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Toward new analogues of vitamin E: new potential inhibitors of 5-lipoxygenase
Štůsková, Martina ; Tůmová, Lenka (advisor) ; Doležal, Martin (referee)
Many studies highlighted the biological potential of vitamin E, especially tocotrienols (T3), a vitamin E subfamily, particularly in the field of cardiovascular diseases and chronic inflammation. A pharmacophore based virtual screening of these substances against various antiinflammatory targets showed that this class could be considered as potential inhibitors of 5- lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. Consequently, this screening was confirmed by in vitro assays. However, usual natural sources of T3 provide complex mixtures involving particularly challenging purification processes. Thus, this work aims at designing and optimizing efficient semisynthesis towards pharmacologically relevant T3 derivatives were developed from δ- tocotrienol, the main T3 isolated from Bixa orellana seeds, a renewable and easily available vegetal source from tropical regions, analyzed mainly by HPLC chromatography. Verification of the most effective reaction conditions of semisynthesis and synthesis another potential inhibitors of 5-LOX based on tocotrienols' structure are the following aims of the work. During this study, the semisynthesis based on δ-tocotrienol was completely optimized and 3 new T3 derivatives were synthesized and fully characterized....
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Commented translation of a text on science and technology
Doležal, Martin ; Smutný, Milan (referee) ; Krhutová, Milena (advisor)
Tato bakalářská práce se zabývá používáním technického jazyka v češtině i angličtině, v čem si jsou tyto jazyky podobné a v čem se naopak liší. Pro studování jazyků v elektrotechnice byl vybrán technicky zaměřený text k přeložení a poté byl přeložen do angličtiny. Po překladu byla provedena analýza jazyka, které se zaměřovala jak na lingvistické, tak extralingvistické vlastnosti, které jsou často specifické pro odborné texty. Tyto vlastnosti pokrývají širokou škálu lingvistických oborů, jako jsou například lexikologie, morfologie, stylistika, syntax, ale i extralingvistické záležitosti, jako třeba pragmatika. Analýza originálního a přeloženého textu odhalila spoustu rozdílů, jak malých, tak i velkých, které jsou výsledkem pokusu o přenos informace v jazyce, který je poměrně rozdílný oproti originálnímu jazyku.
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Propargyltacrines - acetylcholinesterase inhibitors with anti-MAO activity
Nemčíková, Lenka ; Kučerová, Marta (advisor) ; Doležal, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Lenka Nemčíková Supervisor: PharmDr. Marta Kučerová, Ph.D. Title of Thesis: Propargyltacrines - acetylcholinesterase inhibitors with anti-MAO activity Alzheimer's disease (AD) is a serious neurodegenerative disorder that affects mainly aged people. Neurodegenerative disorders lead to dementia. However, dementia is not a part of normal aging. It is the result of pathologigal process. Alois Alzheimer was the first who described AD. The causes of this disease are not clear, however partial pathological mechanisms and the risk factors are known. There is no drug for casual treatment of AD. Nowadays, we can only slow down the symptoms or development of dementia by combining pharmacological and non-pharmacological techniques. Such approach could improve the quality of life of affected people. The treatment of AD involves acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptor antagonist (NMDA). Donepezil, rivastigmine and galantamine belong to AChE inhibitors. Decrease in AChE activity leads to balance in acetylcholine transmission, which is disturbed in early stages of the disease. Tacrine was the first drug launched on the market for the treatment of...
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Pyrazine derivatives as potential drugs V.
Mindlová, Alžběta ; Doležal, Martin (advisor) ; Kučerová, Marta (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Author: Alžběta Mindlová Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Title of diploma thesis: Pyrazine Derivatives as Potential Drugs V This study deals with the issue of tuberculosis, which is a second leading cause of deaths after HIV from all infectious diseases worldwide. This is supported by an ever increasing number of mycobacteria, which is resistant to conventional antituberculotics. Because of grow of the multidrug-resistant tuberculosis, there is need for the development of new drugs in the therapy of this disease. The design of final compounds was based on the previously prepared pyrazine-2- carboxilic acid, which exerted antituberculotic activity. The object of study was to verify the effectiveness of N-(pyrazine-2-yl)benzamides created by an imaginary variation of the connecting bridge between the pyrazine and benzene ring. In the experimental part of the work the synthesis of twenty three substances derived from 2-aminopyrazin or 6-chlor-2- aminopyrazin is described. All products have been described by melting point, 1 H, 13 C NMR, IR spectroscopy and the elementary analysis. The substances were send for the biological evaluation, where were tested for...
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Definition of the carbohydrate binding capacities of the novel enterotoxin LT-IIc
Juhás, Martin ; Doležal, Martin (advisor) ; Jirkovská, Anna (referee)
Diarrhoea as a disease is still the leading cause of malnutrition and a major cause of deaths in children under 5 years of age in the low-income countries. Additionally, it is the most common health problem associated with travelling to the developing countries. In all the mentioned cases, enterotoxigenic E. coli (ETEC) is one of the most frequent causes. ETEC is defined as a pathogenic strain of E. coli producing enterotoxins. So far, two types of enterotoxins have been identified: heat-stable (ST) and heat-labile (LT). LTs are further divided into two categories based on their relatedness with cholera toxin to type I (LT-I) and type II (LT-II). All of these enterotoxins have been found to bind to carbohydrate structures on glycosphingolipids by their respective B subunits, however, their binding patterns differ. While LT-I, LT-IIa and LT-IIb have been previously studied in terms of binding specificities, the newest LT-IIc was tested only on few commercially available ganglio-series gangliosides. In this thesis, the binding capabilities of this novel enterotoxin were re-examined by series of binding assays using more ganglio-series and some neolacto-series gangliosides as well as other glycolipids and glycoproteins, to establish the basics of the recognition pattern and to characterize the optimal...
