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Zusammenfassung. Mit Umberto Eco hat die Semiotik einen der originellsten Zeichentheoretiker und zugleich einen Zeichen-setzenden Intellektuellen verloren. Dies ist mehr als eine Metapher: Ecos Analysen zeitgenössischer Kulturphänomene gingen so weit, dass er durch sie die betreffenden Kulturen veränderte. Er nahm als einer der ersten die Popkultur des späten zwanzigsten Jahrhunderts vom Krimi bis zum Comic unter die (semiotische) Lupe und wurde damit schließlich selbst zu einem Teil der Gegenwartskultur. Glaubt man gewissen Rankings, dann war Eco, der verschmitzte Analytiker der Massenkultur, gegen Ende seines Lebens ein weltweiter Popstar der Wissenschaft wie Chomsky oder Dawkins. Der Nachruf auf Umberto Eco stellt – ausgehend von der Erstveröffentlichung einer Karikatur Ecos, die als humoristischer Kommentar zu Kommunikationstheorien gelesen werden kann – wichtige Entwicklungslinien der Semiotik Umberto Ecos vor., Zeitschrift für Semiotik, Vol 37 No 1-2 (2015): Lachen als Zeichenprozess

Summary. The present article investigates laughter in the context of laughter therapy. Laughter yoga, a technique developed in India, is based on a prolonged voluntary laughter in the group, combined with yogic breathing and stretching. According to programmatic statements of laughter yoga founder Madan Kataria, his practice can be characterized as “laughing for no reason”. This phrase became a slogan of laughter yogis, although it is not fully realistic, since this exercise program contains various elicitors of laughter and exhilaration that are interrelated with the laughter itself. Laughing is embedded in funny situations by which emotional contagion is specifically supported. Furthermore, the trainer’s laughter can function as an invitation or a request to laugh. The present article focuses on sign processes connected with laughter and deals with the following question: How can contagious laughter, invitation and request to laugh be modeled on a semiotic basis? Pantomimic laughter yoga exercises also show an interesting interplay between laughter and gestures that shall be discussed. Zusammenfassung. Der vorliegende Artikel untersucht Lachen im Kontext der Lachtherapie. Das in Indien entstandene Lachyoga beruht auf dem willkürlichen Lachen in der Gruppe, welches durch einfache Yoga-Atem- und Dehn-Übungen begleitet wird. Sein Urheber Madan Kataria hat die Technik als „Lachen ohne Grund“ charakterisiert, was zum Slogan der Lachyogis wurde. Bei genauerem Hinsehen bildet Lachyoga jedoch ein durchdachtes System von Auslösern der Erheiterung und des Lachens, in dem das Lachen selbst instrumentalisiert wird. Lachen wird in spielerische Kontexte eingebettet, wobei gezielt emotionale Ansteckung gefördert wird; außerdem fungiert das Lachen des Leiters als Einladung beziehungsweise Aufforderung zum Mitlachen. In diesem Artikel werden ansteckendes Lachen, Einladungen und Aufforderungen zum Mitlachen semiotisch modelliert. Da die meisten Lachübungen pantomimische Darstellungen von mehr oder weniger typischen Lachsituationen enthalten, bieten sie außerdem Anlass zu Überlegungen über das Verhältnis zwischen Lachen und Gesten., Zeitschrift für Semiotik, Vol 37 No 1-2 (2015): Lachen als Zeichenprozess

Summary. Introduction to the special issue “Laughing as a sign process”, Journal of Semiotics 37, 1-2 (2015). Zusammenfassung. Einführung in das Themenheft „Lachen als Zeichenprozess“, Zeitschrift für Semiotik 37, 1-2 (2015)., Zeitschrift für Semiotik, Vol 37 No 1-2 (2015): Lachen als Zeichenprozess

The bachelor thesis deals with cyberbullying in children and youth and possible preventive measures. The theoretical part deals with the concept of cyberbulling, describes the participants cyberbullying and cyberspace. It deals with preventive measures from the point of view of the school, parents and describes safe internet and non-label rules (of internet). The aim of the bachelor thesis is to map the experience of the professional public with implemented preventive measures against cyberbullying. The semi-structured interview and their evaluation using the trick method were used to achieve the goal. The research highlights to the effectiveness of preventive measures used, the lack of cooperation of experts with parents and the importance of the role of preventists in the development of information technology.

Künftige Standards wissenschaftlicher Lexikographie. Europäischer Workshop an der Berlin-Brandenburgischen Akademie der Wissenschaften in Berlin, 25.–27. März 2012 (Marco Scheider, Christiane Unger) "Bild ist Text ist Bild. Narration und Ästhetik in der Graphic Novel". Konferenz an der Universität Wien, 03.–04. Dezember 2012 (Susanne Hochreiter, Ursula Klingenböck) Emotionalität im Text. Konferenz an der Universität Ostrava, 20.–23. Februar 2013 (Ágnes Veszelszki) "Stiftungslehrstühle des BKM in Ost- und Mitteleuropa". Wissenschaftliche Tagung in Olomouc, 11. April 2013 (Veronika Opletalová) 21. Franz Werfel-Tagung "Reise und Raum. Ortsbestimmungen der österreichischen Literatur" in Wien, 26.–27. April 2013 (Zdeněk Pecka)

