Comparative studies on the inhibitory activities of selected benzoic acid derivatives against secretory phospholipase A2, a key enzyme involved in the inflammatory pathway.

Inflammation is considered to be a key factor in major diseases like cancer, Alzheimer's disease, Parkinson's disease, etc. For the past few decades, pharmaceutical companies have explored new effective medications against inflammation. As a part of their detailed studies, many drug targets and drugs have been introduced against inflammation. In the present study, the inhibiting capacities of selected benzoic acid derivatives like gallic acid, vannilic acid, syringic acid and protocatechuic acid against secretory phospholipase A2 (sPLA2), a major enzyme involved in the inflammatory pathway, have been investigated. The detailed in vitro, biophysical and in silico studies carried out on these benzoic acid derivatives revealed that all the selected compounds have a uniform mode of binding in the active site of sPLA2 and are inhibitory in micromolar concentrations. The study also focuses on the non-selective inhibitory activity of an NSAID, aspirin, against sPLA2.

Design of a novel metal binding peptide by molecular dynamics simulation to sequester Cu and Zn ions.

Heavy metal toxicity has serious adverse effects on the environment. The metal sequestering characteristics of a novel metal binding peptide (Glu-Cys)11 Gly+linker+hexahistidine (EC11:His6) was investigated to determine if it can absorb Cu(2+) or Zn(2+) cations. Molecular dynamics simulations were carried out using a model of 6 Cu(2+) or Zn(2+) and other ions enclosed in a fully hydrated simulation box with the designed peptide. Totally, 240 nano second (ns) simulations were done in three phases. Results showed that the selected linker is able to separate two domains of this peptide and that the carboxyl oxygens of Glu residues of EC11 in the designed peptide can absorb these ions. Sequestration of Cu(2+) or Zn(2+) ions by the designed peptide does not change overall tertiary and secondary structures of peptide.

Prediction of partition coefficient of some 3-hydroxy pyridine-4-one derivatives using combined partial least square regression and genetic algorithm.

A quantiatative structure property relationship (QSPR) treatment was used to a data set consisting of diverse 3-hydroxypyridine-4-one derivatives to relate the logarithmic function of octanol:water partition coefficients (denoted by log po/w) with theoretical molecular descriptors. Evaluation of a test set of 6 compounds with the developed partial least squares (PLS) model revealed that this model is reliable with a good predictability. Since the QSPR study was performed on the basis of theoretical descriptors calculated completely from the molecular structures, the proposed model could potentially provide useful information about the activity of the studied compounds. Various tests and criteria such as leave-one-out cross validation, leave-many-out cross validation, and also criteria suggested by Tropsha were employed to examine the predictability and robustness of the developed model.

Synthesis and tyrosinase inhibitory properties of some novel derivatives of kojic acid.

Tyrosinase is a multifunctional oxidase that is widely distributed in nature. It is a key enzyme in melanin biosynthesis and is involved in determining the color of mammalian skin and hair. In addition it is responsible for the undesirable enzymatic browning that occurs in plant-derived foods, limiting the shelf-life of fresh-cut products with the resultant economic loss. In recent years there has been considerable interest to study the inhibitory activity of tyrosinase and a number of inhibitory compounds derived from natural sources or partly/fully synthetic have been described. However, the current conventional methods to control tyrosinase action are inadequate. Considering the significant industrial and economic impact of the inhibitors of tyrosinase, this study was set to seek new potent inhibitors of this enzyme. A series of 3-hydroxypyridine-4-one derivatives were prepared in high yield and evaluated for their inhibitory activity on tyrosinase enzyme using dopachrome method. Our results show that all synthesized compounds have inhibitory effect on tyrosinase activity for the oxidation of L-DOPA. Among compounds studied those containing two free hydroxyl group (ie Va and V'a) were more potent than their analogues with one hydroxyl group (ie Vb and V'b). Also substitution of a methyl group on position N(1) of the hydroxypyridinone ring seems to confer more inhibitory potency.

Quantitative structure activities relationships of some 2-mercaptoimidazoles as CCR2 inhibitors using genetic algorithm-artificial neural networks.

