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Derivates of Pyrazine as potentional drugs III.
Gryc, Michal ; Doležal, Martin (advisor) ; Zimčík, Petr (referee)
Title of the diploma thesis: Derivates of Pyrazine as potentional drugs III. Within this thesis the research focused on the current influence of tuberculosis in the world was carried out as well as its therapy. In the chemical literature, there were found some methods to prepare the substituted esters of pyrazincarboxylic acid. There was synthesized six substances of the character like esters pyrazincarboxylic acid, that had not been described so far. The compounds were synthesized in the CEM Discover microwave system with Explorer 24 autosampler and purified and separated using a CombiFlash ® Rf. Device. All the products were characterized by melting point, TLC, IR, 1 H, 13 C NMR spectra. Series of substances were subjected to in vitro biological evaluation. The work result brings some new information on the antimycobacterial activity. In addition, the calculated log P values of newly prepared compounds are also presented in this thesis.
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Synthesis of model water-soluble azaphthalocyanine fluorescence quencher
Subara, Ljiljana ; Zimčík, Petr (advisor) ; Opletalová, Veronika (referee)
1 Abstract Faculty of Pharmacy in Hradec Králové, Charles University in Prague Department of Pharmaceutical Chemistry and Drug Control Ljiljana Subara Synthesis of Model Water-Soluble Azaphthalocyanine Fluorescence Quencher Azaphthalocyanine (AzaPc) or tetrapyrazinoporphyrazine as they are often termed in literature, and its substituted derivatives have been investigated extensively for applications as photodynamic therapeutics, dyes, catalysts, liquid crystals, non-linear optical materials and as a red fluorophore. Quenching in general is a process that decreases the fluorescence of another compound. Azaphthalocyanine quenchers are synthetic dyes that decrease fluorescence by absorbing energy over a wide range of wavelengths to dissipate their absorbed energy as non fluorescence. However, in order to do so they must remain in close contact with the fluorescent compound. In this work, we describe the approaches used for the synthesis of azaphthalocyanines (AzaPc) and ways to increasing quenching properties while attaining water solubility. We synthesized a compound which had water solubility as a hydrochloride and no aggregation, however it lacked sufficient quenching properties, and remained difficult to purify on TLC. For improvement of quenching an alternative precursor substituted with a tertiary amine...
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Derivatives of Rhodanine as Potential Antifungal and Antimycobacterial Drugs
Mahmoudi Majd, Morid ; Opletalová, Veronika (advisor) ; Zimčík, Petr (referee)
MORID MAHMOUDI MAJD: Derivatives of Rhodanine as Potential Antifungal and Antimycobacterial Drugs". Diploma Thesis, Department of Pharmaceutical Chemistry and Drug Control, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, 2007 Abstract In the theoretical part of my diploma thesis some issues concerning tuberculosis and mycoses are discussed. Experimental part focused on the preparation of the following compounds 5-(2-methoxybenzylidene]-2-thioxo-1,3-thiazolidin-4-one 5-(3-methoxybenzylidene]-2-thioxo-1,3-thiazolidin-4-one 5-(4-methoxybenzylidene]-2-thioxo-1,3-thiazolidin-4-one 5-(4-bromobenzylidene]-2-thioxo-1,3-thiazolidin-4-one 5-pyridin-2-ylmethyliden-2-thioxo-1,3-thiazolidin-4-one. The compounds were prepared by the condensation of rhodanine with aromatic aldehydes in ethanol using a mixture NH4OH/NH4Cl as the catalyst. Their purity was checked by the elemental analysis and HPLC. The products were characterized by IR and NMR spectra. The susceptibility of 8 pathogenic fungal strains (Candida albicans ATCC 44859, Candida tropicalis 156, Candida krusei E 28, Candida glabrata 20/I, Trichosporon asahii 1188, Aspergillus fumigatus 231, Absidia corymbifera 272 and Trichophyton mentagrophytes 445) to these substances was determined by the microdilution broth method. No interesting...
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Development of peptidomimetics on alpha(v)beta(3) integrin receptor for tumor imaging
Fuxa, Jiří ; Miletín, Miroslav (advisor) ; Zimčík, Petr (referee)
The integrins are family of heterodimeric receptors with high importance in many cell processes. They are expressed by all multicellular animals. Mainly alpha(v)beta(3) subset plays important role in cells adhesion with surroundings. Adhesion decrease by occupation of these receptors is used as restriction for tumor metastasis or for early tumor imaging. Description of structure and three-dimensional orientation of binding place of this subset were set RGD (Arg-Gly-Asp) peptide as high affinite ligands. According to computing accounted models of interaction between RGD peptide and binding place were also nonpeptide ligands prepared. In this publication we tried to prepare potentionally usable molecules for tumor imaging on PET scanners. For the base we chose already known molecules with high affinity to alpha(v)beta(3) integrins and with iodine substitution we got possibility for radioactive labelling. Unfortunately, this incorporation of iodine into the molecule decreased IC50 to value preclusive practical using.