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Analysis Student: Markéta Kerhartová Supervisor: PharmDr. Marta Kučerová, Ph.D. Consultant: PharmDr. Jan Korábečný, Ph.D. Title of diploma thesis: Synthesis of novel hybrid molecules combining an M1 agonist and acetylcholinesterase inhibitors Alzheimer's disease (AD) is a neurodegenerative disorder of complex etiology, with insidious progression and fatal consequences. Its global incidence rates are very high, rising in line with the aging population. AD is manifested as a progressive decline of cognitive and intellectual functions. Histopathological hallmarks include the presence of β-amyloid neuritic plaques, neurofibrillary tangles composed of hyperphosphorylated τ protein and atrophy of brain tissue. Neurotransmitter levels are decreased in case of acetylcholine (ACh) while glutamate levels are elevated. Nowadays, there are two pharmacological groups employed in the treatment of AD: acetylcholinesterase inhibitors (AChEIs) and antagonist of N-methyl-D-aspartate receptors (NMDARs) - memantine. Both groups act only symptomatically, not having disease-modifying effect. The aim of our study was preparation of a series of novel hybrid molecules combining AChEIs, namely tacrine, 7-methoxytacrine...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Michaela Poledníková Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Consultant: Mgr. Martin Andrš Title of diploma thesis: Synthesis and biological evaluation of purine inhibitors of phosphatidylinositol 3-kinases and related protein kinases I. Cancer is a group of diseases characterized by the uncontrolled, abnormal growth of cells. Anticancer chemotherapy is one of the basic methods for treatment, but its mechanism of action is not specific and targets rapidly dividing cells, including cancer cells as well as certain normal tissues. In recent years one of the most studied ways to improve cancer treatment is inhibition of DNA repair mechanisms. This process can lead to potentially higher efficacy of cytotoxic therapy and thus lower doses of cytostatic agents with benefit of less adverse side effects for the patient. Suitable candidate for this purpose is family of phosphatidylinositol 3-kinase- related protein kinases (PIKK). In this diploma thesis, sixteen purine analogs of nonselective inhibitor PIKK LY294002 were prepared. We also analyzed chemo-sensitizing properties of these newly synthesized inhibitors in combination with a chemotherapeutic agent doxorubicin in...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Kateřina Vejrychová Supervizor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Consultant: Mgr. Martin Andrš Title of diploma thesis: Synthesis and biological evaluation of purine inhibitors of phosphatidylinositol-3-kinases and related protein kinases II Cancer is a serious disease with an uncertain prognosis and difficult treatment. Nowadays, cancer is one of the most common causes of death worldwide. Options of therapies are evolving every year; nevertheless, we still do not have effective treatment available for all types of tumours. Patients often undergo conventional cytotoxic therapy or radiotherapy, which unfortunately have many side effects and they are not always effective. One of the highly researched ways how to make this treatment more effective is to disrupt corrective mechanisms of DNA damage, which are the essence of radiotherapy and some chemotherapeutics. For this purpose, phosphatidylinositol-3-kinase-related proteinkinases, especially DNA-dependent proteinkinase (DNA-PK) seem to be very useful, because they are highly involved in DNA repair. In this diploma thesis, 12 potential inhibitors of DNA- PK were prepared, from which 9 substances were tested alone on 9...

Preparation and evaluation of potential drugs inhibiting mitochondrial enzymes Summary in English Alzheimer's disease (AD) is the most common cause of senile dementia worldwide. Despite being subject to intensive research, the pathogenic mechanisms of AD are still not fully understood and consequently an effective treatment is yet to be developed. Although the aetiology of AD is still unknown, a build-up of amyloid-beta peptide (Aβ) is considered to play an important role in disease progression. The original amyloid cascade hypothesis proposed that insoluble extracellular plaques were responsible for the majority of Aβ toxicity. This hypothesis has since been refined, as recent data indicates that soluble intracellular oligomers are now responsible for the majority of Aβ induced toxic effects. The mitochondrial dysfunction also plays an important role in the pathophysiology of AD. Aβ was detected inside mitochondria and several mitochondrial proteins were found to interact directly with Aβ. Such interactions can affect a protein's function and cause damage to the mitochondria, which finally results in progression of AD. The background for the experimental part of this dissertation thesis was literature review summarizing current knowledge on mitochondrial proteins directly interacting with Aβ in order to...