Quantitative relationships between structures of twenty six of 2-mercaptoimidazoles as C-C chemokine receptor type 2 (CCR2) inhibitors were assessed. Modeling of the biological activities of compounds of interest as a function of molecular structures was established by means of genetic algorithm multivariate linear regression (GA-MLR) and genetic algorithm (GA-ANN). The results showed that, the pIC50 values calculated by GA-ANN are in good agreement with the experimental data, and the performance of the artificial neural networks regression model is superior to the multivariate linear regression-based (MLR) model. With respect to the obtained results, it can be deduced that there is a non-linear relationship between the pIC50 s and the calculated structural descriptors of the 2-mercaptoimidazoles. The obtained models were able to describe about 78% and 93% of the variance in the experimental activity of molecules in training set, respectively. The study provided a novel and effective approach for predicting biological activities of 2-mercaptoimidazole derivatives as CCR2 inhibitors and disclosed that combined genetic algorithm and GA-ANN can be used as a powerful chemometric tools for quantitative structure activity relationship (QSAR) studies.

Antimicrobial evaluation of some novel derivatives of 3,4-dihydropyrimidine-2(1H)-one.

The antimicrobial activity of thirty six novel dihydropyrimidine derivatives was evaluated against common pathogenic bacteria. Significant antimicrobial activity (MIC=32, 64 µg/ml) was observed. Escherichia coli and Pseudomonas aeruginosa as Gram-negative bacteria and Staphylococcus aureus as Gram-positive bacteria were determined to be the most susceptible pathogens in this study. The highest inhibitory activity was observed against Gram-negative microorganisms. The widest spectrum of antibacterial activity was exerted by C6 and C22. Most of the compounds had remarkable antifungal activity (MIC=32 µg/ml).

Synthesis and antioxidant evaluation of 4-(furan-2-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate esters.

Biginelli-type pyrimidines contain an interesting moiety which has attracted considerable attention of medicinal chemists in the last few decades. Despite the very diverse pharmacologic effects ascribed to this kind of pyrimidines, there are few reports on the antioxidant evaluation of Biginelli pyrimidines. In this study synthesis of some novel Biginelli-type pyrimidines is reported. The prepared compounds are ester derivatives of 6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with a simple hetaryl group, furan, at C-4 position of the pyrimidine ring. These compounds were evaluated for free radical and H(2)O(2) scavenging activities. The reducing power of these compounds was also determined. Compound 3c was the most potent one in diphenyl picrylhydrazine scavenging activity assay with the IC(50) of 0.6 mg/ml. The results of reducing power assays proved that 3d and 3e are moderate reducing agents. All of the studied compounds were very weak in scavenging hydrogen peroxide compared with gallic acid.

A study on the analgesic effects of four new derivatives of 3-hydroxy pyridine-4-one.

Derivatives of pyridine-4-one are iron chelators with various biological activities including antifungal, anti-malarial, antiviral, anti-inflammatory and analgesic activities. This study was aimed to evaluate the analgesic effect of four new derivatives of 3-hydroxy pyridine-4-one in animal models. Acetic acid-induced writhing and formalin tests were used to assess the analgesic activity in male mice (18-22 g). Compound A (2.5-10 mg/kg), B (100-400 mg/kg), C and D (50-200 mg/kg) were administered intraperitoenally. Indomethacin and morphine were used as reference analgesic drugs. All tested compounds showed significant analgesia in acetic acid-induced writhing and the second phase of formalin test. All compounds except compound B also had analgesic activity in the first phase of formalin test. Among the investigated compounds, compound A which showed analgesic activity at doses of 2.5-10 mg/kg considered as the most potent analgesic compound. Structurally compound A lacks polar moieties such as -OH or -COOH and is less polar than the others. Therefore it seems that it has a better penetration into lipophilic sites of action.

Synthesis and antioxidant evaluation of some novel ortho-hydroxypyridine-4-one iron chelators.

A series of ortho-hydroxypyridine-4-ones were prepared in high yields and evaluated for antioxidant and iron chelating activities. N(1)-H hydroxypyridinones Va, Vb, and Ve were the best radical scavengers in DPPH free radical scavenging assay. Compound Vb was proved to be the most potent compound in hydrogen peroxide scavenging assay. All of the synthesized compounds had very close chelating ability, compounds containing N(1)-CH3 hydroxypyridinone ring were stronger chelating agents.

Evaluation of the in vitro antiretroviral potential of some Biginelli-type pyrimidines.

