Design, synthesis, biological evaluation, and molecular modeling studies of pyrazole-benzofuran hybrids as new α-glucosidase inhibitor.

In this work, new derivatives of biphenyl pyrazole-benzofuran hybrids were designed, synthesized and evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase activity. Newly identified inhibitors were found to be four to eighteen folds more active with IC50 values in the range of 40.6 ± 0.2-164.3 ± 1.8 µM, as compared to the standard drug acarbose (IC50 = 750.0 ± 10.0 µM). Limited Structure-activity relationship was established. A kinetic binding study indicated that most active compound 8e acted as the competitive inhibitors of α-glucosidase with Ki = 38 µM. Molecular docking has also been performed to find the interaction modes responsible for the desired inhibitory activity. As expected, all pharmacophoric features, used in the design of the hybrid, are involved in the interaction with the active site of the enzyme. In addition, molecular dynamic simulations showed compound 8e oriented vertically into the active site from mouth to the bottom and stabilized the enzyme domains by interacting with the interface of domain A and domain B and the back side of the active site while acarbose formed non-binding interaction with the residue belong to the domain A of the enzyme.

Design, synthesis, and bio-evaluation of new isoindoline-1,3-dione derivatives as possible inhibitors of acetylcholinesterase.

BACKGROUND AND PURPOSE: Alzheimer's disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer's disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects. EXPERIMENTAL APPROACH: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. The structure of the compounds were confirmed by various methods of analysis such as HNMR, CNMR, and FT-IR. Molecular modeling studies were also performed to identify the possible interactions between neprilysin and synthesized compounds. FINDINGS/RESULTS: The biological screening results indicated that all synthesized compounds displayed potent inhibitory activity with IC50 values ranging from 2.1 to 7.4 µM. Among synthesized compounds, para-fluoro substituted compounds 7a and 7f exhibited the highest inhibitory potency against AChE (IC50 = 2.1 µM). Molecular modeling studies indicated that the most potent compounds were able to interact with both catalytic and peripheral active sites of the enzyme. Also, some of the most potent compounds (7a, 7c, and 7f) demonstrated a neuroprotective effect against H2O2-induced cell death in PC12 neurons. CONCLUSION AND IMPLICATIONS: The synthesized compounds demonstrated moderate to good AChE inhibitory effect with results higher than rivastigmine.

Design and synthesis of novel quinazolinone-pyrazole derivatives as potential α-glucosidase inhibitors: Structure-activity relationship, molecular modeling and kinetic study.

In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 µM) in comparison to standard acarbose (IC50 = 750.0 ± 10.0 µM). Limited structure-activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 µM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme.

Design and synthesis of novel pyrazole-phenyl semicarbazone derivatives as potential α-glucosidase inhibitor: Kinetics and molecular dynamics simulation study.

A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the α-glucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast α-glucosidase inhibition (IC50 values in the range of 65.1-695.0 µM) even much more potent than standard drug acarbose (IC50 = 750.0 µM). Among them, compounds 8o displayed the most potent α-glucosidase inhibitory activity (IC50 = 65.1 ± 0.3 µM). Kinetic study of compound 8o revealed that it inhibited α-glucosidase in a competitive mode (Ki = 87.0 µM). Limited SAR suggested that electronic properties of substitutions have little effect on inhibitory potential of compounds. Cytotoxic studies demonstrated that the active compounds (8o, 8k, 8p, 8l, 8i, and 8a) compounds are also non-cytotoxic. The binding modes of the most potent compounds 8o, 8k, 8p, 8l and 8i was studied through in silico docking studies. Molecular dynamic simulations have been performed in order to explain the dynamic behavior and structural changes of the systems by the calculation of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF).

Optimizing the production of vitamin D in white button mushrooms (Agaricus bisporus) using ultraviolet radiation and measurement of its stability.

This study was conducted to determine the most efficient method to produce vitamin D in mushrooms using UV radiation. For this purpose, mushrooms were irradiated with UV-B and UV-C lamps from their caps, stems, both caps and stems (oblique), and sliced surface at doses of 12.5 kJ m-2 and 3.6 kJ m-2, respectively. Then, they were treated by UV-B at 27 °C, 35 °C, and 43 °C. In the next steps, samples were placed in 30 cm and 50 cm distances from the UV source. Afterward, they were irradiated from 15 to 120 min at an intensity of 3.5 W m-2. In the stability tests, samples were stored at 25 °C, frozen, refrigerated and were cooked and their vitamin D2 content was re-analyzed using HPLC. All experiments were repeated three times. In the sliced group treated with UV-B, vitamin D2 content 14.43 µg gr-1 was significantly higher than other groups. The internal temperature of 27 °C was found as optimum temperature with the production of 3.81 µg gr-1 vitamin D. It was revealed that increasing the distance from the UV source had a significant effect on vitamin D production. After 90 min of exposure, the highest amount of vitamin D2 was produced. Data showed that the vitamin D2 content remained almost stable after one day at 25 °C and during the cooking but it decreased about 50% after 7 days of cold storage. The optimal method observed in this study incorporates the use of UV-B lamps, incensement of radiation area in mushrooms and distance reduction from the UV source within 30 cm the internal temperature of 27 °C should be considered as well in the experiment.