Charles University in Prague Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Drug Control Student: Michaela Jarošová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Consultant: PharmDr. Jan Korábečný, Ph.D. Title of thesis: Study and biological evaluation of new tacrine-tryptophan derivatives Alzheimer's disease (AD) is a chronic neurodegenerative disease with characteristic histopathological changes in the brain. It is the most common cause of dementia. There is about 7.4 million people affected by AD in Europe today. In connection with aging of the population a significant increase of patients affected by the disease can be expected in the coming years. The cause of neural tissue damage is aggregated amyloid β (Aβ), which disrupts neurons by creating glial hem with consequent inflammatory processes. Hyperphosphorylated τ-protein causes neuronal damage intracellularly by forming so-called neurofibrillary tangles. This leads to macroscopically visible brain atrophy and loss of neurons. Current AD pharmacotherapy is based on influencing the cholinergic system. Acetylcholinesterase inhibitors (AChEIs) - rivastigmine, donepezil and galanthamine are used for this purpose. Memantine, antagonist of N-methyl-D-aspartate receptors (NMDA) has been approved for the...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Lenka Richterová Consultant Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis Chalcones and their analogues as potential drugs X. Theoretical part of the thesis is devoted to current possibilities in the treatment of mycoses. Some examples of natural chalcones with antifungal properties are given, and various modifications of their structures and the influence of these modifications on antifungal activity are described. Experimental part deals with the synthesis of fluorinated (2E)-3-phenyl-1-pyrazin-2-ylprop-2-en-1-ones (Obr. 1). N N O R 1 R 2 R1 = H, tert-butyl, isobutyl, butyl, propyl R2 = 2-F, 4-F Obr. 1 Structure of the studied compounds The compounds were obtained by the Claisen-Schmidt condensation in pyridine using diethylamine as condensing agent. The syntheses yielded one compound already reported in literature and four novel analogs. The structures of the products were corroborated by means of IR a NMR spectra and their purity checked by melting point and elemental analysis. Antifungal activity of the prepared compounds was evaluated by microrodilution broth method against eight strains of pathogenic fungi. The highest potency in both...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Tutor - specialist: PharmDr. Jan Zitko, Ph.D. Candidate: Ondřej Valášek Title of diploma thesis: Pyrazine Derivatives as Potential drugs IV. Even in the year 2016, tuberculosis is still worldwide problem which is addressed by many national and supra-national organizations trying to eliminate it. It burdens the most developing countries which don't usually have the opportunity to access the potential of modern medicine to its full extent. In relation to ineffective treatment, there grows prevalence of tuberculosis, which can't be managed by standard treatment. There is an urgent need to find new compounds and change structures of current antituberculars, which will help us defeat multi-drug resistant M. tuberculosis. The objective of my work was to find out the influence of inversion of the amidic group in derivatives of pyrazin-2-carboxylic acid (-CO-NH- to -NH-CO-) and their efficacy and toxicity. In the theoretical part I focused on resuming all the basic facts about tuberculosis and its causing agent, about possibilities in prevention and diagnostics as well as the antituberculars, both used and currently tested, which can help us in the future. In the experimental part I wrote down the reactions and procedures, which were used...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Hana Leblochová Consultant Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis Preparation and testing of bisquarternary pyridinium reactivators of acetylcholinesterase Within this rigorous thesis, 21 new potential bisquarternary pyridinium AChE reactivators were prepared and their reactivation abilities on dichlorvos and paraoxon inhibited AChE were determined in vitro. Pralidoxime (2-PAM), obidoxime, asoxime (HI-6), trimedoxime (TMB-4), methoxime (MMC), K027 and K203 were used as reference compounds as they are known to be able to partially reactivate paraoxon and dichlorvos inhibited AChE. The experimental data showed that 6 compounds were able to achieve reactivation parameters recommended for in vivo testing on dichlorvos inhibited hAChE and 8 compounds on paraoxon inhibited hAChE. The compounds (9), (19), (20) and (21) seem to be very promising reactivators since they were able to reactivate hAChE inhibited by both pesticides. Based on in vitro results the structure activity relationships for newly prepared compounds were determined. Compounds having an oxime group in the 2- and 4- position to the pyridinium ring, the 1,4-phenyldimethylenyl or...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical analysis Candidate: Mgr. Jiří Binder Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Doctoral Thesis: In silico studies of cholinesterases interactions with their modulators and design of new compounds of this type Computer modeling is an important tool of contemporary scientific research. It allows to study the structure, conformation, dynamics and mutual interaction of nonbinding interactions of a biological system. The main objective is to find the best energy conformations by minimizing the energy of the system. On the base of these calculated values, one can predict the loss of activity for certain analogous compounds, thus reducing the number of materials that would be needed to subsequently synthesize. A molecular modeling contributes to describe the interactions of ligands with larger systems and improves the orientation in millions of active substances that could be used as potential drug. It becomes an important part of the pharmaceutical industry. The aim of this study was to verify the selected methodology of computer prediction of protein-ligand complexes, to obtain a description of the basic interactions of the modulators of cholinesterase...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Ngoc Lam Pham Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Thesis Title: Synthesis of novel blebbistatin derivatives as myosin inhibitors Myosins constitute a large and diverse superfamily of ATP-dependent motor proteins responsible for actin-based motility. Currently, based on phylogenetic analyses, myosins are classified into at least twenty four groups. The members of this superfamily are involved in several cell processes such as muscle contraction, cytokinesis, organelle transport, cell polarization and signal transduction. Thus, dysfunction and mutation of myosins can cause several diseases. Therefore, design of myosin inhibitors seems to be very attractive research field from the point of view of characterization of intracellular processes as well as development of novel targeted therapy against diseases implicating myosin dysfunction. Nowadays, one of the most well-known and widely used inhibitors of myosin is (S)-blebbistatin. This inhibitor of myosin II has many advantages, nevertheless it possesses also several limiting factors impeding the biological studies such as photosensitivity and low solubility in water. The aim of this Thesis was to...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jan Král Supervisor: doc. RNDr. Veronika Opletalová, Ph.D. Consultant: PharmDr. Jan Korábečný, Ph.D. Title of diploma thesis: Synthesis and biological evaluation of tacrine-amantadine derivatives Alzheimer's disease (AD) is a fatal neurodegenerative disorder of brain. Nowadays there is only paliative treatment available, which can be further subdivided into two groups: acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist. Donepezil, rivastigmine and galantamine represents AChEIs currently available for AD treatment. Tacrine is the first AChEIs to be approved for AD treatment, however, it was withdrawn from the market due to its side effects, especially due to its hepatotoxicity. 7-Methoxytacrine (7-MEOTA) is less toxic tacrine derivative preserving pharmacological profile of tacrine. This diploma thesis describes synthesis of multifunctional 7-MEOTA- amantadine derivatives as potential drugs to confront AD. Using Ellmanʼs method, we have established their efficacy to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. All new synthesized hybrids from 7-MEOTA- amantadine family proved to be better...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Tadeáš Pešek Supervisor: PharmDr. Marta Kučerová, Ph.D., Charles University in Prague, Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Thesis Title: Design and synthesis of rutaecarpine analogs as potential cytotoxic agents for cancer chemotherapy treatment Cancer is a progressive multifactorial collection of diseases that causes disorders and decreases quality of life of patients and in some cases results in death. Cancer can affect people of all ages, sexes and races and can be diagnosed in tissues of whole body. It is the second leading cause of death in the world after cardiovascular disorders. There are many ways how to treat cancer and they variy with each type of cancer. Nowadays treatment of cancer is based on surgery, chemotherapy, radiotherapy, biological treatment, immunotherapy and hormonal therapy. Chemotherapy represents the basis of cancer cure and is often used in combination with other approaches for tumour treatment and maximal effect of therapy and to prevent and cure metastases. Chemotherapy consists of cytotoxic agents that induce apoptosis by various pathways. These drugs interfere with cell cycle of all body cells but, in...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Emmanouil Lioudakis Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Diploma Thesis: Current trends in the development of steroidal hormone modulators Steroidal hormone modulators are considered to be both effective and vital agents concerning the treatment of various types of cancer, as well as playing a crucial role in the regulation of a wide range of physiological actions. Since the development of the very first modulators, a significant progress has been made regarding the development of new ones with limited adverse effects. The current thesis provides information concerning older drugs and recent data about them. In addition, new drugs which are under clinical trials are described and their structures are referred. New drugs have been developed in order to be safer and more efficient than older ones. A lot of promising agents which are considered as a successful alternative treatment and carry less risk are either already approved or will be accepted in the near future.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Konstantinos Kolotsios Consultant: Assoc. Prof. PharmDr. Miroslav Miletin, Ph.D. Title of Thesis: Literature review in field of blood clotting influencing drugs From 1919, when the heparin and 1920's, when hydroxycoumarin, were isolated, many important steps in agents affecting blood clotting have been done. All these years until now, several agents were tested and used for prevention and treatment of thromboembolism and other conditions like deep vein thrombosis, acute coronary syndrome and others. This thesis is a review of agents that influence blood clotting. The first two chapters, are to understand the pathways that are activated after an injured blood vessel wall and all these enzymes, factors and receptors that play a crucial role in formation of clots. On third chapter, all agents, old, current, discontinued, or under development are analyzed according to their mechanism of action. Many agents are used in our days with great efficacy and safety, but also with important side effects. A lot of agents are under investigation for better safety, quality and efficacy. It is important to develop the ideal agent and many scientists try to overcome this challenge nowadays.