Despite the success of highly active antiretroviral therapy, AIDS still remains as one of the most important world health problems. Toxicity of current available drugs and inevitable emergence of multi-drug resistant strains makes things worse. In the present study a series of novel Biginelli-type pyrimidine compounds were evaluated as potential anti-human immunodeficiency virus (HIV)-1 agents using green fluorescence protein (GFP) reporter single round HIV-1 infection assay. The rate of infected cells was monitored by flowcytometry. The effect of compounds on the cellular proliferation was considered as the cyotoxicity. The anti-HIV-1 active compounds were selected for HIV-1 replication and syncytium formation assays. The antiretroviral activity of compounds was measured against luciferase reporter A murine leukemia virus (AMLV) virions as the retrovirus control. Compounds 2, 5, 6, 8, 11, 12, 13, 17, 18, 20, and 21 were the most potent against HIV-1. Compound 8 had the 50% inhibitory concentration (IC50) of 100 nmol/l for inhibiting HIV-1 replication and 50% cytotoxic concentration (CC50) was up to 100 µmol/l (therapeutic index (TI) >1000). Results show that the active compounds were able to inhibit the retrovirus control as well. Analysis of structure of the studied compounds proved relationships with their anti-HIV-1 effects. Some of the studied compounds seem to be promising anti-HIV-1 drug candidates. Structural manipulation based on the well-defined structure-activity relationships might propose some new leads for anti-HIV-1 drug discovery programs.

A QSAR study of some cyclobutenediones as CCR1 antagonists by artificial neural networks based on principal component analysis.

BACKGROUND AND PURPOSE OF THE STUDY: A quantitative structure activity relationship (QSAR) model based on artificial neural networks (ANN) was developed to study the activities of 29 derivatives of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy) phenylamino) cyclobutenedione as C-C chemokine receptor type 1(CCR1) inhibitors. METHODS: A feed-forward ANN with error back-propagation learning algorithm was used for model building which was achieved by optimizing initial learning rate, learning momentum, epoch and the number of hidden neurons. RESULTS: Good results were obtained with a Root Mean Square Error (RMSE) and correlation coefficients (R(2)) of 0.189 and 0.906 for the training and 0.103 and 0.932 prediction sets, respectively. CONCLUSION: The results reflect a nonlinear relationship between the Principal components obtained from calculated molecular descriptors and the inhibitory activities of the investigated molecules.

A modeling study of aldehyde inhibitors of human cathepsin K using partial least squares method.

Quantitative relationships between molecular structure of forty eight aldehyde compounds with their known Cathepsin K inhibitory effects were discovered by partial least squares (PLS) method. Evaluation of a test set of 10 compounds with the developed PLS model revealed that this model is reliable with a good predictability. Since the QSAR study was performed on the basis of theoretical descriptors calculated completely from the molecular structures, the proposed model could potentially provide useful information about the activity of the studied compounds. Various tests and criteria such as leave-one-out cross validation, leave-many-out cross validation, and also criteria suggested by Tropsha were employed to examine the predictability and robustness of the developed model.

QSAR study of some 5-methyl/trifluoromethoxy- 1H-indole-2,3-dione-3-thiosemicarbazone derivatives as anti-tubercular agents.

In the present study, quantitative relationships between molecular structure and anti-tubercular activity of some 5-methyl/trifluoromethoxy-1H-indole-2,3-dione-3-thiosemicarbazone derivatives were discovered. The detailed application of an efficient linear method and principal component regression (PCR) for the evaluation of quantitative structure activity relationships of the studied compounds is demonstrated. Components produced by principal component analysis were used as the input for a linear model development. Results indicate a linear relationship between the principal components obtained from molecular descriptors and the inhibitory activity of this set of molecules. The maximum variance in the activity of the molecules in PCR method was 73%. The performance of the developed model was tested by several validation methods.

Synthesis and calcium antagonist activity of 1,4-dihydropyridines containing phenylaminoimidazolyl substituents.

Alkyl ester analogues of nifedipine, in which the ortho-nitrophenyl group at position 4 is replaced by 2-methylthio-1-phenylamino-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K(+) contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that in the series of alkyl esters increasing the length of methylene chain in C-3 and C-5 ester substituents for more than two methylene units decreases activity. In the phenylalkyl ester series increasing the length of methylene chain also decreases activity. The results demonstrate that most of the compounds had similar activity to the reference drug nifedipine. In addition, two compounds, 5b and 5f were more active than the nifedipine.

Synthesis and calcium channel blocker activity of alkyl 1,4-dihydro-2,6-dimethyl-4-nitrobenzyl thioimidazolyl-3,5-pyridinedicarboxylates.

New alkyl ester analogues of nifedipine, in which the orthonitrophenyl group of position 4 is replaced by 1-methyl 2-(p-nitrobenzyl)thio-5-imidazolyl substituent, were synthesized and evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylen chain in C3 and C5 ester substituents decreased activity. When the presence of bulky lipophilic esters increased activity. In unsymmetrical diester series, the results showed when R1 is a small substituent (R1 = Me), increasing of the lipophilic property in R2 substituent increased the activity if this high lipophilicity don't accompany with steric hinderance. Our results demonstrate that the most active compound was diphenyl ester derivative and it was almost seven times more active than the reference drug nifedipine.

