For this reason they are an object of continuously growing interest amongst the scientists. However, much of the pharmacological potential of chalcones is still not utilized. The purpose of this review is to provide an overview of the pharmacological activity of naturally occurring and synthetic chalcones. This review highlights more recent pharmacological screening of these compounds, their mechanisms of action and relevant structure-activity relationships.

Qsar study of some substituted 4-quinolinyl and 9-acridinyl hydrazones as antimalarial agents.

The quantitative structure-activity relationship (QSAR) analysis of some synthesized substituted 4-quinolinyl and 9-acridinyl hydrazone derivatives were performed to find out the structural requirements of their antimalarial activities. Various 2D descriptors were calculated and used in the present analysis. The 2D-QSAR studies were performed using three statistical methods: the multiple linear regressions, giving square of correlation coefficient (r(2)) = 0.8456, cross validated squared correlation coefficient (q(2)) = 0.7814 and predictable ability (pred_r(2)) = 0.7443; the partial least squares regression, with r(2) = 0.8402, q(2) = 0.7879 and pred_r(2) = 0.7680; and principle component regression, giving r(2) = 0.8392, q(2) = 0.7979 and pred_r(2) = 0.6440. Best equation was selected on the basis of high r(2), q(2) and pred_r(2). The QSAR model indicated that the T_N_O_3, IdAverage, chiV6chain, Most-vePotential and T_C_N_6 played an important role in determining antimalarial activities. The results of the present study may be useful on the designing of more potent analogues as antimalarial agents.

Visible spectrophotometric method for the determination of aripiprazole in tablets.

A simple, accurate and economic spectrophotometric method for the determination of aripiprazole in tablet formulation is proposed. In the present method acidic solution of the aripiprazole formed colored ion-association complexes with bromocresol green, soluble in chloroform. Yellowish orange chromogen showed λ(max) at 414 nm and obeyed Beer's law in the concentration range of 10-60 µg/ml. Statistical analysis and recovery studies validated the method. The proposed method is rapid, precise and accurate and can be applied for the routine estimation of aripiprazole in the laboratory.

Nanoparticle-based immunopotentiation via tetanus toxoid-loaded gelatin and aminated gelatin nanoparticles.

Gelatin nanoparticles (GNPs) and aminated gelatin nanoparticles (AGNPs) were prepared and used as an adjuvant to improve the delivery of tetanus toxoid (TT). Nanoparticles were characterized in vitro for their size, shape, entrapment, and release. TT-FITC conjugate was used to determine entrapment and release from nanoparticles. The immune-stimulating activity was studied by measuring anti-TT IgG, IgG1, and IgG2a isotype and cytokine responses following subcutaneous (s.c) injection of nanoparticles in BALB/c mice and was compared with alum-TT vaccine. Gelatin and aminated gelatin (AG) specific IgG response was also determined. Both GNPs and AGNPs demonstrated comparable IgG response and a significantly higher (p < 0.05) cytokine response (IL-2 and IFN γ) as compared to alum-TT vaccine. Nanoparticulate formulations elicited both Th1 and Th2 responses and induced negligible undesirable immunogenicity against the carrier, as demonstrated by lower level of gelatin and AG-specific IgG response as compared to control.

Comparison of humoral and cell-mediated immune responses to cationic PLGA microspheres containing recombinant hepatitis B antigen.

Presently available marketed alum adsorbed hepatitis B vaccine used for prophylactic immunization, can effectively elicit humoral immunity but is poor inducer of cell-mediated immunity (CMI). Besides, conventional alum-adjuvant vaccines require multiple injections to achieve long-lasting protective immune responses. Therefore, as a result of insufficient immunization, infections are still the leading killer among diseases. The present investigation was therefore, aimed at developing "single-shot" HBsAg adsorbed microspheres of poly (DL)-lactide-co-glycolide (PLGA) (L/G 50:50 and 75:25) and their capability to stimulate the cell mediated immune response against hepatitis B surface antigen. These microspheres were characterized in vitro for their size, shape polydispersity index, percentage HBsAg adsorption efficiency and in vitro release profile. The immune-stimulating activities were also studied following subcutaneous injection of HBsAg adsorbed PLGA microspheres (single-dose on day 0) and compared with alum adsorbed vaccines (two-doses on 0 and 28 days) in Balb/c mice. Specific cell-mediated immune responses such as lymphocyte transformation assay (stimulation-index) including release of interferon-gamma (IFN-γ), interleukin-2 (IL-2) and nitric-oxide were determined. Cellular responses in case of alum adsorb HBsAg vaccine was very low. These studies demonstrate the potential of cationic polymeric microspheres based vaccine in stimulating cell mediated immune response along with humoral response against hepatitis B.

Development and characterization of lectin-functionalized vesicular constructs bearing amphotericin B for bio-film targeting.