Identification of Essential 2D and 3D Chemical Features for Discovery of the Novel Tubulin Polymerization Inhibitors.

BACKGROUND: Tubulin polymerization inhibitors interfere with microtubule assembly and their functions lead to mitotic arrest, therefore they are attractive target for design and development of novel anticancer compounds. OBJECTIVE: The proposed novel and effective structures following the use of three-dimensionalquantitative structure activity relationship (3D-QSAR) pharmacophore based virtual screening clearly demonstrate the high efficiency of this method in modern drug discovery. METHODS: Combined computational approach was applied to extract the essential 2D and 3D features requirements for higher activity as well as identify new anti-tubulin agents. RESULTS: The best quantitative pharmacophore model, Hypo1, exhibited good correlation of 0.943 (RMSD=1.019) and excellent predictive power in the training set compounds. Generated model AHHHR, was well mapped to colchicine site and three-dimensional spatial arrangement of their features were in good agreement with the vital interactions in the active site. Total prediction accuracy (0.92 for training set and 0.86 for test set), enrichment factor (4.2 for training set and 4.5 for test set) and the area under the ROC curve (0.86 for training set and 0.94 for the test set), the developed model using Extended Class FingerPrints of maximum diameter 4 (ECFP_4) was chosen as the best model. CONCLUSION: Developed computational platform provided a better understanding of requirement features for colchicine site inhibitors and we believe the results of this study might be useful for the rational design and optimization of new inhibitors.

Correlation of Shape and Size of Sella Turcica With the Type of Facial Skeletal Class in an Iranian Group.

BACKGROUND: In orthodontic science, diagnosis of facial skeletal type (class I, II, and III) is essential to make the correct treatment plan that is usually expensive and complicated. Sometimes results from analysis of lateral cephalometry radiographies are not enough to discriminate facial skeletal types. In this situation, knowledge about the relationship between the shape and size of the sella turcica and the type of facial skeletal class can help to make a more definitive decision for treatment plan. OBJECTIVES: The present study was designed to investigate this relationship in patients referred to a dental school in Iran. PATIENTS AND METHODS: In this descriptive-analytical study, cephalometric radiographies of 90 candidates for orthodontic treatment (44 females and 46 males) with an age range of 14 - 26 years and equal distribution in terms of class I, class II, and class III facial skeletal classification were selected. The shape, length, diameter, and depth of the sella turcica were determined on the radiographs. Linear dimensions were assessed by one-way analysis of variance while the correlation between the dimensions and age was investigated using Pearson's correlation coefficient. RESULTS: Sella turcica had normal morphology in 24.4% of the patients while irregularity (notching) in the posterior part of the dorsum sella was observed in 15.6%, double contour of sellar floor in 5.6%, sella turcica bridge in 23.3%, oblique anterior wall in 20% and pyramidal shape of the dorsum sella in 11.1% of the subjects. In total, 46.7% of class I patients had a normal shape of sella turcica, 23.3% of class II patients had an oblique anterior wall and a pyramidal shape of the dorsum sella, and 43.3% of class III individuals had sella turcica bridge (the greatest values). Sella turcica length was significantly greater in class III patients compared to class II and class I (P < 0.0001). However, depth and diameter of sella turcica were similar in class I, class II, and class III patients. Furthermore, age was significantly correlated to the diameter of sella turcica as greater diameters were observed in older ages (P < 0.04). CONCLUSION: A significant relationship exists between the type of facial skeletal classification and the shape of the sella turcica; as in class III patients, sella turcica bridge was reported with a higher frequency. Also, sella turcica had a significantly higher length in these patients than in those with class I and class II facial skeletal types.

Designing of a Computer Software for Detection of Approximal Caries in Posterior Teeth.