Post-marketing drug surveillance--concepts, insights and applications.

At the present drug approval process consists of preclinical animal testing, followed by three phases of clinical testing. Phase I is usually conducted on non-patient volunteers; phase II involves administration of the drug to a small number of selected patients; and phase III is the final premarketing test of the drug's safety and efficacy. These trials have major limitations, such as restricted patient populations, limited duration of patient exposure, and limited patient numbers. Considerable information remains unknown after the end of phase III testing, including: less common adverse effects; delayed adverse effects; efficacy and toxicity in types of patient usually excluded from premarketing testing, e.g. children, pregnant women and old people; efficacy and toxicity in patients with other illnesses and/or ingesting other drugs; efficacy and toxicity relative to other drugs used for the same purpose; efficacy and toxicity when used for indications other than those initially tested; the toxic effects of a massive overdose; physicians' prescribing habits, etc. The attempt to obtain this information after marketing is postmarketing drug surveillance.

Characteristics of hydrogel as disintegrant in solid dose technology.

A comparison between a hydrogel and the disintegrants Ac-di-sol, Avicel, maize starch and Primojel has been made using theophylline as the test drug in direct compression tableting. Results indicate that the disintegrant action of the hydrogel is comparable with that of the other disintegrants used, with no adverse effect on the dissolution of theophylline from these tablets as observed by thermal analysis study. The hydrogel's physicomechanical performance in direct compression processing appears to have no undesirable effect on the physical properties of tablets. Scanning electron micrographs of freeze-etched samples of hydrogel demonstrated its internal structure. These results strongly suggest that hydrogels have great potential as efficient disintegrants in solid dosage formulations.

Dissolution of theophylline from film-coated slow release mini-tablets in various dissolution media.

The dissolution of an experimental formulation of film-coated slow release theophylline mini-tablets has been investigated using the USP paddle apparatus in test media at pH 1.2 (hydrochloric acid), pH 5.4 and 7.4 (phosphate buffers) at 37 degrees C. Monitoring of in-vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in less than 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in-vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasize the usefulness of an animal model for assessment of in-vivo drug release and subsequent absorption, during the development of modified release dosage forms.

Irritation associated with tear-replacement ophthalmic drops. A pharmaceutical and subjective investigation.

Artificial tears, commonly prescribed for correction of the dry-eye syndrome, are formulated with suitably preserved aqueous polymeric solutions to promote corneal wetting without causing such side-effects as burning, itching, blurred vision and scratchiness. Four of the most commonly used commercial tear-replacement solutions were investigated after complaints of irritation by some users. The solutions were tested for tonicity, viscosity and pH and found to be in the tolerable range (tonicity equivalent to 0.5-1.5% m/v sodium chloride, viscosity 1-15 centipoise and pH 4-9). A double-blind cross-over study was conducted on 16 subjects and the degree of discomfort (non-irritant, irritant, and highly irritant) was determined subjectively. Results indicated that 3 of the tear solutions were acceptable. However, over 50% of the subjects reported irritation from the solution comprising polyvinyl alcohol 1.4% m/v preserved with 0.5% m/v chlorobutanol. To identify the cause of irritation, two extemporaneously prepared controls containing polyvinyl alcohol 1.4% m/v, with and without chlorobutanol 0.5% m/v as preservative, were also included in the study. The irritant response was found to be caused by the presence of chlorobutanol in the formulation. An attempt is made to identify and explain formulation properties likely to elicit adverse responses.

Influence of gamma radiation on the gel rigidity index and binding capability of gelatin.

Changes in the rigidity indices of gelatin gel before and after gamma irradiation were characterized by dynamic mechanical testing, and the significance of these changes on the strength of granules was evaluated. Results illustrate the difficulty of obtaining reproducible values for gels containing less than 20% gelatin. However, rigidity indices for gels with a gelatin content of 20% and higher are consistent and may provide a useful controlling factor for preparation of gelatins of more precise specifications. The data indicate that rigidity degradation kinetics of several concentrations of gelatin gel at different radiation doses are complex, showing both increasing and decreasing rates. These findings strongly suggest that doses of less than 2.0 Mrad of gamma radiation should be used in order to obtain gelatins of acceptable quality for pharmaceutical applications. The crushing strength of granules of lactose powder granulated with irradiated gelatin reveals that the binding capability of such gelatin is significantly reduced. The results obtained for various size fractions and granule hardnesses containing different binder concentrations also suggest that particle size influences the granule strength to a lesser extent than does binder concentration and its consistency.