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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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Synthesis and antiinfective evaluation of substituted N-(pyrazin-2-yl)benzenesulfonamides
Paredes De La Red, Cristina ; Doležal, Martin (advisor) ; Kučerová, Marta (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Cristina Paredes de la Red Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Title of diploma thesis: Synthesis and antiinfective evaluation of substituted N-(pyrazine-2- yl)benzenesulfonamide Tuberculosis (TB) is among the ten leading causes of death, especially in developing countries. Even though it is an old disease with established treatment regimen, there has been an increased resistance to anti-TB drugs 1 . The anti-tubercular pyrazinamide has caught the attention of researchers as the different theories for its mechanism of action have made it an interesting entity for further investigation. Here we will discuss N-(pyrazine-2-yl)benzenesulfonamides (General structure is presented in the Figure below) as a new derivatization approach based on synergism methodology between pyrazinamide and sulfonamides. Sulfonamides exert their antimicrobial effect by competitive inhibition of folic acid synthesis and subsequent inhibition of bacterial growth and reproduction 18 . I have contributed to the synthesis and purification of 8 compounds in a series of total 22 N- pyrazinylsulfonamides. Two of the prepared compounds showed activity against Mycobacterium kansasii [2a (MIC...
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Definition of the carbohydrate binding capacities of the novel enterotoxin LT-IIc
Juhás, Martin ; Doležal, Martin (advisor) ; Jirkovská, Anna (referee)
Diarrhoea as a disease is still the leading cause of malnutrition and a major cause of deaths in children under 5 years of age in the low-income countries. Additionally, it is the most common health problem associated with travelling to the developing countries. In all the mentioned cases, enterotoxigenic E. coli (ETEC) is one of the most frequent causes. ETEC is defined as a pathogenic strain of E. coli producing enterotoxins. So far, two types of enterotoxins have been identified: heat-stable (ST) and heat-labile (LT). LTs are further divided into two categories based on their relatedness with cholera toxin to type I (LT-I) and type II (LT-II). All of these enterotoxins have been found to bind to carbohydrate structures on glycosphingolipids by their respective B subunits, however, their binding patterns differ. While LT-I, LT-IIa and LT-IIb have been previously studied in terms of binding specificities, the newest LT-IIc was tested only on few commercially available ganglio-series gangliosides. In this thesis, the binding capabilities of this novel enterotoxin were re-examined by series of binding assays using more ganglio-series and some neolacto-series gangliosides as well as other glycolipids and glycoproteins, to establish the basics of the recognition pattern and to characterize the optimal...
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Pyrazine derivatives as potential drugs I.
Niklová, Pavlína ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Pavlína Niklová Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Title of diploma thesis: Pyrazine Derivatives as Potential Drugs I. Tuberculosis is serious global problem especially due to its fast resistance development to currently used drugs. Therefore drugs used in therapy are only used in combinations to avoid any possible complications due to treatment failure. In addition, global research is focused on finding new potentially successful drugs with sufficient activity against Mycobacterium tuberculosis, main cause of the disease, and acceptable safety, therefore suitable for use in TBC therapy. Research conducted at the Department of Pharmaceutical Chemistry and Pharmaceutical Analysis of Faculty of Pharmacy in Hradec Kralove, Charles University is focused on the synthesis of potential new antituberculotics, especially pyrazine derivatives. This study deals with the synthesis of five aminopyrazine derivatives by the reaction of aminopyrazine with different alkyl substituted isocyanates using microwave reactor. All of the synthesized compounds were characterized by their melting point, elementar analysis, IR spectra and NMR spectra and then tested in vitro for...
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Propargyltacrines - acetylcholinesterase inhibitors with anti-MAO activity
Nemčíková, Lenka ; Kučerová, Marta (advisor) ; Doležal, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Lenka Nemčíková Supervisor: PharmDr. Marta Kučerová, Ph.D. Title of Thesis: Propargyltacrines - acetylcholinesterase inhibitors with anti-MAO activity Alzheimer's disease (AD) is a serious neurodegenerative disorder that affects mainly aged people. Neurodegenerative disorders lead to dementia. However, dementia is not a part of normal aging. It is the result of pathologigal process. Alois Alzheimer was the first who described AD. The causes of this disease are not clear, however partial pathological mechanisms and the risk factors are known. There is no drug for casual treatment of AD. Nowadays, we can only slow down the symptoms or development of dementia by combining pharmacological and non-pharmacological techniques. Such approach could improve the quality of life of affected people. The treatment of AD involves acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptor antagonist (NMDA). Donepezil, rivastigmine and galantamine belong to AChE inhibitors. Decrease in AChE activity leads to balance in acetylcholine transmission, which is disturbed in early stages of the disease. Tacrine was the first drug launched on the market for the treatment of...
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