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Modulation of pKa of the recognition moiety of azaphthalocyanine sensors
Čermáková, Veronika ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Veronika Čermáková Supervisor: Assoc. Prof. Petr Zimčík, Ph.D. Title of Diploma Thesis: Modulation of pKa of the recognition moiety of azaphtalocyanine sensors Azaphthalocyanines (AzaPc) are macrocyclic compounds containing a large system of conjugated double bonds that enables them to absorb light in the red part of the spectrum that is promising in biological applications. They are characterized by intense red fluorescence as one of the relaxation pathways of the excited state after absorbing a photon. The fluorescence of AzaPc substituted with a phenol moieties on the periphery can be switched ON/OFF depending on the pH of the environment and the pKa of the phenolic group. In basic medium, the molecule occurs as phenolate and undergoes intramolecular charge transfer between the phenolate group (a donor) and the electron- deficient macrocyclic core (an acceptor). As a consequence of this process, the fluorescence is quenched. Switching between ON/OFF states in phenol-substituted AzaPc is dependent on the proton concentration and thus can be utilized in pH sensing. The aim of this work was to synthesize derivatives of phenol-substituted AzaPcs whose pKa is...
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Oxadiazoles as potential drugs
Dzámová, Pavlína ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Candidate: Pavlína Dzámová Supervisor: PharmDr. Marta Kučerová, Ph. D. Title of diploma thesis: Oxadiazoles as Potential Drugs Due to the increasing resistence of bacteria and fungi against conventional drugs, it is imperative to design and develop new antibacterial or antifungal agents. In the theoretical part of this diploma thesis,I focused on the biological activities of 1,2,4- oxadiazoles, that are known as the compounds with promising future in this direction. They are very important heterocyclic compounds with various bioactivities, such as tyrosine kinase inhibition, muscarinic agonism, histamine H3 antagonism, anti- inflammatory, antitumoral, antimicrobal and monoamine oxidase inhibition. Methodical part resumes the most important procedures for the preparation of 1,2,4-oxadiazoles. In the experimental part of this study, six new oxadiazole derivates have been synthesized. 5-Methyl-3-pyrazin-2-yl-1,2,4-oxadiazoles variably alkylated in position 5 of the pyrazine ring resulted from cyclization of corresponding pyrazin-2- karboximidamides with acetanhydride. Starting compounds for cyclization were available in our laboratory. In case of absence, they were prepared by radical alkylation of pyrazincarbonitrile and by...
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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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Solving bordered linear systems
Štrausová, Jitka ; Janovský, Vladimír (advisor) ; Zítko, Jan (referee)
The comparison of two algorithms for solving bordered linear systems is considered. The matrix of this system consists of four blocks (matrices A,B,C,D), the upper left one is a sparse matrix A, which is ill-conditioned and structured. The other blocks (B,C,D) are dense. We say that the matrix A is bordered with the matrices B,C,D. It is desirable to preserve the block structure of the matrix and take advantage of sparsity and structure of the matrix A. The literature suggests to use two different algorithms: The first one is the method BEM for matrices with the borders of width equal to one. The recursive alternative for matrices with wider borders is called BEMW. The second algorithm is an iterative method. Both techniques are based on different variants of the block LU-decomposition.
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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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Derivatives of 5-alkylpyrazine-2-carboxylic acid as potential anti-infectives
Halířová, Martina ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
DERIVATIVES OF 5-ALKYLPYRAZINE-2-CARBOXYLIC ACID AS POTENTIAL ANTI-INFECTIVES HALÍŘOVÁ MARTINA Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic In our previous study, we have demonstrated that 5-alkylamino-N- phenylpyrazine-2-carboxamides with longer alkyl chain (C5-C8) exerted micromolar growth inhibition activity against M. tuberculosis H37Rv. We speculated that the long alkylamino chain could facilitate the penetration of lipophilic mycobacterial cell envelope. To test this hypothesis, we performed the amino to methylene isosteric exchange and designed a series of 5-alkyl-N-phenylpyrazine-2-carboxamides. 5- Alkylpyrazine-2-carboxylic acids (5-Ak-POA) were prepared by homolytic alkylation of commercially available pyrazine-2-carbonitrile by respective alkanoic acid, followed by hydrolysis of the carbonitrile group. Final derivatives were prepared by CDI mediated coupling of 5-Ak-POA with corresponding aniline at RT. Final compounds were described by melting point, elementary analysis, IR spectroscopy and 1 H, 13 C NMR. Then they were tested in vitro for antimycobacterial activity against M. tuberculosis H37Rv and several non-tuberculous mycobacterial strains. Several compounds exerted MIC of 3.13-6.25 µg mL-1 ....
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Synthesis of BODIPY derivatives for photodynamic therapy
Rydrych, Milan ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Milan Rydrych Supervisor: Prof. PharmDr. Petr Zimčík, PhD. Name of the thesis: Synthesis of BODIPY dyes for photodynamic therapy Borron-dipyromethene dyes (BODIPYs) have been used since the 1990s for their photostability, high absorption coefficients and fluorescence quantum yields. Recently, a modification of the structure using the heavy atom effect was discovered, where high quantum yields of singlet oxygen were also achieved. This fact helped creating a family of compounds with the potential for use in photodynamic therapy (PDT). Previously described BODIPY preparations for PDT are limited by poor solubility in polar environments. This study provides an overview of current synthetic options and basic structure-effect relationships. In the experimental part of the work, three styryl disubstituted substances were prepared with λmax (absorption maximum) at wavelengths in near infrared region with good quantum yields of singlet oxygen and very good photostability. In addition to the target compounds, three 3,5- dialkoxy substituted benzaldehyde derivatives were prepared and characterized as precursors for the final compounds. Finally, the already published synthetic...
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Synthesis and biological evaluation of novel tacrine-tryptophan derivatives
Astapenko, Michaela ; Opletalová, Veronika (advisor) ; Zitko, Jan (referee)
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...
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Synthesis of aerothionin analogs as potential antimycobacterial agents
Šimovičová, Martina ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Martina Šimovičová Supervisors: Assoc. Prof. PharmDr. Jan Zitko, Ph.D.; Adjunct Prof. Paula Kiuru, Ph.D. Title of diploma thesis: Synthesis of aerothionin analogs as potential antimycobacterial agents Key words: antimycobacterial; tuberculosis; synthesis; aerothionin; bromotyrosines Drugs currently used for the treatment of tuberculosis are the result of studies carried out 50 or 60 years ago. With the constantly growing bacterial resistance to these pharmaceuticals grows also the importance of research for new antimycobacterially active compounds. The marine environment undoubtedly holds an enormous potential for discovering new leads for the development of antitubercular agents. One of these leads is a spirocyclic compound called aerothionin (1), which was found to be active against multidrug-resistant strains of Mycobacterium tuberculosis, as well as three non-tuberculosis mycobacteria (Figure 1). In addition, several spirocyclic structures (not only from marine origin) were discovered to affect on the M. tuberculosis in recent years, making this structure segment attractive for antitubercular research. Figure 1: Aerothionin (1) and general structure of the...
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