Sci. Pharm., Volume 76, Issue 3 (September 2008) – 14 articles , Pages 333-566

Computational screening of databases has become increasingly popular in the pharmaceutical research. Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Virtual screening is divided into structural based screening (docking) and screening using active compounds as templates (ligand based virtual screening). Ligand based screening techniques mainly focus on comparing molecular similarity analyses of compounds with known and unknown moiety, regardless of the methods of the used algorithm. Docking is a computational tool of structure based drug design to predict protein ligand interaction geometries and binding affinities. In this review we provide an overview of the already used ligand based virtual screening and the docking with various databases, filters, scores and applications in the recent research in the pharmaceutical field. Full article

A new cerebroside (1), together with three known ones (2–4) have been isolated from the whole plants of Euphorbia platyphyllos L. The structures were established by FT-IR spectroscopy, FAB-MS, advanced two-dimensional NMR, including ¹H-NMR, ¹H,¹H-COSY, HMQC and HMBC experiments and chemical reactions. The structures of the cerebrosides were characterized as 1-O-β-D-glycosides of phytosphingosines, which comprised a common long-chain base, (2S,3S,4R,8Z)-2-aminooctadec-8-ene-1,3,4-triol (1–3) and (2S,3S,4E,8E)-2-aminooctadeca-4,8-diene-1,3-diol (4) with 2-hydroxy fatty acids of varying chain lengths (C16, C24, C26:1, C28:1) linked to the amino group. The isolated compounds have been evaluated for their antifungal and antitubercular activities. Full article

The potential derivatives of caprylic acid were subjected to preservative efficacy testing in Aluminium Hydroxide Gel – USP using Staphylococcus aureus MTCC 2901, Bacillus subtilis MTCC 2063, and Escherichia coli MTCC 1652 as representative challenging microorganisms for antimicrobial effectiveness testing as per USP 2004. The caprylic acid derivative, capryl hydrazide exhibited better preservative efficacy than caprylic acid as well as the standard preservatives, methyl paraben and propyl paraben. Full article

A rapid high-performance liquid chromatographic (HPLC) method using a monolithic column has been developed for determination of valsartan in human plasma. The assay is based on protein precipitation using acetonitrile and fluorescence detection. The assay enables the measurement of valsartan for therapeutic drug monitoring with a minimum quantification limit of 20 ngml^-1. The method involves simple, one-step extraction procedure and analytical recovery was nearly complete. The separation was carried out in reversed-phase conditions using a Chromolith Performance (RP-18e, 100×4.6 mm) column with an isocratic mobile phase consisting of 0.01 M disodium hydrogen phosphate buffer-acetonitrile (60:40 v/v) adjusted to pH 3.5 with diluted phosphoric acid. The excitation and emission wavelengths were set at 230 and 295 nm, respectively. The calibration curve was linear over the concentration range 20-2000 ngml^-1. The coefficients of variation for inter-day and intra-day assay were found to be less than 6%. The assay was applied for the analysis of blood samples from a pharmacokinetic study. Full article

Abstract A major problem in ocular therapeutics is the attainment of optimal drug concentration at the site of action, which is compromised mainly due to precorneal loss resulting in only a small fraction of the drug being ocularly absorbed [1]. The effective dose administered may be altered by increasing the retention time of medication into the eye by using in situ gel forming systems. The aim of the present investigation is to prepare and evaluate novel in situ gum based ophthalmic drug delivery system of linezolid. Hydroxypropyl guar (HPG) and xanthum (XG) were used as gum with the combination of hydroxyethyl cellulose (HEC), carbopol (CP), and sodium alginate as viscosity enhancing agents. Suitable concentrations of buffering agents were used to adjust the pH to 7.4. All the formulations were sterilized in an autoclave at 121°C for 15mins. The formulations were evaluated for clarity, pH measurement, gelling capacity, drug content estimation, rheological study, in vitro diffusion study, antibacterial activity, isotonicity testing, eye irritation testing. The developed formulations exhibited sustained release of drug from formulation over a period of 6hr thus increasing residence time of the drug. The optimized formulations were tested for eye irritation on albino rabbit (male) using the Draize test protocol with crossover studies. The formulations were found to be non-irritating with no ocular damage or abnormal clinical signs to the cornea, iris or conjunctiva observed. Thus these in situ gelling systems containing gums may be a valuable alternative to the conventional systems. Full article

