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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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Porphyrin-based porous frameworks
Hynek, Jan ; Lang, Kamil (advisor) ; Zimčík, Petr (referee) ; Dědic, Roman (referee)
Porous frameworks are a class of materials including metal-organic frameworks (MOFs), covalent organic frameworks (COFs) or conjugated microporous polymers (CMPs). Porous frameworks are widely studied as materials for gas storage and separation, catalysis, sensing, drug delivery, water purification, microelectronics, etc. The results presented in the Thesis document that porous frameworks with photoactive porphyrin molecules incorporated in the structure are photosensitizers of singlet oxygen, O2(1 g), and can be used for photodynamic applications including the construction of antibacterial coatings and of organized structures for photodynamic therapy. The Thesis presents a complex study of photophysical properties of porphyrin-based CMPs and COFs and, for the first time, demonstrates the application of porphyrin-based COFs for photodynamic inactivation of microorganisms. The CMPs and COFs were prepared by Suzuki-Miyaura cross-coupling and Schiff base formation, respectively. The materials were characterized by IR and solid-state NMR spectroscopy. The porosity of the materials was determined via N2 adsorption. The CMPs are microporous with pore sizes varying from 1.4 to 2.1 nm and with specific surface areas up to 624 m2 g-1 . On the other hand, the porphyrin-based COFs are only slightly...
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Oxadiazoles as potential drugs II.
Kolčárková, Lucie ; Kučerová, Marta (advisor) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Kolčárková Lucie Supervisor: PharmDr. Marta Kučerová, Ph.D. Title of diploma thesis: Oxadiazoles as Potential Drugs II. My work was focused on finding new potential drugs with antibacterial and antifungal activity, from the reason of increasing microbial resistance against current drugs. 3-Pyrazin-2-yl-1,2,4-oxadiazole was chosen as the structural scaffold for the research. In the theoretical part of this diploma thesis I have reviewed various procedures of the preparation of 1,2,4-oxadiazoles. The methods of preparation have been assorted according to the starting material used. In the experimental part of this study several different ways of preparation to synthesize these compounds were explored and then improvement of reaction conditions in order to gain the pure product in good yields were tested. None of compounds has been reported so far. They have been characterized by IR and NMR spectra and by melting points as well. Their purity was checked by TLC and elemental analysis. Six of the synthesized compounds have been tested in vitro for their antibacterial and antifungal activity. One of the compounds has shown medium antifungal activity and another one has...
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Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars
Žecová, Jana ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Jana Žecová Supervisor: PharmDr. Jan Zitko, Ph.D. Title of diploma thesis: Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars Tuberculosis is a severe infectious disease, which has been afflicting the human world population for centuries. It's figuring in the scale of the deadliest diseases as well as the occurring of strains resistant to therapy requires a serious approach to this problem and the research of new therapeutic means. Among the actual antituberculars figure two compounds, PZA and PAS. Pyrazinamide is a first line drug, and its derivatives are subject of the research in the Department of Pharmaceutical chemistry and Pharmaceutical analysis. Structurally similar to 4-aminobenzoic acid, PAS is a second line antitubercular, which is again actual in the therapy of resistant form of TBC. This diploma thesis treats about possibilities of the use of compounds combining fragments of PZA and 4-aminobenzoic acid as potential antituberculars. Furthermore, this thesis evaluates the influence of PAS fragment in the derivatives prepared with this antimycobacterial purpose. The theoretical part describes the actual state of...
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Synthesis of novel cardioprotectants and metabolites of potent anticancer drug - Bp4eT
Eisner, Tomáš ; Roh, Jaroslav (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Tomáš Eisner Supervisor: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of novel cardioprotectants and metabolites of potent anticancer drug Bp4eT Anthracyclines (ANT) such as doxorubicin, daunorubicin, or epirubicin rank among the most effective anticancer drugs. However, their major side effect is chronic cardiotoxicity leading to irreversible cardiac damage and congestive heart failure. It is assumed that this side effect is caused by reactive oxygen species, whose formation is catalyzed by the complexes of anthracyclines with iron ions. The only clinically used drug preventing ANT cardiotoxicity is dexrazoxane (DXZ, Figure 1). In this work we dealt with the synthesis of novel DXZ analogues, because the structure-activity relationship studies have not been performed yet. The main analogue named ES-5 (Figure 1) was synthesized and its cardioprotective effect was evaluated both in vitro and in vivo. Fig. 1. Structures of DXZ and ES-5 Furthermore, thiosemicarbazone Bp4eT (2-benzoylpyridine 4-ethyl-3- thiosemicarbazone, Figure 2), a potent anticancer iron chelator and its metabolites were synthesized. These compounds were used as standards in metabolic...