Charles University in Prague Faculty of Pharmacy Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Kateřina Babková Supervisor: Assoc. Prof. Veronika Opletalová, Ph. D. Specialized supervisor: Janne Weisell, Ph. D. Title of diploma thesis: Microorganism based polyamines. Detection of prostate cancer Prostate cancer is the most prevalent type of solid malignant tumour among men and the second highest cause of cancer related mortality of men after lung cancer. Every year the number of new cases is growing. To prevent this disease it is important to think about a healthy lifestyle and not to underestimate regular health checks because prevention and early diagnosis can bring better therapy results. Among others, prostate cancer can be diagnosed from urine samples. Increased levels of polyamines are the sign that something is wrong. Polyamines are ubiquitous in living mammalian cell, their metabolic pathways are still not clarified in depth but if a problem appears in their metabolism (for example enzyme overproducing, higher levels of any polyamine metabolite) it won't mean anything good. The aim of my work was to synthesize natural polyamines and their analogues which are produced by microorganism causing urinal infections of patients. Their metabolic end product can...

Substances which can bind selectively to the DNA structures and modify its' functions are in the center of study of many researchers for several decades. A place of their action is the minor groove of DNA. Distamycin A, netropsin, Hoechst 33258 and many other compounds are substances with a potential to interact with DNA sequences, especially with A T base pairs rich ones. My thesis is focused on searching and synthesizing of molecules structurally and functionally similar to compounds mentioned above. In order to find the structure with required properties as well as the method for the synthesis, screening by preparation of various compounds has been made. Each synthesis was performed using various methods confirming that the methodology is not entirely uniform. Common required result of each synthesis was preparation of final compound in a water soluble salt. Many partial reactions were not always successful, but necessary for terminal synthesis of required compounds. Syntheses of four compounds were successful, which were tested by molecular biology methods for increasing the melting temperature. The performed tests have shown low activity of the prepared compounds. N,N'-(1,3-phenylenebis(methylene))bis(4- ((diaminomethylene)amino)-1-methyl-1H-pyrrole-2-carboxamide) seems to be the most...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Zach Jaroslav Supervisor: Doc. RNDr. Veronika Opletalová, Ph. D. Title of Diploma Thesis: Cationic antimicrobial peptides as potential drugs With the rapid rise in the emergence of bacterial strains resistant to multiple classes of antimicrobial agents, there is an urgent to need to develop novel antimicrobial therapies to combat these pathogens. Antimicrobial peptides (AMPs) are small, predominantly cationic ribosomally synthesized peptides, which permealize biological membranes. The assets of these peptides in clinical application include their potential for broad-spectrum activity, rapid bactericidal activity and low propensity for resistance development. This article is focused on history, mechanism of action and types of peptides that are produced by various organisms. Given the extensive topic only cationic antimicrobial peptides are discussed.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Pavla ábelová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Supervisor specialist: PharmDr. Jan Korábe ný, Ph.D. Title of diploma thesis: Synthesis, biological evaluation and in silico studies in the series of novel 7-methoxytacrine-donepezile like compounds Alzheimer's disease (AD) is an irreversible neurodegenerative disorder of the brain characterized clinically by loss of memory, deterioration of activities of daily living and cognition. The pathological hallmarks of AD include neuritic plaques composed of extracellularly stored fibrils of amyloid- peptide, intracellular deposits of hyperphosphorylated tau and neurotransmitter deficits. The aim of the study was to design and synthesize 7-methoxytacrine-donepezil-like compounds as potential inhibitors of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8). New compounds consist of 7-methoxytacrine representing less toxic derivative of tacrine and benzylpiperazine moiety corresponding to donepezil fragment. To determine the potential of new derivatives, AChE and BChE inhibitory activities of the new molecules were assessed in vitro according to the method of Ellman et al....

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Mgr. Oto Drobík Consultant Assoc. Prof. Veronika Opletalová, Ph.D. Title of Thesis Colorimetric assay based on immobilized acetylcholinesterase for the determination of efficiency of inhibitors used in pharmacotherapy. There is a large number of substances belonging to acetylcholinesterase (AChE) inhibitors that are used in agriculture, for example as insecticides or pesticides. They are also used as nerve paralytic agents for military purposes. Some of them have been applied in treatment of diseases such as myasthenia gravis or Alzheimer's disease. Within the thesis, AChE was successfully immobilized on the bottom of a 96 well microplate, using gelatine. By means of a colorimetric method, the reaction conditions were optimized; the resistance of the immobilized AChE against the washout was also tested. Furthermore, an inhibition rate of AChE by solvents was determined and kinetic parameters of an enzymatic reaction were evaluated. Tacrine and pyridostigmine were tested as representatives of AChE inhibitors. A long-term stability test of the immobilized AChE was further performed. The results that have been achieved indicate that the method described is...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Analysis Student: Ondřej Tomek Supervisor: PharmDr. Kamil Kopecký, Ph.D. Title of diploma thesis: Synthesis of alkylaminoderivates of phthalocyanines The aim of my diploma thesis was the synthesis and the characterization of phthalocyanine alkylaminoderivates and the comparison of their photophysical and photochemical properties with similarly substituted azaphthalocyanines. I start with the synthesis of dialkylaminodichlorophthalonitrile by the substitution of tetrachlorophthalonitrile. Then I use these derivates of tetrachlorophthalonitrile for cyclotetramerization reaction. As a result of my work, I received only diethylaminosubstituted phthalocyanines with undesirable butoxy-substituents. I was not successful in the preparation of phthalocyanines substituted with cyclic amines by the used methods. The prepared compounds were characterized by using the standard spectral methods (UV-VIS, IR, 1 H NMR, 13 C NMR, mass spectra).

