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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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Synthesis and evaluation of N-pyridylbenzamides as potential antimicrobial compounds
Suchánková, Eliška ; Zitko, Jan (advisor) ; Nováková, Veronika (referee)
SYNTHESIS AND EVALUATION OF N-PYRIDYLBENZAMIDES AS POTENTIAL ANTIMICROBIAL COMPOUNDS Eliška Suchánková Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic The derivatives of N-pyridylbenzamide were designed and synthesized to be in vitro tested for antimycobacterial activity against Mycobacterium tuberculosis H37Ra, M. smegmatis, M. aurum and in vitro cytotoxicity in HepG2 cells. These compounds are pyridinyl analogues of previously prepared N-pyrazinylbenzamides that have shown a significant in vitro antimycobacterial activity. The title compounds were synthesized by acylation of aminopyridine or chloropyridine-2-amine by selected benzoyl chlorides. Final compounds were described by elementary analysis, melting point, 1 H and 13 C spectra and IR spectroscopy. Generally, prepared compounds possess lower antimycobacterial activity than previously tested N-pyrazinylbenzamides. However, there are some cases, in which the derivatives of pyridine were more effective compared to the derivatives of pyrazine; mainly against M. smegmatis. The best antimycobacterial activity was proved for derivatives of 2-amino-6-chloropyridine and substituted benzoyl chloride, corresponding with higher lipophilicity of these compounds;...
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Intracellular trafficking of an anti - Amyloid Protein Precursor antibody.
Zitko, Jan ; Doležal, Martin (advisor) ; Trejtnar, František (referee)
Intracellular trafficking of an anti-Amyloid Protein Precursor antibody Alzheimer's disease is characterized by over-accumulation of beta-amyloid peptide (Aβ) in the brain. Aβ is produced by proteolytic cleavage of beta-amyloid precursor protein (APP) by β- and γ-secretases. Novel monoclonal antibody, 2B12, has been shown to bind to β-secretase cleavage site of APP, reducing the production of APP, presumably by preventing the cleavage by steric hindrance. 2B12 is hypothesized to bind to APP molecules exposed on the cell surface and to be internalized in the form of complex with APP via natural endocytic pathway. This hypothesis was confirmed by San Pei Ho's (2007), who followed the internalization of 2B12 in living astrocytoma MOG-G-UVW, cells in time-course experiment. This project is focused on intracellular trafficking of 2B12 and its localization within specific cellular compartments. Experiments were performed with fixed astrocytoma MOG- G-UVW cells (constitutively expressing APP). Originally planned experiments with live cells could not be performed due to decreased stability of 2B12 (causes remain unknown). 2B12 was tested for colocalization with polyclonal affinity purified antibodies labelling subcellular markers (proteins) associated with compartments known to participate in APP...
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Peano kernel of the quadrature formula
Valešová, Petra ; Kofroň, Josef (advisor) ; Zítko, Jan (referee)
Nazev prace: Poanovo jadro kvadraturni formula Autor: Pctra Valcsova Katedra (ustav): Katedra numcricke matciriatiky Vcdouci bakalarskc pracc: Doc. RNDr. Josef Kofroii, CSc. c-inail vcdouciho: Josef.Kohxm^.tinff.cuni.cz Abstrakt: V pfedlozcnc praci studujcme vyjadfcni chyb kvadraturnich for- rnuli pomoci Peanova jadra. Nejprve je definovano Peanovo jadro kvadra- turni fornmlc. dale jsou uvcdcny a dokazany ricktcrc jcho vlastnosti a na dvou pfikladoch jc ukazan vypocct Peanovych jadcr. Kaslcdneje vyuzito Peanova jadra k nalezeni optimalni kvadraturni for mule. Potc jc popsana kon.strukce Rombergovy kvadraturni formulc a pfislusncho Peanova jadra. Jc uvcdcno a dokazano nekolik vlastnosti Peanovych jadcr Rombergova kvadraturniho vzorce. Dale jc na nekolika pfikladcch srovnan odhad chyby kvadraturnich formuli. Na /,;iver jc definovano Sardovo jadro kubatumi for mule a na pfi- kladc je ukazan vypocet Saixlova jadra. Klicova slova: kvadraturni vzorcc, Pcanovo jadro, chyba kvadraturni fonnule Title: Pcario kernel of the quadrature formula Author: Pctra Valesova Department: Department of Numerical Mathematics Supervisor: Doc. RNDr. Josef Kofroil, CSc. Supervisor's e-mail address: .loscf.Kofrori'il'mff.cuni.r/, Abstract: In the present work we study the expressing of errors of a qua- drature formula by Pcano kernel....
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Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers
Kollár, Jan ; Zimčík, Petr (advisor) ; Mosinger, Jiří (referee) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Jan Kollar Supervisor: prof. PharmDr. Petr Zimcik, Ph.D. Advisor: doc. PharmDr. Veronika Novakova, Ph.D. Doctoral Thesis: Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers Phthalocyanines (Pcs) and their aza-analogues (e.g. tetrapyrazinoporphyrazines, TPyzPzs) represent a promising group of organic dyes with interesting photophysical properties (strong absorption in area 650-750 nm, strong singlet oxygen production) highly suitable for the use in photodynamic therapy (PDT) of cancer. However, they have also some drawbacks lowering their potential use in PDT (low solubility in water, strong tendency to aggregate). The topic of my dissertation thesis closely follows the topic of my diploma thesis, during which TPyzPz with sixteen carboxylate groups in rigid arrangement was prepared and in which we have disclosed strong negative effect of low pH and serum proteins on photodynamic activity. In the first part of this thesis I prepared new zinc TPyzPz with eight sulfonate groups on periphery, which was characterised by good solubility in water. Sulfonates were chosen as stronger acids than carboxylic groups, so they were...
