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Synthesis and Biological Activity of Dihydroxybenzoic Acids Derivates
Skála, Pavel ; Macháček, Miloš (advisor) ; Pytela, Oldřich (referee) ; Doležal, Martin (referee)
The dissertation focuses on such derivatives of dihydroxybenzoic acids which can be considered to be derived from salicylic acid. The prepared substances were evaluated for their antimycobacterial and antifungal activity in vitro. The work on the dissertation produced 102 compounds, including 72 original ones. The prepared initial compounds included four series of dihydroxy-N- phenylbenzamides, in which one hydroxy group is in position 2 and the position of the second one is successively changed. Their thionation using the patented method developed by our laboratory produced the corresponding dihydroxy-N-phenylthiobenzamides. The cyclization reaction of the initial dihydroxy-N-phenylbenzamides with methyl-chloroformate yielded four series of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones with hydroxy groups in positions 8, 7, 6, and 5. Direct melting of prepared 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones with Lawesson's reagent provided the expected products, 3-phenyl-4-thioxo-3,4-dihydro-2H- 1,3-benzoxazin-2-ones and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones, but only in the series of 5-hydroxy derivatives. It was the reason for a search for other methods for the preparation of thionated derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione. The highest antifungal activities were exerted by...
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Design and synthesis of BCA2 inhibitors.
Soukupová, Jitka ; Doležal, Martin (advisor) ; Musílek, Kamil (referee) ; Westwell, Andrew D. (referee)
BCA 2 (Breast Cancer Associated Protein2) is a novel monomeric RING (Really Interesting New Gene 2) - type ubiquitin E3 ligase. It was found to be overexpressed in 56 % of invasive breast cancers and its expression is correlated with a positive estrogen receptor status. The RING-type family of proteins possesses ubiquitin ligase activity and involves in protein degradation. Ubiquitylation is used to target proteins of different biological processes including proteosomal degradation or endocytosis. Polyubiquitination of target protein substrates is carried out by three classes of ubiquitin ligase enzymes, of which the diverse E3 ligase family catalyse the final step of ubiquitin transfer to specific lysyl residues of target proteins prior to proteosomal destruction. The RING-type proteins can be defined as unique linear series of conserved cysteine and histidin residues and binds two zinc atoms in a cross-brace arrangement. Studies of zinc-ejecting compounds have led to the identification of disulfiram, which has been used for alcohol aversion therapy for alcohol aversion therapy as an alcohol dehydrogenase inhibitor. In this thesis I describe the synthesis of three series of novel zinc-affinic compounds, in order to optimise selectivity of BCA2 inhibitors which could lead to the identification of...
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Chalcones and Their Analogues as Potential Drugs IX
Kopcová, Petra ; Kučerová, Marta (advisor) ; Doležal, Martin (referee)
7.2 Příloha 2 Abstract of the diploma thesis CHALCONES AND THEIR ANALOGUES AS POTENTIAL DRUGS IX. Petra Kopcová Department of Pharmaceutical Chemistry and Drug Control, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic In the theoretical part of this diploma thesis, the beneficial effects of chalcones on cardiovascular diseases are summarized. Possible mechanisms of action of synthetic and naturally occurring compounds are mentioned too. Both expected and documented effects are described. The experimental part deals with the products of Claisen-Schmidt condensation. Pyrazine analogues of chalcones with methoxy-group in the position 4 of the phenyl ring B and different alkyls in the position 5 of pyrazine ring A were synthesized. Also some intermediate products for the condensation were prepared. Five final products resulted from the experimental work. None of them has been described in literature yet. The compounds were characterized by their melting point, NMR and IR spectra. Their purity was verified by thin-layer chromatography and elemental analysis.
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Pyrazine derivatives as potential drugs I
Sedlák, Petr ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Title of diploma thesis: Pyrazine derivates as potential drugs I. Review of tuberculosis therapy and modern research were presented in this diploma thesis. Novel pyrazine derivates connected via CO-NH-NH- bridge with substituted phenyl derivates were synthesized. Novel structures were characterized by melting points, TLC, IR, 1H and 13C NMR. This set was put through in vitro biological evaluation. Log P and Clog P were also calculated and were compared with novel synthesized structures.
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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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Pyrazine derivates as potential drugs IV.
Schürger, Oliver ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Oliver Schürger: Pyrazine derivates as potential drugs IV. Keywords : tuberculosis, Mycobacterium tuberculosis, Directly Observed Treatment Strategy, Multi drug Resistence, pyrazinamide Abstract of Diploma Thesis: This review is about worldwide problem of tuberculosis and about new trends in its treatment. Also chemical search about methods of preparing substituted amides of pyrazinecarboxylic acid and pyrazine-2,5-dinitril was done. All products were characterized by melting point, TLC, elemental analysis, IR analysis, log P and some of the final products have also 1 H, 13 C NMR spectra made. Products were not been tested in biological studies yet.
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Pyrazine derivates as potential drugs III.
Bielesz, Stanislav ; Doležal, Martin (advisor) ; Chlupáčová, Marta (referee)
Derivates of pyrazine as potential drugs III Degree paper Stanislav Bielesz Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Chemistry and Drug Control, Heyrovského 1203, Hradec Králové The aim of this degree paper was to synthetise a series of derivates of pyrazine-2-carboxylic acid. In the concrete it was the series of substituated 3-phenylaminopyrazine-2,5- dicarboxamides. The substances were synthetised by common synthesis, they were characterised by their physiochemical properties (melting point, lipophility), IR spectroscopy and 1 H and 13 C NMR spectroscopy. The synthetised substancies were tested in USA for anti-tubercular activity by TAACF. The results of in vitro testing were good, but not enough for the further testing in vivo. They were also tested on the Faculty of Pharmacy against fungi. No activity was found.
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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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