Our laboratory has been credited for the discovery of a unique membrane bound enzyme termed Acetoxy Drug: Protein Transacetylase (TAase) catalyzing the transfer of acetyl group from polyphenolic peracetates (PA) to certain functional proteins resulting in the modulation of their catalytic activity. In this report, we have synthesized eight novel 4-methylcoumarins and demonstrated the comparisons of acetoxy derivatives of 4-methylcoumarin with their propoxy and butoxy derivatives for the modulation of some receptor proteins such as cytochrome P-450 (Cyt.P-450), NADPH cytochrome c reductase and cytosolic glutathione S-transferase (GST). The results clearly indicated that acetoxy derivatives have very high efficacy for the modulation of above mentioned functional proteins as compared to their other derivatives. We have also compared the acetoxy derivatives of 4-methylcoumarin with their acid substituted acetoxy derivatives and found that inclusion of carboxylic acid groups on the benzenoid rings of the coumarins system hardly affected TAase mediated catalytic activity. Full article

The aim of this work was to develop and validate a dissolution test for diacerhein in capsules using spectrophotometric method. The dissolution established conditions were: 900 mL of sodium phosphate buffer pH 7.0 with 0.75 % of sodium lauryl sulphate as dissolution medium, using a basket apparatus at a stirring rate of 50 rpm. The drug release was evaluated by UV spectrophotometric method at 258 nm. The method was validated to meet requirements for a global regulatory filing. The validation included specificity, linearity, precision and accuracy. In addition, filter suitability and drug stability in medium were demonstrated. The comparison of the obtained dissolution profiles of capsules, obtained from three different brands (denominate product A, B and C) of 50 mg diacerhein, was performed and the results showed no significative difference among the products. Full article

Influence of pH, buffer, preservative, tonicity and viscosity modifiers on in vitrotranscorneal permeation of ofloxacin was studied using excised goat cornea. Permeation studies were carried out by putting 1 ml of test formulation on the cornea (0.78cm²) mounted between the donor and receptor compartments of an all glass modified Franz diffusion cell and measuring ofloxacin concentration in the receptor (containing bicarbonate ringer under stirring at 35°C) by spectrophotometry at 288 nm, at various time intervals up to 120 min. Buffering the formulation with phosphate buffer or use of combination of methyl and propyl paraben or benzalkonium chloride or combination of benzalkonium chloride and disodium edetate as preservative provided significant increase in the apparent corneal permeability coefficient of ofloxacin. While the use of phenyl mercuric acetate as preservative or tonicity adjustment with mannitol showed a significant decrease in apparent corneal permeability of ofloxacin. Raising the pH of test formulation from 6.4 to 7.2 or addition of hydroxyl-propyl-β-cyclodextrin or use of viscosity modifier had no significant effect on apparent corneal permeability of drug. Full article

Certain properties relevant to probiotic action, e.g. resistance to acid, bile tolerance, adhesive properties, antibacterial activity, and antibiotic susceptibility were investigated of lactobacilli isolated from four kinds of Thai traditional fermented foods. Media of pH = 2.0–7.0 and bile salt concentrations of 0.3–1.0% were used as stress conditions. The adhesive properties were assessed by determination of bacterial hydrophobicity. Antibacterial activity of the probiotic lactobacilli was determined by means of the spot-on-lawn method. Among 563 isolates, only 3 strains (two from fermented pork and one from fermented tea leaves) showed extremely high survival rates under stress caused by acid or bile salts. The identification by PCR techniques revealed that these three strains were Lactobacillus fermentum. The strains from fermented pork showed higher adhesive potential than those from fermented tea leaves. The three strains inhibited test pathogenic bacteria to different extents. They were sensitive to chloramphenicol, quinupristin, erythromycin, kanamycin linezolid, rifampicin, streptomycin, and tetracycline but resistant to ciprofloxacin and vancomycin. Full article

