Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2-d]pyrrolo[1,2-a]pyrimidines,Pyridofuro[3,2-d]pyrido[1,2-a]pyrimidines and Pyridofuro[3′,2′:4,5]pyrimido[1,2-a]azepines

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions. Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity. Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used. Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of “open field” and “elevated plus maze” (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of “forced swimming” (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABA_A receptor with a value of the scoring function that estimates free energy of binding (ΔG) at −7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT_1A receptor. Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.     

Investigation of cobalt doped tin dioxide structure and defects: Density functional theory and empirical force fields

The structure and defects of cobalt doped tin dioxide were investigated using the density functional theory and empirical force fields. The computations were carried out for different concentrations of cobalt (3.125, 6.25, 12.5, and 18.75 at%). It is shown that at the cobalt doping less than 4 at%, the oxygen vacancy occurs at the place of the oxygen bounded by cobalt. The electron density of states is computed when cobalt creates the states near a conduction band. By further increase in the cobalt concentration, the order of the structure begins to destroy.     

IMRT treatment planning for prostate cancer using prioritized prescription optimization and mean-tail-dose functions

Treatment planning for intensity modulated radiation therapy (IMRT) is challenging due to both the size of the computational problems (thousands of variables and constraints) and the multi-objective, imprecise nature of the goals. We apply hierarchical programming to IMRT treatment planning. In this formulation, treatment planning goals/objectives are ordered in an absolute hierarchy, and the problem is solved from the top-down such that more important goals are optimized in turn. After each objective is optimized, that objective function is converted into a constraint when optimizing lower-priority objectives. We also demonstrate the usefulness of a linear/quadratic formulation, including the use of mean-tail-dose (mean dose to the hottest fraction of a given structure), to facilitate computational efficiency. In contrast to the conventional use of dose-volume constraints (no more than x% volume of a structure should receive more than y dose), the mean-tail-dose formulation ensures convex feasibility spaces and convex objective functions. To widen the search space without seriously degrading higher priority goals, we allowed higher priority constraints to relax or 'slip' a clinically negligible amount during lower priority iterations. This method was developed and tuned for external beam prostate planning and subsequently tested using a suite of 10 patient datasets. In all cases, good dose distributions were generated without individual plan parameter adjustments. It was found that allowance for a small amount of 'slip,' especially in target dose homogeneity, often resulted in improved normal tissue dose burdens. Compared to the conventional IMRT treatment planning objective function formulation using a weighted linear sum of terms representing very different dosimetric goals, this method: (1) is completely automatic, requiring no user intervention, (2) ensures high-priority planning goals are not seriously degraded by lower-priority goals, and (3) ensures that lower priority, yet still important, normal tissue goals are separately pushed as far as possible without seriously impacting higher priority goals.     

Mathematics teachers’ specialized knowledge: a secondary teacher's knowledge of rational numbers

Recognising teachers’ knowledge as one of the main factors influencing their practices and student learning, we aim to contribute to obtaining a better and deeper understanding of the specificities of teachers’ mathematical knowledge. A case study involving one 8th-grade Chilean mathematics teacher is presented in the context of rational numbers. Using video and audio recordings of classroom practices, questionnaires, and an interview, we sought to characterise, and better understand the content of the Knowledge of Topics from the perspective of the Mathematics Teachers’ Specialized Knowledge (MTSK) theoretical framework. The results reveal some critical aspects that teacher education should focus on, while also identifying lost opportunities and examples of “good” practices, thus contributing to the refinement of the MTSK conceptualisation. The conclusions can be considered in a broader perspective, with implications for teacher education in other contexts.     

Map of Two-Dimensional Tungsten Chalcogenide Compounds (W–S,W–Se,W–Te) Based on USPEX Evolutionary Search

JETP Letters - New two-dimensional nanostructures of W–X composition (X = S, Se, Te) are predicted using the evolutionary algorithm implemented in the USPEX software package. Based on the...     

A new intramolecular recyclization in water‐base cleavage reaction of 2,2‐dialkyl‐4‐hydroxymethylbenz[f]iso indolinium bromides and chlorides

The water‐base cleavage reaction of 2,2‐dialkyl‐4‐hydroxymethylbenz[f]isoindolinium bromides and chlorides (2b‐g) and (4a‐g) was investigated. It was established that the above‐mentioned salts in water‐base cleavage reaction undergo intramolecular recyclization. As a result 1,3‐dihydro‐4‐dialkylaminomethyl‐naphto[1,2‐c]furans (5a‐g) are obtained in 62‐72% yields. The same products in 65‐70% yields may be obtained by step cyclization cleavage reaction of dialkyl‐4‐hydroxybutyn‐2‐yl‐(3‐phenylpropargyl) ammonium salts (1b‐g) and (3a‐g) , as well. The structure of the resulting amines 5a‐g are determined and approved by X‐ray diffraction, nmr and ir spectroscopic methods.