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Pyrazine derivatives as potential drugs IV
Janoutová, Alena ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Author: Alena Janoutová Supervisor: PharmDr. Jan Zitko, PhD. Title of diploma thesis: Pyrazine Derivatives as Potential Antituberculosis Drugs IV Drug research, potentially effective against tuberculosis, progress already for several years in the Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec Králové. This study is focused on new derivatives of pyrazinamide (PZA) prepared as potential antituberculars. PZA itself is a well-established first-line antitubercular agent and a constituent of all basic tuberculosis treatment regimens. The design of final compounds was based on the previously synthesized 5-alkylamino-N-phenylpyrazine-2-carboxamides1, which possessed promising in vitro antimycobacterial activity with MIC ranging from 0.78 to 3.13 µg/mL. The object of this study was to test the activity of derivatives with alkylamino chain modified with terminal phenyl, hydroxyl or methoxy group. Final compounds were prepared by nucleophilic substitution of chlorine with respective amines in refluxing EtOH. Reaction yields, after all purification steps, were 58-87%. Compounds were characterized by 1 H and 13 C NMR, IR, elementary analysis and...
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Pharmacological characterization of the MAS-Related G Protein-Coupled Receptor D
Navrátilová, Michaela ; Zitko, Jan (advisor) ; Trejtnar, František (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Michaela Navrátilová Supervisors: Dr. Kristina Hoffmann PharmDr. Jan Zitko, Ph.D. Title of diploma thesis: PHARMACOLOGICAL CHARACTERIZATION OF THE MAS-RELATED G PROTEIN-COUPLED RECEPTOR D The human MRGPRD (Mas-related G protein-coupled receptor D) belongs to the big family of GPCRs (G Protein-coupled receptors). Signaling pathways mediated by GPCRs regulate a high number of vital body functions and approximately 30 % of all modern clinical drugs target GPCRs (Overington et al., 2006). The MRGPR subfamily was discovered 10 years ago and still remains mainly unexplored and considered "orphan" (Solinski et al., 2014). Several ligands such as β-alanine, GABA, β-aminobutyric acid (Shinohara et al., 2004; Ajit et al., 2010; Uno et al., 2012), angiotensin and alamandine (Gembardt et al., 2008; Lautner et al., 2013) are able to bind to the human MRGPRD. The hMRGPRD is specifically expressed in the primary sensory trigeminal ganglia neurons. Activation of the receptor by β-alanine has shown to elicit pruritogenic sensation and to contribute to normal mechanical and thermal pain thresholds. The restricted expression pattern suggests that the hMRGPRD could be a new specific target for the...
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Synthesis and in vitro testing of tacrine-troloxic derivatives as potential inhibitors of acetylcholinesterase
Ondřejíček, Aleš ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Aleš Ondřejíček Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Supervisor specialist: PharmDr. Jan Korábečný, Ph.D. Title of Diploma thesis: Synthesis and in vitro testing of tacrine-trolox derivatives as potential inhibitors of acetylcholinesterase Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves gradual loss of episodic memory and impairment of cognitive functions. Characteristic histopathological hallmarks of AD are neuritic plaques and neurofibrillary tangles present in brain tissue as well as deterioration of cholinergic neurotransmission. Currently there are only two classes of drugs used for the treatment of AD. The first group represents inhibitors of acetylcholinesterase (AChEI), whereas the second only memantin, NMDA receptor antagonist. The aim of the thesis was to synthesize three series of tacrine - trolox derivatives. In particular derivatives of trolox with tacrine, 7-methoxytacrine and 6- chlorotacrine, which were connected by various linkers. To determine the therapeutical potential of new compounds Ellman method was used and results were compared with tacrine, 7-methoxytacrine and 6-chlorotacrine as standards. The...
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Regularizační metody založené na metodách nejmenších čtverců
Michenková, Marie ; Hnětynková, Iveta (advisor) ; Zítko, Jan (referee)
Title: Regularization Techniques Based on the Least Squares Method Author: Marie Michenková Department: Department of Numerical Mathematics Supervisor: RNDr. Iveta Hnětynková, Ph.D. Abstract: In this thesis we consider a linear inverse problem Ax ≈ b, where A is a linear operator with smoothing property and b represents an observation vector polluted by unknown noise. It was shown in [Hnětynková, Plešinger, Strakoš, 2009] that high-frequency noise reveals during the Golub-Kahan iterative bidiagonalization in the left bidiagonalization vectors. We propose a method that identifies the iteration with maximal noise revealing and reduces a portion of high-frequency noise in the data by subtracting the corresponding (properly scaled) left bidiagonalization vector from b. This method is tested for different types of noise. Further, Hnětynková, Plešinger, and Strakoš provided an estimator of the noise level in the data. We propose a modification of this estimator based on the knowledge of the point of noise revealing. Keywords: ill-posed problems, regularization, Golub-Kahan iterative bidiagonalization, noise revealing, noise estimate, denoising 1
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Alkylamino- Derivatives of Pyrazinamide as Potential Antituberculotic Drugs
Mlčoch, Michal ; Zitko, Jan (advisor) ; Musílek, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Michal Mlčoch Supervisor: Mgr. Jan Zitko, Ph.D. Title of candidate thesis: Alkylamino- derivatives of pyrazinamide as potential antituberculotic drugs This thesis is a result of intention to prepare potential effective derivatives from pyrazinamide (PZA) structure. These results contribute to enrichment of the research of new antituberculars (antiTBC) which has been carried out at the Dpt. of Pharmaceutical Chemistry and Drug Control at the Faculty of Pharmacy in Hradec Králové. The aim of the research to produce the new effective antituberculars is supported by the contemporary state of tuberculosis in the world. This state is closely described in this thesis. Despite of decreasing number of new cases in all six WHO regions, spreading of this infectious disease is not under the control. The main reason is a resistance formation of new mycobacterial strains which can cause hardly treatable cases. The prepared substances are PZA derivatives which represent one of the most important first line drugs for tuberculosis treatment. The latest research focused on mechanism of PZA showed new information which was included in this thesis. Furthermore, some...