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Olga Ioannidou Consultant: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Current trends in the development of antiviral drugs Since the introduction of the first antiviral drug, a great progress has been made. Every year, many substances are tested for their activity against a wide range of viruses. Especially for serious diseases, like AIDS and hepatitis C, the need for safer and more effective drugs is increased. In the first part of the thesis older, but still important drugs are described and also their structures are given. Some of them have a wide spectrum of activity, such as ribavirin, which is used for the treatment of both hepatitis C and viral hemorrhagic fever. In the second part, newly developed drugs and drugs that are under clinical trials are discussed. New drugs have greater efficacy and fewer side effects. Nevertheless, there are some viral diseases that could not be managed with drugs and must be prevented by vaccines. To overcome all difficulties and develop both new drugs and vaccines remains a great challenge for the scientists

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Jana Heczková Consultant Doc. RNDr. Veronika Opletalová, Ph.D. Title of Thesis Acetylpyrazin-thiosemicarbazone analogues as potential drugs In the theoretical part of this thesis new findings on antifungal and antibacterial effects of thiosemicarbazones published in 2005 - 2012 were described. Thiosemicarbazones have a very broad range of antimicrobial activity, their effects are in many cases comparable or even better than already used pharmaceuticals. In the experimental part, the preparation procedures of thiosemicarbazones were described and following 7 compounds were prepared:  (2E)-2-[1-(pyridine-2-yl)ethylidene]hydrazinecarbothioamide  (2E)-2-[1-(pyridine-3-yl)ethylidene]hydrazinecarbothioamide  (2E)-2-[1-(pyridine-4-yl)ethylidene]hydrazinecarbothioamide  (2E)-2-[1-(2-hydroxyphenyl)ethylidene]hydrazinecarbothioamide  (2E)-2-(2-hydroxybenzylidene)hydrazinecarbothioamide  (2E)-2-[1-(2-hydroxyphenyl)ethylidene]-N,N-dimethylhydrazinecarbothioamide  (2E)-2-(2-hydroxybenzylidene)-N,N-dimethylhydrazinecarbothioamide All prepared thiosemicarbazones were characterized by melting point, IR and NMR spectra. Purity was verified by elemental analysis. The...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Eugenie Nepovimová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Design and synthesis of tacrine-quinone hybrids as multi-target ligands against Alzheimer's disease Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder that manifests as memory loss, personality changes, global cognitive dysfunction, and functional impairment. It is the leading cause of dementia in aged humans. Nowadays, there are no effective preventative measures, definitive diagnostic guidlines, or curative therapy for AD, its precise ethiology, too, remains unknown. To date, the pharmacotherapy of AD has relied on acetylcholinesterase (AChE) inhibitors - donepezil, rivastigmine and galantamine - and, more recently, on an N-methyl-D- aspartate (NMDA) receptor antagonist - memantine. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting AChE which hydrolyses acetylcholine. Furthermore, it has been demonstrated that AChE plays an important role in Aβ-aggregation during the early stages of senile plaque formation, one of the hallmarks of AD. Therefore, AChE inhibition represents a critical target for the effective...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Jan Doležel Supervisor Doc. RNDr. Veronika Opletalová, Ph.D. Title of Doctoral Thesis Derivatives of thiazole as potential drugs The doctoral thesis is focused on preparation of thiazole derivatives. Sixty seven compounds were prepared, thirty one of them are original. Structure-activity relationships between the chemical structure, physical properties and biological activities of the evaluated compounds are discussed. First from five series were 5-benzylidenerhodanine derivatives and 5-hetarylmethylidenerhodanine derivative. Compounds were gained by Knovenagel condensation of rhodanine with aromatic or heterocyclic aldehydes. At the same time the earlier prepared condensation product of rhodanine and ketones derived mainly from substituted acetylpyrazines were further tested for biological properties. The next part was given to the preparation of condensation products of N-substituted rhodanine with aromatic and heterocyclic aldehydes or ketones. Last series of compounds are of 5-(1-hetarylalkylidene)hydrazonothiazolidine-4-one derivatives prepared by cyclization of analogous thiosemicarbazones. The prepared compounds were evaluated for their antifungal and...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Petra Vavrošová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of thesis: Modulation of acetylcholinesterase activity using different organic compounds Acetylcholinesterase is a vital enzyme because of its ability to end a nerve impulse by decomposition of neurotransmitter acetylcholin. Inhibitors of cholinesterases have been used in many sectors, such as drugs, pesticides, or substances abused as biological weapons. Using chosen agents an existence of acetylcholinesterase inhibition was detected together with its rate and character. The detection was accomplished by the method of measuring the decrease of acetylcholinesterase activity. In this experiment some organic solvents, metal salts, and other agents like gelatine, tacrine or caffeine were used. Ellman's spectrophotometrical detection was used to determine the decrease of acetylcholinesterase activity. The data were evaluated by the graphical representation by Dixon and Boltzmann. In this experiment the acetylcholinesterase from electric eel was used. Results showed that many chosen agents have the ability to inhibit acetylcholinesterase and on the other hand many of them do not have this...