BACKGROUND: Radiographs, adjunct to clinical examination are always valuable complementary methods for dental caries detection. Recently, progressing in digital imaging system provides possibility of software designing for automatically dental caries detection. OBJECTIVES: The aim of this study was to develop and assess the function of diagnostic computer software designed for evaluation of approximal caries in posterior teeth. This software should be able to indicate the depth and location of caries on digital radiographic images. MATERIALS AND METHODS: Digital radiographs were obtained of 93 teeth including 183 proximal surfaces. These images were used as a database for designing the software and training the software designer. In the design phase, considering the summed density of pixels in rows and columns of the images, the teeth were separated from each other and the unnecessary regions; for example, the root area in the alveolar bone was eliminated. Therefore, based on summed intensities, each image was segmented such that each segment contained only one tooth. Subsequently, based on the fuzzy logic, a well-known data-clustering algorithm named fuzzy c-means (FCM) was applied to the images to cluster or segment each tooth. This algorithm is referred to as a soft clustering method, which assigns data elements to one or more clusters with a specific membership function. Using the extracted clusters, the tooth border was determined and assessed for cavity. The results of histological analysis were used as the gold standard for comparison with the results obtained from the software. Depth of caries was measured, and finally Intraclass Correlation Coefficient (ICC) and Bland-Altman plot were used to show the agreement between the methods. RESULTS: The software diagnosed 60% of enamel caries. The ICC (for detection of enamel caries) between the computer software and histological analysis results was determined as 0.609 (95% confidence interval [CI] = 0.159-0.849) (P = 0.006). Also, the computer program diagnosed 97% of dentin caries and the ICC between the software and histological analysis results for dentin caries was determined as 0.937 (95% CI=0.906-0.958) (P < 0.001). Bland-Altman plot showed an acceptable agreement for measuring the depth of caries in enamel and dentin. CONCLUSIONS: The designed software was able to detect a significant number of dentin caries and acceptable measuring of the depth of carious lesions in enamel and dentin. However, the software had limited ability in detecting enamel lesions.

Radiologic assessment and frequency of idiopathic osteosclerosis of jawbones: an interpopulation comparison.

BACKGROUND: Idiopathic osteosclerosis is a localized growth of compact bone with an unknown cause. This asymptomatic lesion is an insignificant finding and as such requires no treatment. It should be distinguished from other types of osteosclerosis created by inflammatory processes and systemic diseases. PURPOSE: To determine the prevalence and distribution of idiopathic osteosclerosis in the jawbones in Iran and to compare this prevalence and distribution with other populations. MATERIAL AND METHODS: This cross-sectional descriptive study was performed in the Dental School of Shahid Beheshti University of Medical Sciences, Tehran, between 2010 and 2011. Data were collected from the files of patients who underwent panoramic radiography for dental treatment. Location, shape, and relation between idiopathic osteosclerosis and the tooth as well as the resorption of the tooth involved were evaluated. Lesion distribution regarding age, gender, localization, shape, dental relationship, and root resorption was assessed using the chi-squared test. RESULTS: In total, 787 panoramic radiographs of 456 women and 331 men were assessed. Idiopathic osteosclerosis was detected in 75 (9.5%) patients. The prevalence of idiopathic osteosclerosis was significantly higher in the women (11.8% vs. 6.3%; P < 0.01). The mean age of the patients with idiopathic osteosclerosis was 31.9 ± 17.9 years and 30.8 ± 13.3 years in the patients without idiopathic osteosclerosis. The distribution of idiopathic osteosclerosis in the mandible (97.3%), mostly in the premolar region, was significantly higher than that in the maxilla (2.7%). CONCLUSION: Our results showed high frequencies of idiopathic osteosclerosis in Iran in comparison to some other countries.

Electrochemical spectroscopic investigations on the interaction of an ytterbium complex with DNA and their analytical applications such as biosensor.

Metal ion-DNA interactions are important in nature, often changing the genetic material's structure and function. A new Yb complex of YbCl(3) (tris(8-hydroxyquinoline-5-sulfonic acid) ytterbium) was synthesized and utilized as an electrochemical indicator for the detection of DNA oligonucleotide based on its interaction with Yb(QS)(3). Cyclic voltammetry (CV) and fluorescence spectroscopy were used to investigate the interaction of Yb(QS)(3) with ds-DNA. It was revealed that Yb(QS)(3) presented an excellent electrochemical activity on glassy carbon electrode (GCE) and could intercalate into the double helix of double-stranded DNA (ds-DNA). The binding mechanism of interaction was elucidated on glassy carbon electrode dipped in DNA solution and DNA modified carbon paste electrode by using differential pulse voltammetry and cyclic voltammetry. The binding ratio between this complex and ds-DNA was calculated to be 1:1. The extent of hybridization was evaluated on the basis of the difference between signals of Yb(QS)(3) with probe DNA before and after hybridization with complementary DNA. With this approach, this DNA could be quantified over the range from 1 × 10(-8) to 1.1 × 10(-7)M. The interaction mode between Yb(QS)(3) and DNA was found to be mainly intercalative interaction. These results were confirmed with fluorescence experiments.