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Approximate Polynomial Greatest Common Divisor
Eliaš, Ján ; Zítko, Jan (advisor) ; Hnětynková, Iveta (referee)
Title: Approximate Polynomial Greatest Common Divisor Author: Ján Eliaš Department: Department of Numerical Mathematics, MFF UK Supervisor: Doc. RNDr. Jan Zítko, CSc., Department of Numerical Mathematics, MFF UK Abstract: The computation of polynomial greatest common divisor (GCD) ranks among basic algebraic problems with many applications. The Euclidean algorithm is the oldest and usual technique for computing GCD. However, the GCD computation problem is ill-posed, particularly when some unknown noise is applied to the polyno- mial coefficients. Since the Euclidean algorithm is unstable, new methods have been extensively studied in recent years. Methods based on the numerical rank estimation represent one group of current meth- ods. Their disadvantage is that the numerical rank cannot be computed reliably due to the sensitivity of singular values on noise. The aim of the work is to overcome the ill-posed sensitivity of GCD computation in the presence of noise. Keywords: AGCD, Sylvester matrix, numerical rank, TLS
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Synthesis of NK1 antagonists.
Puchnerová, Lucie ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Synthesis of NK-1 antagonists Lucie Puchnerová Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy University of Seville NK-1 receptor antagonists are represented so far by only one drug, Aprepitant, which is available on the market for prevention of chemotherapy-induced nausea and vomiting. Nevertheless, it is assumed that NK-1 antagonists will be able to participate in treatment of migraine, rheumatoid arthritis, asthma, pain, inflammatory bowel disease, Parkinson's disease, anxiety and depression in future. This thesis is concerned with asymmetric synthesis of derivatives of 2-amino-4H-pyran, which thanks their substitutions are in accordance with structure of pharmacophore of NK-1 antagonists. As a starting material for their preparation has been used commercial methyl p-tolyl sulfone and (R)-methyl p-tolyl sulfoxide, which was synthesized from menthyl-(S)-p- toluenesulfinate by nucleophilic substitution. These compounds were subjected to reaction with ethyl 2-picolinate. From prepared β- ketosulfoxide and β-ketosulfone were obtained 2-amino-4H-pyrans by Michael addition. The derivatives proceeding from β-ketosulfoxide were subjected to reduction of the sulfoxide and trifluoroacetylation of the amine group on the carbon 2 of the pyran ring. Prepared derivatives had agonistic activity...
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Amidoxime derivatives as synthetic intermediates and potential drugs
Hariková, Michaela ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Title of diploma thesis: Amidoxime derivatives as synthetic intermediates and potential drugs Student: Michaela Hariková Supervisor: PharmDr. Marta Kučerová, Ph.D. In the theoretical part of this diploma thesis, biological effects of N-hydroxykarbimidoylchlorides and amino derivatives are summarized. In addition, biologically active compounds which are synthesized from N-hydroxykarbimidoylchlorides, in particular the compounds containing isoxazole. In the experimental part, the procedures used for the synthesis of amidoxime derivatives are described. Initial compounds for the synthesis of N-hydroxykarbimidoylchlorides were the corresponding alkylated amidoximes available at the Department of Pharmaceutical Chemistry and Pharmaceutical Analysis or prepared by radical alkylation of pyrazinecarbonitrile followed by conversion to amidoxime. From the N-hydroxykarbimidoylchloride, an amino derivative was subsequently prepared. All prepared compounds were characterized by melting point, NMR and IR spectra. The purity of the substances was checked by TLC and elemental analysis. The prepared derivatives were tested in vitro for their antibacterial, antimycobacterial and antifungal activity.
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Cationic surfactants as the hydrolytic micellar catalysts
Janošcová, Petra ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Cationic surfactants as the hydrolytic micellar catalysts Petra Janošcová The effectiveness of hydrolytic cleavage of the pesticide fenitrothionin cationic surfactants micellar media has been tested. All used surfactants increased the rate of fenitrothionhydrolysis, which was the evidence of micellar catalysis. For some surfactants decreases has been evident at the highest rate of hydrolysis concentrations. It has been the result of a phenomenon called the effect of empty micelles. High hydrolytic performance was achieved with surfactants contained ionisable hydroxyl groups in the molecule. The most significant increase of kinetic rate has been observed with benzoxonium surfactant.
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Synthesis of arylsufanyl phthalocyanines and their aza-analogues
Málková, Anna ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
8 3. ABSTRACT Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Anna Málková Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Title of Thesis: Synthesis of arylsulfanyl phthalocyanines and their aza-analogues. Phthalocyanines (Pcs) and their aza-analogues (AzaPc), chemical substances used in photodynamic therapy, are characterized by interesting photophysical properties which may substantially vary in dependence on the character of peripheral substituents. For example, sum of singlet oxygen and fluorescence quantum yields reaches typically a value of 1 for Mg and Zn complexes while is significantly decreased for metal-free derivatives. It has been suggested from several previous experiments that this effect can be influenced by bulkiness of the peripheral substituents. The aim of this work was the synthesis of bulky 2,6-diphenylphenylsulfanyl substituted Pcs and AzaPcs with subsequent study of their photophysical properties. The synthesis started from 2,6-diphenylphenol, a commercially available substance, which was converted to corresponding O-carbamothioate with dimethylcarbamoylchloride. Isomeric S-carbamothioate was prepared using Newman-Kwart rearrangement at high temperatures and then reduced to corresponding...
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