The long-term goal of this work will be to develop a topical formulation for oropharyngeal candidosis. Liposomes were prepared by the vesicle extrusion technique from mixtures of dipalmitoylphosphatidylcholine, cholesterol, and stearylamine incorporating a reactive phospholipid, the m-maleimidobenzoyl-N-hydroxysuccinimide ester derivative of dipalmitoylphosphatidylethanolamine, which was conjugated with the N-succinimidyl-S-acetylthioacetate derivatives of succinyl concanavalin A. Morphology of liposomes was studied by transmission electron microscopy and bio-film architecture using fluorescence microscopy. Lectinized vesicles were put into contact with bovine submaxillary mucin, to determine the in vitro activity and specificity. Targeting study was performed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The liposomes were found to have a diameter in the range of 360-450 and 390-510 nm for uncoated and coated formulations, respectively. The MTT assay showed a strong association of lectin-bearing liposomes with candidal bio-film. The results suggest that surface-modified liposomes can effectively target candidal bio-film in vitro.

Transferrin-conjugated liposomal system for improved delivery of 5-fluorouracil to brain.

The objective of this study is to achieve the enhanced delivery of 5-fluorouracil to brain through transferrin-coupled liposomes. 5-Fluorouracil-loaded liposomes were prepared by cast film method and characterized for particle size, shape, percent encapsulation efficiency and in vitro drug release. Biodistribution studies were carried out with the help of radiolabelled 5-fluorouracil. 5-Fluorouracil was labelled with (99m)Tc-DTPA by oxidation-reduction method using stannous chloride and optimized for labelling parameters to get a high labelling efficiency. The in vitro stability was determined to check the efficiency of a system to find out the suitability of the radiolabelled system for in vivo studies. (99m)Tc-DTPA-labelled 5-fluorouracil bearing non-coupled and coupled liposomes were administered intravenously and biodistribution studies were performed. The distribution of 5-fluorouracil via non-coupled and coupled liposomes was determined in various organs, such as lungs, liver, kidneys, spleen and brain, by measuring the radioactivity using a gamma scintillation unit. The results of in vivo studies confirmed a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. An average of 10-fold increase in the brain uptake of the drug was observed after the liposomal delivery of 5-fluorouracil, while the transferrin-coupled liposomes caused a 17-fold increase in the brain uptake of 5-fluorouracil. Therefore, it can be concluded that transferrin-coupled liposomes enhance the brain uptake of the drug, like 5-fluorouracil.

Antisense technology: a selective tool for gene expression regulation and gene targeting.

This review deals with the antisense technology that, together, forms a very powerful tool to inhibit gene expression and may be used for studying gene function (functional genomics) and for therapeutic purpose (antisense gene therapy). Antisense oligonucleotides block translation of target mRNAs in a sequence specific manner, either by steric blocking of translation or by destruction of the bound mRNA via RNase-H enzyme. For proper designing, accessible sites of the target RNA for binding antisense oligonucleotides have to be identified. Whether being used as an experimental reagent or pharmaceuticals, several problems or drawbacks have to be overcome for successful applications. Toward this direction, various modifications of sugar, bases and phosphate backbone of antisense oligonucleotides have been attempted. In recent years valuable progress has been achieved through the development of advanced cellular delivery systems and novel chemically modified nucleotides with improved properties such as enhanced serum stability, higher target affinity and low toxicity. These qualities and the specificity of binding make this technique a potentially powerful therapeutic tool for gene targeting and/ or expression regulation. This review discusses the basis of structural design, mode of action, chemical modification, enhanced cellular uptake, therapeutic application and future possibilities in the field of advanced antisense technology.

Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil.

Diseases and disorders of the brain are extremely difficult to treat pharmacologically because most drugs are unable to pass across the blood--brain barriers. Complex multi-strand tight junctions between adjacent cerebral endothelial cells and between choroid plexus epithelial cells form a physical barrier and prevent the passage of water soluble drugs from the blood into the brain, whereas the inward passage of lipid soluble drugs is restricted by drug efflux pumps which act as a functional barrier. In the present work, a transferrin-coupled liposomal system for brain delivery of 5-florouracil has been investigated.5-florouracil and (99m)Tc-DTPA bearing non-coupled liposomes were prepared by cast film method, which were coupled with the transferrin by incubating these liposomes with transferrin in the presence of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in saline phosphate buffer (pH 7.4). These liposomal systems were characterized for vesicle size, percent drug entrapment, and in vitro drug release. The size of the liposomes was increased on coupling with transferrin while percent drug entrapment reduced. The results of the in vitro release profile demonstrated that non-coupled liposomal formulation releases a comparatively higher percent (i.e. 74.8+/-3.21%) of drug than coupled liposomes. Results of in vivo study suggested a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. In case of coupled liposomes, the level of radioactivity was 17-fold more as compared to the free radioactive agent and 13 times more with the non-coupled liposomes. Therefore, it could be concluded that using transferrin coupled liposomes the brain uptake of the drug could be enhanced.

Nalidixic acid prodrugs: amides from amino acid ester and nalidixic acid.

Amides from amino acid ester and nalidixic acid were synthesized. The solubility characteristics and partition coefficient of the compounds were studied. The hydrolysis of the compounds was studied in the simulated gastric fluid and simulated intestinal fluid. Some compounds showed better antibacterial activity than nalidixic acid.