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Synthesis of a combinatorial compound library based on the double click reaction
Krutáková, Mária ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
(English) Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mária Krutáková Supervisor: Assoc. Prof. PharmDr. Jan Zitko, Ph.D. Title: Synthesis of a combinatorial compound library based on the double click reaction Click chemistry is a powerful tool in drug discovery. It is very efficient in creating compound libraries through the combinatorial methodology. The copper(I)-catalyzed 1,2,3-triazole- forming reaction between azides and terminal alkynes has become the gold standard of click chemistry due to high reaction efficiency, mild reaction conditions, chemo- and regioselectivities. The molecules with triazole moiety display a broad spectrum of favorable properties and have been used in the development of antibacterial, antiviral, anti-inflammatory, anticancer, and anti-tubercular agents. This work focused on preparing a compound library using double-click reactions. Firstly, we synthesized several compounds with two alkyne groups ("alkyne cores") and a diverse group of structurally simple azides. In the next step, one equivalent of alkyne core was reacted with two equivalents of all prepared azides. The reaction between each alkyne core and ten azides yielded 100 compounds. The prepared libraries of compounds were...
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Design, synthesis and evaluation of pyridine derivatives as potential antimicrobial compounds
Bachtíková, Andrea ; Zitko, Jan (advisor) ; Demuth, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Thesis title: Design, synthesis and evaluation of pyridine derivatives as potential antimicrobial compounds Author: Andrea Bachtíková Thesis supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: PharmDr. Martin Juhás Tuberculosis is a global problem even today. It is the second most common cause of death from infectious diseases according to the WHO and resistance to common antituberculosis drugs, which have been used in therapy for decades, increases. These facts are the main reasons why research into new potential drugs is needed. This thesis presents design, synthesis and evaluation of antimicrobial properties of a series of substituted N-oxazolyl and N-thiazolyl carboxamides of different pyridinecarboxylic acids. Final compounds were characterized by 1 H and 13 C-NMR spectroscopy, IR spectra, melting point and HRMS (High resolution mass spectrometry). Obtained compounds were tested for in vitro activity against M. tuberculosis H37Rv, M. tuberculosis H37Ra and four other clinically less important mycobacterial strains. In addition, compounds were tested for antibacterial activity against four G+ and four G- bacterial strains, antifungal activity against yeasts and fungi,...
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Preparation of fluorescent phthalocyanines for labeling of oligonucleotide probes IV.
Mikula, Daniel ; Miletín, Miroslav (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Daniel Mikula Supervisor doc. PharmDr. Miroslav Miletín, Ph.D. Consultant Mgr. Michaela Kolářová Title of thesis Preparation of fluorescent phthalocyanines for labeling of oligonucleotide probes IV. Phthalocyanines (Pcs) are macrocyclic compounds with a conjugated system of double bonds. Thanks to this, they have interesting photophysical and photochemical properties that enable their practical use in pharmacy and medicine in the field of diagnostics or treatment of cancer diseases. This work deals with the preparation of axially disubstituted silicon complexes of phthalocyanines (SiPcs), which would have suitable properties for subsequent use in the labeling of oligonucleotide probes. The theoretical part is primarily devoted to the methods of Pcs preparation, from the choice of precursors, through the formation of the macrocycle and insertion of the central atom, to the modifications of the resulting molecule, including the specifics related to SiPcs. The basic properties of Pcs and the degree of influence of different changes of the molecule on these properties are also described. The basic areas of use of Pcs are also mentioned. The experimental part...
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Synthesis of thiazolidin-2,4-dione derivatives as potential drugs III
Fontánová, Karolína ; 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: Synthesis of thiazolidine-2,4-dione derivatives as potential drugs III Student: Karolína Fontánová Supervisor: PharmDr. Marta Kučerová, Ph.D. The theoretical part is focused on the biological activity of thiazolidine-2,4-dione (TZD) derivatives, especially on their antibacterial (including antimycobacterial) and antifungal effects. The cited literature shows that in many cases the presence of an aromatically substituted thiazolidine-2,4-dione nucleus in the molecule conditions antimicrobial activity. TZD derivatives seem to be suitable candidates for the development of new drugs. In the experimental part molecular docking of a series of 5-(hetero)arylmethylidenethiazolidine-2,4-diones, including the substances synthesized by us, was performed into the MurD ligase of E. coli. Furthermore eleven syntheses of 5-(hetero)arylmethylidenethiazolidine-2,4-diones were performed using Knoevenagel condensation of TZD with (hetero)aromatic aldehydes. Ten products were successfully synthesized and were characterized by melting points, NMR, IR, and MS spectra, and their purity was verified by accomplishment of elemental analysis. The obtained substances were tested...
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Modulation of pKa of the recognition moiety of azaphthalocyanine sensors II.
Karlíková, Martina ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Martina Karlíková Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Title of diploma thesis: Modulation of pKa of the recognition moiety of azaphthalocyanine sensors II. Our research group recently developed the sensors based on azaphthalocyanine (AzaPc) core containing one or two phenolic groups as recognition moiety and because of them, the AzaPcs can be utilized as fluorescent sensors. The fluorescent state of the molecule depends on the pH of the environment and the pKa of the recognition moiety. The latter can be modified by altering the substituents on phenol. The formation of AzaPcs was initiated by the synthesis of their precursors. In most of the cases, the starting material was 4-hydroxyacetophenon that was modified by electrophilic substitution. The products were oxidized to corresponding vicinal ketoaldehydes using selenium dioxide and immediately condensed with diaminomaleonitrile to substituted pyrazine-2,3-dicarbonitriles. Synthesis were completed by the cyclotetramerization reaction of this dicarbonitrile with 5,6-bis(tert-butylsulfanyl)pyrazine-2,3-dicarbonitrile using magnesium butoxide as initiator. Six different congeners were obtained by this...
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Creation of a virtual library of synthetic compounds for practical use in a molecular modelling study
Vávrová, Jitka ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Jitka Vávrová Supervisor: PharmDr. Marta Kučerová, Ph.D. Title of Diploma Thesis: Creation of a virtual library of synthetic compounds for practical use in a molecular modelling study Drug development is a process requiring the analysis of a large amount of data.Creating a virtual library of synthesized compounds provides access to primary data concerning structure, results of biological activity studies, and molecular descriptors necessary for drug- like prediction. Chemical databases are usually used in virtual screening, which is a modern strategy of Computer Assisted Drug Design (CADD). Molecular docking is one of the methods. Microsoft Excel was used to create the database, which includes different structural types, e.g., pyrazine, rhodanine, thiazolidin-2,4-dione, and 1,2,4-oxadiazole derivatives prepared in the research group Design and Development of New Antimicrobial Agents. Molecules are available in a spreadsheet containing all compounds in a line-notation ready-to- dock format. To demonstrate this database's actual usage, a molecular modelling study was performed using the software Molecular Operating Environment (MOE). This study...
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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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