15 extracts of different polarities (dichloromethane, methanol and aqueous extracts) from 5 Yemeni medicinal plants (Aspilia helianthoides, (Schumach. & Thonn.) Oliv. & Hiern subsp. ciliate (Schumach.) C.D. Adams leaves; Ceropegia rupicola, Defl. var. rupicola whole plant; Kniphofia sumarae, Defler whole plant; Pavetta longiflora, Vahl. subsp. longifloraleaves; and Plectranthus cf barbatus (Thulin & Gifri) leaves) were tested for their inhibitory effects against the enzymatic activity of human neutrophil elastase (HNE) (EC 3.4.21.37) in an in vitro human neutrophil elastase inhibition assay. 14 extracts at various concentrations were found able to inhibit the activity of HNE. Among the plants tested,A. helianthoides was the most active inhibitor of HNE. The dichloromethane extracts of all tested plants, exhibited more inhibitory effect on HNE activity than the methanolic and aqueous extracts. The dichloromethane extract of A. helianthoides showed the most active inhibitory effect on the HNE activity (IC₅₀ = 0.4μg/ml). Within the HNE inhibitory active methanolic extracts, those of A. helianthoides and P. cf barbatus were the most active inhibitors with IC₅₀ of about 3μg/ml. These results provide some scientific justification for the use of A. helianthoides in traditional medicine and indicate the presence of HNE inhibitory constituents in the active tested plants. Full article

Novel 5H-thiazolo[3,2-a]pyrimidin-5-one derivatives linked through an ethylene bridge to various phenylpiperazine groups were prepared for evaluation as 5-HT_2A receptor antagonists. The target compounds 11a–p were prepared through the initial synthesis of the 2-chloroethyl intermediates 10a–d which were then reacted with the appropriate phenylpiperazines. All compounds were tested for their antagonistic activity on 5-HT_2Areceptors using inhibition of 5-hydroxytryptophan(5-HTP)-induced head twitches in mice. Pharmacophore modeling study, based on a hypothetical pharmacophore template generated from a set of diverse known active ligands, revealed good fitting of the designed compounds to the generated hypothetical pharmacophore. Full article

A group of 5-substituted-2-(4-azido or (methylsulfonyl)phenyl)-1H-indoles were designed and synthesized as selective cyclooxygenase (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition studies were carried out to investigate the effect of different substituents (H, F, Cl, Me, OMe) at C-5 position and different pharmacophore groups (azido or methylsulfonyl) at para position of phenyl ring at C-2 position of the 1H-indole ring on COX-2 selectivity and potency. The structure-activity relationship study of these compounds indicated that the introduction of a methoxy substituent at C-5 position and 4-(methylsulfonyl) phenyl group at C-2 position of the 1H-indole ring (compound 4e) had the best COX-2 selectivity (S.I= 291.2). A molecular modeling study where 4e was docked in the binding site of COX-2 showed that the methylsulfonyl group at para position of phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. Full article

The topological indices were used to encode the structureal features of cephalosporins. Both topostructural and topochemical versions of a distance based descriptor, three adjacency based descriptors and five distance-cum-adjacency based descriptors were calculated. The values of 18 indices for each cephalosporin in the dataset were computed using an in-house computer program. Multiple pharmacokinetic parameters of cephalosporins were predicted using random forest, decision tree and moving average analysis. Random forest correctly classified the pharmacokinetic parameters into low and high ranges upto 95%. A decision tree was constructed for each pharmacokinetic parameter to determine the importance of topological indices. The decision tree learned the information from the input data with an accuracy of 95% and correctly predicted the cross-validated (10 fold) data with an accuracy of upto 90%. Three independent moving average based topological models were developed using a single range for simultaneous prediction of multiple pharmacokinetic parameters. The accuracy of classification of single index based models using moving average analysis varied from 65% to 100%. Full article