Synthesis and in vitro evaluation of bispyridinium type acetylcholinesterase inhibitors Michal Kočí Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec Králové, Charles University in Praze ABSTRACT: Competitive acetylcholinesterase (AChE, EC 3.1.1.7) inhibitors are routinely used as prophylactics against nerve agents intoxication in the Czech Army. The goal of the thesis has been to rationally design new bis-quaternary pyridinium compounds, prepare them and finally assess their in vitro inhibition activity. The molecules have originated in variably substituted pyridine-derivates and different connecting linkages (6-12 carbon atoms). Compounds derived from 4-(3-hydroxypropyl)pyridine were successfully synthesized as the representatives of the hydroxyalkyl-derived inhibitors; the more lipophilic inhibitors have been derived from ethyl- isonicotinate. The preparation took place in dimethylformamide, at temperatures varying from 60 řC to 75 řC. The identity and purity of the prepared compounds were confirmed by NMR- analysis, elementary analysis and mass spectrometry. Finally, the Ellman's method was used for the inhibitory screening. 14 molecules were synthesised, 7 substances from each structural group. Compounds of both series showed significant inhibitory properties towards...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Eliška Kučerová Supervisor: PharmDr. Kamil Kopecký, Ph.D. Title of diploma thesis: Dichloroquinoxalinodicarbonitrile - the precursor for quinoxalinoporhyrazines This diploma thesis deals with preparation of 2,3-dichloroquinoxaline-6,7- dicarbonitrile, precursor for synthesis of quinoxalinoporhyrazines. In the theoretical part, the main topic is methodology of preparation of two crucial compounds or their derivatives to obtain the final product. The ways of synthesis of 4,5- diaminophthalonitrile are described in the first part together with advantages and disadvantages of each of them and they are farther debated in the discussion. The second part shows the possibilities of synthesis of various quinoxaline derivatives and emphasizes their positives and negatives. Individual methods are systematically arranged according to character of initial substances of individual reaction and reaction conditions, respectively. The experimental part shows procedures, which were used during processing of this diploma thesis. 2,3-dichloroquinoxaline-6,7-dicarbonitrile was prepared by condensation of 4,5-diaminophthalonitrile and diethyloxalate and by subsequent nucleophilic...

Charles University in Prague, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Veronika Krepsova Supervisor: doc. PharmDr. Petr Zimcik, Ph.D. Title of Diploma Thesis: Azaphthalocyanines substituted with one aminogroup - distance dependence on photoinduced electron transfer Azaphthalocyanines (AzaPc), the aza-analogues of phthalocyanines are macrocyclic compounds with large conjugated system and mostly with high quantum yields of singlet oxygen and fluorescence. Intramolecular charge transfer (ICT) was discovered to proceed in AzaPc when alkylamino group is present on AzaPc periphery. ICT is responsible for quenching of excited states causing disappearance of singlet oxygen production and fluorescence emission. The aim of this thesis was to synthesize AzaPcs suitable for studying a similar process called photo-induced electron transfer (PET). In this process donor amino group is not in conjugation with AzaPc macrocycle, electron must "jump" over a distance leading to the quenching of excited states of molecules. In the first part of my work 5-chloro-6-methylpyrazine-2,3-dicarbonitrile was synthesized using nucleophilic substitution on 5-[2-(diethylamino)ethylsulfanyl]-6- methylpyrazine-2,3-dicarbonitrile (precursor A). The synthesis...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Ondřej Holas Supervisor Doc. RNDr. Veronika Opletalová Ph.D. Title of Doctoral Thesis The relationship between structure and activity of potential modulators of acetylcholinesterase The Ph. D. thesis is focused on finding structure activity relationships for the acetylcholinesterase activity modulating compounds. Standard in vitro test using rat brain homogenate as the source of acetylcholinesterase was chosen for enzyme activity assay. Later, the procedure employing the colorimetric approach according to Ellman was developed. New procedure for inhibitory efficacy assessment based on Ellmanʼs method was designed as well. Aldoxime reactivators are mainly used as the causal antidotes of organophosphorus compounds intoxications. Organophosphorus compounds are widely used for agricultural purposes as pesticides, and in the industry as a plasticizers or flame retardants. Beside the peaceful purposes, they were also developed as nerve agents applicable for chemical warfare. Toxic mechanism of the compounds is formation of covalent bond with serine (Ser203) hydroxyl in active site of acetylcholinesterase. Unfortunately, none of the currently used reactivators is able...

Distamycin A, netropsin, Hoechst 33258 and other are substances that bind in minor groove in the double helix of A·T base pairs DNA sequences. This diploma thesis describes the synthesis of compounds structurally derived from the model molecule distamycin A and their conjugation with oligonucleotides. Synthesis of compounds derived from distamycin A was performed by methods of peptide synthesis in solution and on solid phase. For preparation of desired compounds have been carried out a number of sectional reactions which were only partially successful. The most promising seems to be molecule tert-butyl-5- (5-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethylcarbamoyl)-1-methyl-1H-pyrrole-3- ylcarbamoyl)-1-methyl-1H-pyrrole-3-yl-carbamate.

Title: Preparation of modulators of cholinesterases and cholinergic receptors Author: Jan Röder Organophosphorus compounds are widely used as pesticides and were also misused as chemical warfare agents. Up to date, the pre-exposure treatment of organophosphorus compounds intoxication consists in use of carbamate cholinesterase inhibitors. Carbamates act as reversible inhibitors of acetylcholinesterase (AChE) and thus protect it against irreversible inhibition with organophosphorus compounds. However, carbamates showed severe undesirable effects caused by carbamylation of AChE, and therefore there is trend to find novel compounds, which could more effectively act as protection against intoxication with organophosphorus compounds. Twenty modulators of cholinesterases and cholinergic receptors were prepared in this project. These compounds showed promising inhibition ability during in vitro testing and four of them were chosen for further molecular modelling studies. The former studies of AChE and its receptors features were also taken into account. The properties of newly prepared compounds were discussed. Based on promising results after in vitro evaluation, several compounds were recommended for further in vivo studies in order to prove or disprove their effectiveness in pre-exposure treatment with...

CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADCI KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND DRUG CONTROL Candidate: István Füri Supervisor: Assoc. Prof. RNDr. Veronika Opletalová Ph.D. Diploma Thesis: Preparation and in vitro testing of byspiridine inhibitors of cholinesterases - influence of functional groups In my thesis I was concerned with synthesis and in vitro testing of bispyridinium inhibitors of cholinesterases. Bispyridinium inhibitors were prepared with 8 to 12 carbon chain linkers and naphtyl chain linker with carbamoyl, carbamide or acetyl group in para position in the pyridine ring. In the next step, inhibitory activity of the compounds against AChE and BChE was determined in vitro. The inhibitory activity was measured using modified Ellman's photochemical method. BW-284c51 (for AChE) and ethopropazine (for BChE) were used as standards. Substances with carbamoyl and acetyl functional group showed higher AChE inhibitory activity than compounds with carboxyl functional group. Carboxyl functional group was not suitable for inhibitory activity against BChE, too.