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Synthesis of zinc (II) aryloxy azaphthalocyanines
Vůjtěch, Petr ; Zimčík, Petr (advisor) ; Doležal, Martin (referee)
SYNTHESIS OF ZINC (II) ARYLOXY AZAPHTHALOCYANINES Petr Vujtech Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague The aim of my diploma thesis was synthesis of azaphthalocyanine (AzaPc) derivate which should be free of aggregation. The aggregation is unfavorable property of AzaPc that reduces the singlet oxygen quantum yield. There are several methods to increase the ratio monomer/aggregates. The most effective strategy involves the use of bulky substituents attached to the AzaPc`s periphery. That is why, 2,3,9,10,16,17,23,24-octa(2,6-di-iso-propyphenoxy)- 1,4,8,11,15,18,22,25-octaazaphthalocyaninato zinc(II) was prepared. Alkoxides cannot be used for cycloteramerization of aryloxy derivatives due to the well-described transetherification problems. Cyclizations in dichlorobenzene and quinoline with zinc(II) acetate were unsuccessful. Some AzaPc products appeared in reactions performed with zinc(II)acetate in pyridine or dimethylformamide, but the yields were small and the products were not perfectly pure. The best way to synthesis of aryloxy derivatives of AzaPc is reaction with Zn(quinoline)2Cl2 in a melt. Temperature of the mixture should be around 260 řC. Lower temperature causes the mixture does not react totally while the product...
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Synthesis of tetrapyridoporphyrazines with potential photodynamic activity
Vavrečková, Magda ; Zimčík, Petr (advisor) ; Kučerová, Marta (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Drug Control Candidate Magda Vavrečková Supervisor Doc. PharmDr. Petr Zimčík, Ph.D. Title of Thesis Synthesis of tetrapyridoporphyrazines with potential photodynamic activity Substituted tetrapyridoporphyrazines represent new structural type of potential photosensitizers with interesting properties for application in photodynamic therapy. The aim of this work was to synthesize two types of tetrapyridoporphyrazines with hydrophilic substituents as potential photosensitizers. Photosensitizers are substances with an ability to produce singlet oxygen after activation by light. Singlet oxygen is the key toxic species in photodynamic therapy. 2-Chloro-5,6-dimethylpyridine-3,4-dicarbonitrile (1) was prepared in the first step by condensation of tetracyanoethylene and butan-2-one. In the next step, a hydrophilic substituent was attached by nucleophilic substitution. The first precursor was prepared by reaction of compound 1 with 2-mercaptoethanol in the presence of sodium hydroxide. Similarly, the second precursor was obtained by reaction of compound 1 with diethylaminoethanol in the presence of sodium hydride. The third step involved cyclotetramerization with magnesium butoxide as...
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Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors
Šebl, René ; Zimčík, Petr (advisor) ; Holas, Ondřej (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND DRUG CONTROL Name: René Šebl Supervisor: Doc. PharmDr. Petr Zimčík,Ph.D Title of the thesis: Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors The topic of my thesis was synthesis of azaphtalocyanines containing pyrazinopyrazine units. These molecules have been published only in few publication till now. Since these molecules are extended by one pyrazine nucleuson each unit, their extended conjugation leads to an increased absorption in the higher regions of the absorption spectrum. In the first step, I focused on the synthesis of precursors for subsequent cyclotetramerization. Starting compound for the preparation of various precursors was 6,7- dichloropyrazino [2,3-b] pyrazine-2,3-dicarbonitrile. It underwent nucleophilic substitution leading to products substituted with various substiuents attached via heteroatoms such as oxygen or nitrogen. Another option is the condensation of 5,6-diaminopyrazine-2,3- dicarbonitrile with appropriate diketon. This attempt did not lead to the successful preparation of the precursor. The precursors were subsequently cyclotetramerized to corresponding macrocycles. We succeeded only with one precursor...
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Derivatives of pyrazinecarboxylic acid as potential antituberculotics (synthesis and biological evaluation)
Vaňásková, Barbora ; Doležal, Martin (advisor) ; Zimčík, Petr (referee) ; Malík, Ivan (referee)
Charles University in Prague, Faculty of Pharmacy v Hradci Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Barbora Vaňásková Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Title of Doctoral Thesis: Derivatives of pyrazinecarboxylic acid as potential antituberculotics (synthesis and biological evaluation) This doctoral thesis deals with searching for potential antituberculotic drugs derived from pyrazinecarboxylic acid. Thesis contains theoretical part, in which problematics of tuberculosis, factors hindering the effectiveness of treatment (development of resistance and HIV coinfection) and current therapeutic practice are outlined. An individual chapter is devoted to the composition of the mycobacterial cell wall. A brief overview of first-line and second-line antituberculars as well as drugs newly introduced into the clinical practice and promising derivatives in various phases of preclinical and clinical trials is further stated. Special attention is dedicated to pyrazinamide, current theories dealing with mechanism of action of this first-line antituberculotic drug and to ribosomal protein S1, a specific target of pyrazinecarboxylic acid. A summary of pyrazinamide derivatives with antimycobacterial activity published since 2011 is listed for...
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