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Enzyme tests with immobilized acetycholinesterase for the anti-Alzheimer's disease drugs characterization
Dulinová, Miriama ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical chemistry and drug control Consultant: prof. PharmDr. Martin Doležal, Ph.D. Supervisor specialist: pplk. prof. RNDr. Miroslav Pohanka, Ph.D., DSc. Student: Miriama Dulinová Title of diploma Thesis: Enzyme assays with bound cholinesterase to characterize drugs for Alzheimer's disease. Alzheimer's disease is a progressive and irreversible neurodegenerative brain disease, which is globally connected with the most common cause of dementia. The pathophysiology of the disease is not yet fully understood. Treatment of this disease is for the time being only symptomatic and is represented by inhibitors of the acetylcholinesterase. The acetylcholinesterase inhibitors are at present practically the only active substances that mitigate the effects of the Alzheimer's disease. In this thesis, we have investigated the ability to inhibit already known AChE inhibitors (rivastigmine, donepezil, galantamine, tacrine), that have been tested for their activity. We tested the effectiveness of the inhibitors with loose acetylcholinesterase (via the reference method) and subsequently with the immobilised acetylcholinesterase in clear gelatine, but also with added netted agents. (glutaraldehyd, EDC). For the purposes of our...
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Sulfonated azaphthalocyanines - synthesis and evaluation of their photodynamic activity
Jančárová, Alena ; Zimčík, Petr (advisor) ; Doležal, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Alena Jančárová Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Co-supervisor: RNDr. Miloslav Macháček, Ph.D. Title of diploma thesis: Sulfonated azaphthalocyanines - synthesis and evaluation of their photodynamic activity Photodynamic therapy is one of the methods used for destruction of undesirable cells. It combines three essentially nontoxic components: light, oxygen and a photosensitizer. Azaphthalocyanines (AzaPcs) are promising compounds with photosensitizing properties. However, their major disadvantage is their low water solubility and significant aggregation that decreases their photodynamic activity. The aim of this work was to synthesize an anionic derivative of AzaPc substituted with sulfonic groups on periphery characterized by good solubility in water and to evaluate its photodynamic properties. The first step in the synthesis was condensation of diaminomaleonitrile with benzil giving 5,6-diphenylpyrazine-2,3-dicarbonitrile. Subsequently, the cyclotetramerisation with zinc acetate in 2-dimethylaminoethanol as a solvent was performed. The final product was obtained by sulfonation with chlorosulfonic acid followed by hydrolysis with sodium hydrogen carbonate....
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Role of Plea Bargaining in the USA
Doležal, Martin ; Gřivna, Tomáš (advisor) ; Bohuslav, Lukáš (referee)
Role of Plea Bargainingin the US The aim of this thesis is to explain to the reader the term Plea Bargaining, to explain the principles of this legal institute and its role in the penal system of the United States of America. The Author does not only describe the Plea Bargaining, but also analyses the institute thoroughly, accenting its positive and negative aspects, considering the point of view of the particular participants of the process. Last but not least, the thesis contains the author's critical evaluation. The institute of Plea Bargaining appears in the common law system from the second half of the nineteenth century, while evincing a quantitative growth in the long term. Currently, it is being used in the absolute majority of penal proceedings, and a change in this trend can in no way be expected in the closest future - therefore, this institute shall be considered as absolutely indispensable for the law of the United States of America. Despite its wide use, its application also gives rise to negative emotions. Relatively often, there are opinions appearing, questioning its legitimacy and legality, for Plea Bargaining is not regulated in the statute law and is not only directly contrary to the Constitution of the United States of America, but also to multiple international treaties on...
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Studies on glycosphingolipids as immune targets in bioprosthetic heart valves
Jansa, Petr ; Doležal, Martin (advisor) ; Jirkovská, Anna (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate: Petr Jansa Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Supervisor - specialist: prof. Susann Teneberg, M.D., Ph.D. Title: Studies on glycosphingolipids as immune targets in bioprosthetic heart valves The treatment of valvular heart disease represents approximately 20% of all cardiac surgery. One alternative of this treatment is replacement of diseased valve with bioprosthetic heart valves (BHV). These BHV are manufactured from divergent human or animal tissues e.g. porcine pericardium. Although this treatment is beneficial for certain groups of patients, it is susceptible to some complications such as rejection of the xenograft or early BHV deterioration. In both of them the immune system is involved and both might result in BHV failure. This study aims to isolate and characterize important targets of this immune response - glycosphingolipids (GSL). Therefore, 8 non-acidic and 7 acidic GSL from porcine pericardium have been isolated and characterized by mass spectrometry and carbohydrate binding assays. The acidic GSL from goat erythrocytes have been isolated and characterized. Notable is characterization of a new NeuGc-containing GSL - NeuGc-GT1b ganglioside....