FOLLOWING OF ACETYLCHOLINESTERASE-PESTICIDE INTERACTION USING BIOSENSOR TECHNOLOGY Oto Drobík Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Organophosphorus and carbamate pesticides are toxic substances used in agriculture as insecticides. These substances are highly toxic for humans as acute poisoning can lead to death via inhibition of acetylcholinesterase. After acetylcholinesterase inhibition, accumulation of acetylcholine follows. In compliance with the thesis aims, functional electrochemical biosensor was constructed. It was based on a standard screen printed amperometric sensor with three electrodes. Herein sensors with platinum and carbon working electrode were tested. Suitable method of electrochemical assay was chosen and some the basic conditions were optimized. Kinetic parameters of enzyme reaction were assessed, too. Various methods of acetylcholinesterase capturing onto sensor were tested and compared one to each other. Paraoxon-methyl and diisopropylfluorophosphate were chosen as the representative of pesticides. Limit of detections for the both pesticides were estimated to be 10-6 - 10-5 mol/l. The prepared biosensors were compared with the standard Ellman's method based on spectrophotometry and the...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Veronika Račáková Consultant: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Study of new acetylcholinesterase modulators. Organophosphorus compounds are chemically organophosphates or organophosphonates. They have been widely used as a pesticides but because of their high toxicity and relatively cheap and easy synthesis they can be easily misused as chemical weapons - nerve paralytic compounds. Toxic effect of these compounds is based on irreversible inhibition of the enzyme acetylcholinesterase (AChE). In case of intoxication by these compounds anticholinergic drugs (atropin) and reactivators of AChE are usually used as antidots. The effect of the reactivators is based on splitting the complex enzyme-inhibitor. Pralidoxim, trimedoxim, obidoxim and asoxim (HI-6) are still the most often used reactivators all over the world. They are the compounds which contain oxime group and one or two quarternary nitrogens in their molecule, what ensures that their affinity to AChE will be strong enough. Screening and synthesis of new more effective broad-spectrum reactivators of AChE with lower side effects is still very actual and discussed theme. Strategy...

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Jana Heczková Consultant Professora Doutora Madalena Maria de Magalhães Pinto, Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis Synthesis of carboxyxanthone derivatives as building blocks for enantiomeric pure compounds. Synthesis and structure elucidation of xanthone derivative (XD) 2-carboxy-6-methoxyxanthone (XD-2) The importance of xanthone derivatives is considerable. They possess large variety of biological and pharmacological activities. Many of them proved to be important building blocks for synthesis of new compounds. Chirality is a fundamental property of biological systems and reflects the underlying asymmetry of matter. Almost one-third of all drug sales worldwide are chiral compounds and the authorities recommend that the chiral drugs should be saled in pure enantiomeric forms because enantiomers may differ both quantitatively and qualitatively in their biological activities. At one extreme, one enantiomer may be devoid of any biological activity; at the other extreme, both enantiomers may have qualitatively different biological activities. Enantiomers also differ in bioavailability - one enantiomer can be more bioavailable than the other,...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Mariana El-Zein Consultant: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Derivatives of Rhodanine as Potential Antifungal Drugs Rhodanine (2-thioxo-1,3-thiazolidin-4-one) forms the basic skeleton of many biologically active substances and potential drugs. Antifungal properties of rhodanine derivatives have been studied since the early 1950s. Theoretical part of the thesis deals with mycoses and drugs that are currently used to treat them. The aim of the experimental work was to find suitable reaction conditions for Mannich reaction of (5Z)-5-(subst.)benzylidenes-2-thioxo-1,3-thiazolidin-4-ones with various amines. The attempts to prepare Mannich bases using diethylamine as the basic component were unsuccessful. (5Z)-5-benzylidene-3-(morpholin-4-yl-methyl)-2-thioxo-1,3-thiazolidin- 4-one was successfully obtained by treating (5Z)-5-benzylidene-2-thioxo-1,3-thiazolidin- 4-one with formaldehyde and morpholine in dimethylformamide. This compound was reported previously and exhibited antibacterial activity and acceptable toxicity. Hence, Mannich bases derived from (5Z)-5-arylalkylidene-2-thioxo-1,3-thiazolidin-4-ones deserve further attention as potential...

Rheinische Friedrich-Wilhelms University Bonn The Faculty of Mathematics and Natural Sciences Pharmaceutical Institute, Pharmaceutical Chemistry I Diploma Thesis Synthesis of Functional Derivatives of Malonic Acid as Buildings Blocs for Elastase Inhibitors Marie Hrušková Human leukocyte elastase (HLE) is a serine protease, which plays an important role in inflammatory diseases. Low molecular weight inhibitors can be therapeutically used for example for the treatment of chronic obstructive pulmonary diseases. In this thesis, azetidin- 2,4-dione derivatives should be prepared as HLE inhibitors. In particular, 3- (benzyloxycarbonylamino)-3-ethyl-N-phenyl-azetidine-2,4-dione should be synthesized. The protected amino group was expected to increase the peptidic character of this molecule and thus, affinity to HLE. The starting compound was 2-aminomalonic acid diethylester hydrochlorid. The amino function was protected in the first step, followed by alkylation and then hydrolysis of 2- (benzyloxycarbonylamino)-2-ethylmalonic acid diethylester to 2-(benzyloxycarbonylamino)- 2-ethylmalonic acid. Both the ester of 2-(benzyloxycarbonylamino)malonic acid and the 2-(benzyloxycarbonyl-amino)ethylmalonic acid showed in their 1 H NMR spectra a multiplet in place of the expected quartet. This phenomenon was...

