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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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Molecular modeling study of potential mycobacterial enoyl-reductase inhibitors
Slovák, František ; Holas, Ondřej (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Diplomate: František Slovák Supervisor: PharmDr. Ondřej Holas, Ph.D. Title of Diploma Thesis: Molecular modeling study of potential mycobacterial enoyl ACP reductase inhibitors. Tuberculosis is a worldwide spread infectious disease. The biggest problem of our time are completely and multi resistant strains of Mycobacterium tuberculosis that do not respond to currently known drugs. The main reason for high resistance and drug resistance is a bacillus composition of its cell wall. It contains a high proportion of mycolic acids. The synthesis of mycolic acids takes several steps. The final step is a catalytic reduction by enzyme enoyl - ACP reductase ( InhA ). This work was focused on finding new potential substances that would be able to inhibit this enzyme. There were used methods of computing and molecular modeling to search these substances. Adjusting of crystallographic structures ran in the program Maestro and docking in the MOE program. Over the 30 000 thousand molecules from the ZND (Zinc Natural Derivates) were tested by molecular docking on 3 crystallographic structures of InhA enzyme. 8 of these molecules were selected from this amount because their...
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Synthesis of arylsufanyl phthalocyanines and their aza-analogues
Málková, Anna ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
8 3. ABSTRACT Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Anna Málková Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Title of Thesis: Synthesis of arylsulfanyl phthalocyanines and their aza-analogues. Phthalocyanines (Pcs) and their aza-analogues (AzaPc), chemical substances used in photodynamic therapy, are characterized by interesting photophysical properties which may substantially vary in dependence on the character of peripheral substituents. For example, sum of singlet oxygen and fluorescence quantum yields reaches typically a value of 1 for Mg and Zn complexes while is significantly decreased for metal-free derivatives. It has been suggested from several previous experiments that this effect can be influenced by bulkiness of the peripheral substituents. The aim of this work was the synthesis of bulky 2,6-diphenylphenylsulfanyl substituted Pcs and AzaPcs with subsequent study of their photophysical properties. The synthesis started from 2,6-diphenylphenol, a commercially available substance, which was converted to corresponding O-carbamothioate with dimethylcarbamoylchloride. Isomeric S-carbamothioate was prepared using Newman-Kwart rearrangement at high temperatures and then reduced to corresponding...
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Transformace Sylvestrovy matice a výpočet největšího společného dělitele dvou polynomů
Eckstein, Jiří ; Zítko, Jan (advisor) ; Tůma, Miroslav (referee)
In this thesis we study the computation of the greatest common divisor of two polynomials. Firstly, properties of Sylvester matrices are considered as well as their role in computation. We then note, that this approach can be naturally generalized for several polynomials. In the penultimate section, Bézout matrices are studied as an analogy to the Sylvester ones, providing necessary comparison. Extension for more than polynomials is presented here as well. Algorithms corresponding to the individual approaches are presented as well. Finally, the algorithms are implemented in MATLAB and are compared in numerical experiments. Powered by TCPDF (www.tcpdf.org)
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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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