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Synthesis and study of photophysical and photochemical properties of phthalocyanines and azaphthalocyanines
Váchová, Lenka ; Zimčík, Petr (advisor) ; Doležal, Martin (referee) ; Imramovský, Aleš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Mgr. Lenka Váchová Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Title of the doctoral thesis:Synthesis and study of photophysical and photochemical properties of phthalocyanines and azaphthalocyanines Phthalocyanines (Pc) and their aza-analogs azaphthalocyanines (AzaPc) are planar macrocyclic complexes derived from porphyrins with a significant absorption band in the range 620-800 nm. Due to their unique photophysical and photochemical properties, together with the high variability of macrocycle substitution, they are important representatives in the modern concepts of materials, industry, electrotechnics and medicine. They are used as photosensitizers in photodynamic therapy of cancerous and non-malignant diseases, fluorescence quenchers for molecular probe labeling in biology or drug and gene delivery agents in cellular environment. The effect of Pc and AzaPc is influenced by their structure, mainly by the character of peripheral substituents, the central chelated metal and the type of the macrocycle. In the first part of the thesis, the influence of intramolecular charge transfer (ICT) on the series of unsymmetrical tetrapyrazinoporphyrazines and...
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Methodical Approach to Evaluate the Efficiency of Road Infrastructure Construction using the PPP Projects
Doležal, Martin ; Póč, David (referee) ; Režňáková, Mária (advisor)
This diploma thesis analyses and elaborates a methodical tool for evaluating the advantage of realization of construction of road infrastructure in the form of a PPP project. Furthermore this tool is subsequent applied to a particular project. The introductory part summarizes the basic theoretical knowledge regarding the project financing in the form of public-private partnerships. In the following part, a methodological tool for comparing the value for money based on different methods of realization. In the last part of the diploma thesis, this methodical tool is applied to a specific project, including a basic feasibility study.
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Preparation of Pyrazinamide Derivatives as Potential Antituberculotics (Study of Structure Activity Relationships)
Semelková, Lucia ; Doležal, Martin (advisor) ; Malík, Ivan (referee) ; Nencka, Radim (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Mgr. Lucia Semelková Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Consultant: PharmDr. Jan Zitko, Ph.D. Title of Doctoral Thesis: Preparation of Pyrazinamide Derivatives as Potential Antituberculotics (Study of Structure Activity Relationships) This doctoral thesis is focused on search for novel pyrazinamide derivatives with potential antitubercular activity. The theoretical part summarizes issues connected with tuberculosis and its epidemiological situation along with factors (resistance and HIV co- infection) that complicate treatment of tuberculosis. A brief overview of antitubercular drugs used in current therapeutic regimens of tuberculosis is outlined. A single chapter is dedicated to pyrazinamide, which belongs to the first-line antitubercular drugs, and its possible mechanisms of action. The last part is focused on potential enzymatic targets of pyrazinamide derivatives. The practical part describes synthesis and biological evaluation of 112 pyrazinamide derivatives with modifications in amide moiety and position 3 on the pyrazine ring. First two series were derived from N-substituted 3-chloropyrazine-2-carboxamides, the third series...
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Design and Synthesis of Hybrid Compounds Based on Tacrin/Resveratrol Derivatives
Jeřábek, Jakub ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...
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Preparation of Pyrazinamide Derivatives as Potential Antituberculotics (Study of Structure Activity Relationships)
Semelková, Lucia ; Doležal, Martin (advisor) ; Malík, Ivan (referee) ; Nencka, Radim (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Mgr. Lucia Semelková Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Consultant: PharmDr. Jan Zitko, Ph.D. Title of Doctoral Thesis: Preparation of Pyrazinamide Derivatives as Potential Antituberculotics (Study of Structure Activity Relationships) This doctoral thesis is focused on search for novel pyrazinamide derivatives with potential antitubercular activity. The theoretical part summarizes issues connected with tuberculosis and its epidemiological situation along with factors (resistance and HIV co- infection) that complicate treatment of tuberculosis. A brief overview of antitubercular drugs used in current therapeutic regimens of tuberculosis is outlined. A single chapter is dedicated to pyrazinamide, which belongs to the first-line antitubercular drugs, and its possible mechanisms of action. The last part is focused on potential enzymatic targets of pyrazinamide derivatives. The practical part describes synthesis and biological evaluation of 112 pyrazinamide derivatives with modifications in amide moiety and position 3 on the pyrazine ring. First two series were derived from N-substituted 3-chloropyrazine-2-carboxamides, the third series...
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Synthesis and study of photophysical and photochemical properties of phthalocyanines and azaphthalocyanines
Váchová, Lenka ; Zimčík, Petr (advisor) ; Doležal, Martin (referee) ; Imramovský, Aleš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Mgr. Lenka Váchová Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Title of the doctoral thesis:Synthesis and study of photophysical and photochemical properties of phthalocyanines and azaphthalocyanines Phthalocyanines (Pc) and their aza-analogs azaphthalocyanines (AzaPc) are planar macrocyclic complexes derived from porphyrins with a significant absorption band in the range 620-800 nm. Due to their unique photophysical and photochemical properties, together with the high variability of macrocycle substitution, they are important representatives in the modern concepts of materials, industry, electrotechnics and medicine. They are used as photosensitizers in photodynamic therapy of cancerous and non-malignant diseases, fluorescence quenchers for molecular probe labeling in biology or drug and gene delivery agents in cellular environment. The effect of Pc and AzaPc is influenced by their structure, mainly by the character of peripheral substituents, the central chelated metal and the type of the macrocycle. In the first part of the thesis, the influence of intramolecular charge transfer (ICT) on the series of unsymmetrical tetrapyrazinoporphyrazines and...
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