Title of diploma thesis: Pyrazine derivates as potential drugs VI. Review of tuberculosis therapy and modern research were presented in this diploma thesis. Six novel compounds substituted anilides pyrazine-2-carboxylic acid character were synthesized. Products were characterized by melting points, TLC, IR, 1 H and 13 C NMR. This set was put through in vitro biological evaluation. Log P and Clog P were also calculated. These values were put into the structure-activity relationships of prepared compounds.

AMIDOXIMES AS SYNTHETIC INTERMEDIATES AND POTENTIAL DRUGS I. Michaela Horká Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control In the theoretical part of this diploma thesis, biological activities of amidoximes are resumed. They have been studied mainly as prodrugs that are reduced to active compounds - amidines. Some amidoximes reached clinical trials but due to their significant undesirable effects have not been developed further. Methodical part deals with various synthetic procedures for the preparation of amidoximes. In the frame of the experimental part, four 5-alkylpyrazine-2-carbonitriles were synthesized at first. Using hydroxylamine hydrochloride, the nitriles were converted to corresponding amidoximes:  N'-hydroxy-5-propylpyrazine-2-carboximidamide  N'-hydroxy-5-isopropylpyrazine-2-carboximidamide  N'-hydroxy-5-pentylpyrazine-2-carboximidamide  N'-hydroxy-5-hexylpyrazine-2-carboximidamide None of the obtained products have been reported yet. They were characterized by melting points, IR, NMR spectra. Their purity was checked by elemental analysis. The compounds were tested for antifungal and antibacterial activity but were found non-effective. This is probably due to the fact that in vitro their bioactivation...

Transport of ion channel blockers across the blood-brain barrier in vitro Diploma thesis, 2010 Hana Leblochová Abstract Six different substances blocking ion channels were chosen (verapamil, diltiazem, nifedipine, phenobarbital, memantine, amantadine) for the purpose of this work. All these substances are routinely used in clinical practice and it is well known that adverse effects on the central nervous system can occur during therapy with them. Therefore, both single and group transport studies were carried out to investigate and compare the transport abilities of chosen ion channel antagonists to penetrate the BBB and to find out the interference between them. The required data for each substance used in single and group studies were determinated using the Transwell BBB in vitro model based on EVC304 cell line. Diazepam and carboxyfluorescein were used as internal standards for normalization of permeability data. According to the obtained data from single studies nifedipine as drug acting in periphery passes the BBB faster than internal standard diazepam (acting in CNS) and much more faster than other ion channel blockers acting in periphery, too. In clinical practice it can mean that nifedipine used for concrete clinical problem can have more CNS adverse effects in comparison to verapamil or diltiazem....

The main task of the thesis was a design and synthesis of new potential antimycobacterial active molecules. Presently, the appearance of MDR-TB strains is alarming and the development of new therapeutical agents is necessary. The work is divided into two parts; first one is related to aminopolysaccharide chitosan and its connection with appropriate antimycobacterial drugs or dyes, second part is concerned with modifications of current antituberculotics. Due to the structure and physico-chemical properties, chitosan has been found as an interesting drug carrier in biomedicinal chemistry. It is used in drug delivery system with control release of the drug in the target cells or tissues. The component of the first part of the thesis was to review molecular modelling of chitosan, especially its usage as a prodrug or carrier in a field of antibacterial, antitumor and antioxidant activity. Derivatives of chitosan linked with the first or second line antituberculotics were prepared for the purpose of decreasing hepatotoxicity of used drugs. Their antimycobacterial activity against M. tbc., M. avium and M. kansasii was 125 µg/mL for all strains. Unexpectedly, O-carboxymethyl chitosan as an intermediate showed better MIC against M. tbc. and M. avium. It means that biological activity of chitosan derivatives...

In vitro reactivation of choliesterases after pesticides inhibition Organophosphate pesticides are toxic substances supplied commercially as insecticides in order to protect agricultural commodities, for suppression of epidemic events etc. The use of pesticides in the Czech Republic is strongly regulated by law similarly as in the whole EU. The regulation is aimed at monitoring and regulating the use of products containing toxic pesticides. In this diploma work, I measured the efficacy of previously synthesized oxime reactivators using the standard spectrophotometric method and multi-channel spectrophotometer. After experimental testing, the ability of selected pesticides to inhibit acetylcholinesterase (AChE) was assessed. I choose tree pesticides that are capable of binding to AChE without any metabolic activation. It was paraoxon ethyl, paraoxon methyl, and DFP. Subsequently, I experimentally observed the ability of 78 selected oximes reactivators to restore AChE activity in vitro. I proved that the DFP inhibited AChE can be reactivated with high efficacy using monopyridinium reactivators but bispyridinium reactivators are also suitable. In contrast to DFP, paraoxon ethyl as well as paraoxon methyl inhibited AChE was reactivated with only bispyridinium reactivators. Number of oxime groups isn not...

The aim of this thesis was to prepare 5-(benzyloxymethyl)-3-(4-bromophenyl)-2,5- dihydrofuran-2-one derived from cytostatically active 5-alkoxymethyl-3-(4-bromophenyl)- 2,5-dihydrofuran-2-ones. However, none of the three proposed synthetic procedures led to the target molecule. Next we focused on the preparation of a series of 5-bis(acetyloxymethyl)-3- aryl-4-phenyl-2,5-dihydrofuran-2-ones with different aryl substitution derived from the antibacterially, antifungally and cytostatically active 5-bis(acetyloxymethyl)-3- (4-bromophenyl)-4-phenyl-2,5-dihydrofuran-2-one. The aim was to explore a relationship between aryl substitution in position 3 and biological activity of the compounds. The spectrum of products was also enriched by 5-acetyloxymethyl-3-aryl-4-phenyl-2,5-dihydrofuran-2-ones. In conclusion aryl substitution leads to a significant decrease or vanishing of the antibacterial, antifungal and cytostatic effects with the exception of 5-acetyloxymethyl-3-aryl-4-phenyl-2,5- dihydrofuran-2-ones, in which marginal antifungal (Absidia corymbifera), antibacterial (Staphycoccus aureus a Staphylococcus epidermidis) and significant cytostatic (L1210, HeLa S3, CCRF-CEM, IC50 < 5 µmol.l-1 ) activities were found.