Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro α-glucosidase inhibition, and computational studies.

BACKGROUND: A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a-o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase. METHODS: The 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. RESULTS: All new derivatives 11a-o (IC50 values = 6.31 ± 0.03-49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound. CONCLUSION: According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.

Design, synthesis, in vitro anti-α-glucosidase evaluations, and computational studies of new phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides as potential anti-diabetic agents.

An important target in the treatment of type 2 diabetes is α-glucosidase. Inhibition of this enzyme led to delay in glucose absorption and decrease in postprandial hyperglycemia. A new series of phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides 11a-n were designed based on the reported potent α-glucosidase inhibitors. These compounds were synthesized and screened for their in vitro inhibitory activity against the latter enzyme. The majority of the evaluated compounds displayed high inhibition effects (IC50 values in the range of 45.26 ± 0.03-491.68 ± 0.11 µM) as compared to the positive control acarbose (IC50 value = 750.1 ± 0.23 µM). Among this series, compounds 11j and 11i represented the most potent α-glucosidase inhibitory activities with IC50 values of 45.26 ± 0.03 and 46.25 ± 0.89 µM. Kinetic analysis revealed that the compound 11j is a competitive inhibitor with a Ki of 50.4 µM. Furthermore, the binding interactions of the most potent compounds in α-glucosidase active site were studied through molecular docking and molecular dynamics. The latter studies confirmed the obtained results through in vitro experiments. Furthermore, in silico pharmacokinetic study of the most potent compounds was also performed.

The effects of two attachment types on the stresses introduced to the mandibular residual ridge: a 3D finite element analysis.

PURPOSE: Two commonly used attachment systems for implant-retained overdentures are bar and ball systems. The aim of this study was to compare these two types of attachments on the basis of the stresses introduced to the mandibular posterior residual ridge by an overdenture retained by two implants. METHOD AND MATERIALS: A basic model was generated from the data provided by a CT scan of a patient's mandible, the diagnostic casts, and the existing overdenture. Two root-form implants were placed in the anterior mandible. Models were used to simulate two situations: The first model represented an edentulous mandible supporting an overdenture retained by two implants connected with a bar and plastic clip system, and in the second model two ball attachments with nylon caps were used as the retention mechanism. A 35 N vertical load was introduced to the first molar region of each group to simulate the occlusal forces of the maxillary complete denture. The stresses in the mandibular residual ridges under the first molar region were measured using Ansys software. RESULTS: The bar-retained overdenture introduced higher stresses to the posterior mandibular residual ridge compared to the ball-retained overdenture (0.4 MPa and 0.1 MPa, respectively). CONCLUSION: Within the limitations of this study, the ball system was shown to introduce a lower amount of stress to the posterior mandibular residual ridge compared to a bar and clip system.

Effect of shifting cultivation on distribution of nutrient elements and carbohydrates within water-stable aggregates in northern Iran.

This study attempts to evaluate the nutrient element and carbohydrate distribution within Water-Stable Aggregates (WSA) of two natural ecosystems, native forest and pasturelands, under different land uses. Soil samples were collected from depths of (0-20) cm in Typic Haploxeroll soils. The overall pattern indicated that Mean Weight Diameter (MWD) and WSA were greater in the pasture and forest soils compared with the adjacent cultivated soils and aggregates of > 1.0 mm size were dominant in the uncultivated soils, whereas the cultivated soils comprised aggregates of the size < or = 0.5 mm. Distribution of organic carbon, nitrogen, phosphorus and carbohydrates within the WSA showed preferential enrichment of these parameters in the macroaggregate fraction (4.75-1.0 mm) for the uncultivated soils and microaggregate fraction (> 0.25 mm) for the cultivated soils. Average distribution of total exchangeable bases within WSA showed that cultivation of forest pastureland soils significantly led to reduce in these nutrient in the 4.75-2.0 mm fraction and increase in concentration of these cations in < 0.25 mm fraction. Since smaller aggregates are preferentially removed by erosion, this study emphasizes the need for sustainable soil management practices that they will minimize nutrient loss when forest or pastures lands are converted to cropland.

Assessment of some soil properties by spatial variability in saline and sodic soils in Arsanjan plain, Southern Iran.

Spatial patterns for several soil parameters such soil texture, Exchangeable Sodium Percentage (ESP), Electrical Conductivity (ECe), soil pH, Cation Exchange Capacity (CEC) were examined in saline and sodic soils in Arsanjan plain, Southern Iran, in order to identify their spatial distribution for implementation of a site-specific management. Soil samples were collected from 0-30, 30-60 and 60-90 cm soil depths at 85 sampling sites. Data were analyzed both statistically and geostatistically on the basis of the semivariogram. The spatial distribution model and spatial dependence level varied between soil parameters. Soil pH and ESP had the minimum and maximum variability at all depths, respectively. Soil properties indicated moderate to strong spatial dependence. ECe exhibited moderate spatial dependence at three depths; pH and ESP had a moderate spatial dependence at 0-30 cm and strong spatial dependence at 30-60 and 60-90 cm depths. Clay and CEC exhibited strong spatial dependence for the 0-30 cm and weak spatial dependence at 30-60 and 60-90 cm depths. Sand and silt had a non-spatial dependence at 0-30 cm and weak spatial dependency at 30-60 and 60-90 cm depths. The spatial variability in small distances of ECe, CEC, pH and ESP generally increased with depth. All geostatistical range values were greater than 1168 m. The results reported herein indicated that the strong spatial dependency of soil properties would lead to the extrinsic factors such as ground water level and drainage. It is important to know the spatial dependence of soil parameters, as management parameters with strong spatial dependence will be more readily managed and an accurate site-specific scheme for precision farming more easily developed.