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Cationic surfactants as the hydrolytic micellar catalysts
Janošcová, Petra ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Cationic surfactants as the hydrolytic micellar catalysts Petra Janošcová The effectiveness of hydrolytic cleavage of the pesticide fenitrothionin cationic surfactants micellar media has been tested. All used surfactants increased the rate of fenitrothionhydrolysis, which was the evidence of micellar catalysis. For some surfactants decreases has been evident at the highest rate of hydrolysis concentrations. It has been the result of a phenomenon called the effect of empty micelles. High hydrolytic performance was achieved with surfactants contained ionisable hydroxyl groups in the molecule. The most significant increase of kinetic rate has been observed with benzoxonium surfactant.
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Derivatives of Pyrazinecarboxylic Acid as Potential Antituberculotics (Synthesis and Biological Evaluation)
Zitko, Jan ; Doležal, Martin (advisor) ; Vinšová, Jarmila (referee) ; Csöllei, Jozef (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Dpt. of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Jan Zitko Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Title of Doctoral Thesis: Derivatives of pyrazinecarboxylic acid as potential antituberculotics (synthesis and biological evaluation) This thesis deals with derivatives of pyrazine-2-carboxylic (POA) acid with potential antimycobacterial activity. In the theoretical part of the thesis there is a short description of tuberculosis (TB) disease, discussion of its epidemiology an associated risk factors of increasing resistance to fist-line antituberculars and the co-infection with HIV. Antituberculars used in clinical practice are described as well as the summary of new antituberculars under clinical trials is presented. Pyrazinamide (PZA) as one of the most important first-line antituberculars is in the focus of this thesis. Multiple up-to-date theories of PZA (POA) mechanism of action are described and discussed. Importantly, a summary of structural changes of PZA/POA attempted in the past to prepare new antituberculars is presented and the importance and relevance of individual structural changes is discussed. In the practical part of this thesis, 76 derivatives of PZA/POA were prepared, 68 of...
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Synthesis of NK1 antagonists.
Puchnerová, Lucie ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Synthesis of NK-1 antagonists Lucie Puchnerová Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy University of Seville NK-1 receptor antagonists are represented so far by only one drug, Aprepitant, which is available on the market for prevention of chemotherapy-induced nausea and vomiting. Nevertheless, it is assumed that NK-1 antagonists will be able to participate in treatment of migraine, rheumatoid arthritis, asthma, pain, inflammatory bowel disease, Parkinson's disease, anxiety and depression in future. This thesis is concerned with asymmetric synthesis of derivatives of 2-amino-4H-pyran, which thanks their substitutions are in accordance with structure of pharmacophore of NK-1 antagonists. As a starting material for their preparation has been used commercial methyl p-tolyl sulfone and (R)-methyl p-tolyl sulfoxide, which was synthesized from menthyl-(S)-p- toluenesulfinate by nucleophilic substitution. These compounds were subjected to reaction with ethyl 2-picolinate. From prepared β- ketosulfoxide and β-ketosulfone were obtained 2-amino-4H-pyrans by Michael addition. The derivatives proceeding from β-ketosulfoxide were subjected to reduction of the sulfoxide and trifluoroacetylation of the amine group on the carbon 2 of the pyran ring. Prepared derivatives had agonistic activity...
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Approximate Polynomial Greatest Common Divisor
Eliaš, Ján ; Zítko, Jan (advisor) ; Hnětynková, Iveta (referee)
Title: Approximate Polynomial Greatest Common Divisor Author: Ján Eliaš Department: Department of Numerical Mathematics, MFF UK Supervisor: Doc. RNDr. Jan Zítko, CSc., Department of Numerical Mathematics, MFF UK Abstract: The computation of polynomial greatest common divisor (GCD) ranks among basic algebraic problems with many applications. The Euclidean algorithm is the oldest and usual technique for computing GCD. However, the GCD computation problem is ill-posed, particularly when some unknown noise is applied to the polyno- mial coefficients. Since the Euclidean algorithm is unstable, new methods have been extensively studied in recent years. Methods based on the numerical rank estimation represent one group of current meth- ods. Their disadvantage is that the numerical rank cannot be computed reliably due to the sensitivity of singular values on noise. The aim of the work is to overcome the ill-posed sensitivity of GCD computation in the presence of noise. Keywords: AGCD, Sylvester matrix, numerical rank, TLS
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Analýza výpočtu největšího společného dělitele polynomů
Kuřátko, Jan ; Zítko, Jan (advisor) ; Janovský, Vladimír (referee)
In this work, the analysis of the computation of the greatest common divisor of univariate and bivariate polynomials is presented. The whole process is split into three stages. In the first stage, data preprocessing is explained and the resulting better numerical behavior is demonstrated. Next stage is concerned with the problem of the computation of the numerical rank of the Sylvester matrix, from which the degree of the greatest common divisor is obtained. The last stage is the actual algorithm for calculating the greatest common divisor of two polynomials. Furthermore, the underlying theory behind the computation of the greatest common divisor is explained and illustrated on many examples. 1
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