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Sulfonated azaphthalocyanines - synthesis and evaluation of their photodynamic activity
Jančárová, Alena ; Zimčík, Petr (advisor) ; Doležal, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Alena Jančárová Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Co-supervisor: RNDr. Miloslav Macháček, Ph.D. Title of diploma thesis: Sulfonated azaphthalocyanines - synthesis and evaluation of their photodynamic activity Photodynamic therapy is one of the methods used for destruction of undesirable cells. It combines three essentially nontoxic components: light, oxygen and a photosensitizer. Azaphthalocyanines (AzaPcs) are promising compounds with photosensitizing properties. However, their major disadvantage is their low water solubility and significant aggregation that decreases their photodynamic activity. The aim of this work was to synthesize an anionic derivative of AzaPc substituted with sulfonic groups on periphery characterized by good solubility in water and to evaluate its photodynamic properties. The first step in the synthesis was condensation of diaminomaleonitrile with benzil giving 5,6-diphenylpyrazine-2,3-dicarbonitrile. Subsequently, the cyclotetramerisation with zinc acetate in 2-dimethylaminoethanol as a solvent was performed. The final product was obtained by sulfonation with chlorosulfonic acid followed by hydrolysis with sodium hydrogen carbonate....
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Study of transalkylation of tert-butylsulfides
Kolenič, Marek ; Zimčík, Petr (advisor) ; Kučerová, Marta (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Mgr. Marek Kolenič Consultant: assoc. prof. PharmDr. Petr Zimčík, Ph.D. Title of Thesis: Study of transalkylation of tert-butylsulfides Novel, atypical and unexpected transalkylation reaction was discovered during the synthesis of highly substituted phthalocyanines. This thesis follows up with previous research and examines effect of peripheral substitution on the course of above-mentioned transalkylation reaction at tert-butysulfides. For this purpose, total six derivatives with both electrondonating and electronaccepting groups, with pyrazine core and also without any substitution, were synthesised and used. Conversion ratio to corresponding aromatic methylsulfides after reaction with methyliodide was analyzed and evaluated by 1 H NMR spectroscopy (via aliphatic signals integration). Compounds with electrodonating groups gave higher reaction rates, on the other hand electronaccepting groups made reaction slower, in extreme cases no product was even observed. One pyrazine derivative gave us new, unpublished molecule via direct N-alkylation of pyrazine instead of transalkylation reaction.
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Functionalized Polystyrene Nanomaterials for Biomedicinal Applications
Dolanský, Jiří ; Mosinger, Jiří (advisor) ; Dědic, Roman (referee) ; Zimčík, Petr (referee)
Nowadays, there is an increasing risk of bacterial infections from bacteria strains resistant towards antibiotics. Thus, it is of utmost importance to research novel therapies which can overcome this difficulty. The presented thesis focuses on the preparation, characterization and antibacterial evaluation of polystyrene polymer nanomaterials (nanofiber membranes and nanoparticles) modified with compounds that can efficiently inhibit bacterial growth either by their nature (polyethyleneimine) or by photoactivation upon visible light excitation (NO- photodonors, photosensitizers) and consequent production of highly reactive inorganic bactericidal species, nitric oxide (NO) and singlet oxygen (O2(1 g)). All materials were fully characterized by several independent methods. The concentrations of NO and O2(1 g) were measured by amperometric and time-resolved spectroscopic techniques and by variety of chemical analytic procedures. Due to the presence of bactericidal species and the efficient photogeneration of NO and O2(1 g) at physiological conditions, all materials exhibit strong antibacterial action tested on a Gram-negative bacterial strain Escherichia coli. Hence, these functionalized polymer nanomaterials may be intriguing systems for medical-, biological-, or environmental- application where a...
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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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Stability evaluation of magnesium complexes of phthalocyanines and azaphthalocyanines under acidic conditions
Mulaku, Anita ; Zimčík, Petr (advisor) ; Miletín, Miroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Anita Mulaku Supervisor: Assoc. Prof. Petr Zimčík, Ph.D. Title of Diploma Thesis: Stability evaluation of magnesium complexes of phthalocyanines and azaphthalocyanines under acidic conditions Phthalocyanines are categorized as analogues of porphyrin where the structures is based on four isoindoline units condensed via a nitrogen atom. Alongside subphthalocyanines, these compounds are attracting attention as useful dyes that find application in photodynamic therapy, organic electronic devices, organic solar cells and other areas. Phthalocyanines are capable of forming complexes with different types of metal and can be used in fluorescence probing due to their suitable absorption and emission in the red region of the visible spectrum. Red or near-infrared excitation and emission is important for biological applications since longer wavelength light penetrates deeper into tissues, it is less scattered and the autofluorescence of endogenous chromophores is limited. The photophysical and photochemical properties of phthalocyanines and their analogues depend highly on the central metal and peripheral substitution. The magnesium complexes are highly suitable for the...
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