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Synthesis of Pyrazine Derivates as Potential Antituberculotics I.
Eibinová, Drahomíra ; Opletalová, Veronika (referee) ; Doležal, Martin (advisor)
Theme of diploma thesis: Synthesis of Pyrazine Derivates as Potential Antituberculotics I. My diploma thesis comprises recherché concerned with contemporary importance of tuberculosis and new treatment approaches in its therapy. We have found out the methods of synthesis of amides of pyrazinecarboxylic acid derivates in chemical literature. Experimental part deal with synthesis of six new amides on the basis of pyrazinecarboxylic acid derivates, till now not published. Newly synthesized compounds have been characterized by melting points, TLC, elemental analysis, IR, 1 H and 13 C NMR spectra. In vitro data of eight new compounds are presented. My diplomat thesis brings new antimycobacterial data, antifungal data and log P values are calculated. Hradec Králové, 2010 Drahomíra Eibinová
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Pyrazine derivates as potential drugs I.
Klusoňová, Petra ; Doležal, Martin (advisor) ; Opletalová, Veronika (referee)
Title of diploma thesis: Pyrazine derivatives as potential drugs I. Review of actual worldwide problem of tuberculosis and trends in the tuberculosis treatment and chemical recherché were the parts of this work. Novel pyrazine derivatives connected via -CONH- bridge with substituted anilines were synthesized. The synthetic approach, analytical, spectroscopic, lipophilicity and biological data of twelve newly synthesized compounds were presented. All products were characterized and tested against Mycobacterium tuberculosis strain H37Rv and against eight fungal pathogen strains. Additionally, the study of inhibition of oxygen evolution rate in spinach chloroplasts and reduction of chlorophyll content in the green algae Chlorella vulgaris in the series of prepared compounds were drawn. Structure-activity relationships among the chemical structure, lipophilicity (log P), and their biological activity of the evaluated compounds were discussed as well.
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Derivatives of Rhodanine as Potential Drugs I.
Vlčková, Martina ; Opletalová, Veronika (advisor) ; Miletín, Miroslav (referee)
Příloha 3 Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Chemistry and Drug Control Diploma paper Rhodanine derivatives as potential drugs II. Martina Vlčková Compounds containing a rhodanine motive create a perspective group of molecules that are studied as antimicrobial and antiprotozoic drugs or as substances with influence on inflammatory and proliferative processes. This paper describes the condensation of rhodanine with aromatic aldehydes in alkaline medium and the biological activity of the products: 5-[4-(dimethylamino)benzylidene]-2-thioxothiazolidin-4-one, 5-(2,4-dihydroxy- benzylidene)-2-thioxothiazolidin-4-one, 5-(4-chlorbenzylidene)-2-thioxothiazolidin- 4-one and 5-pyrazin-2-ylmethylene-2-thioxothiazolidin-4-one. These products don't show significant antifungal activity except 5-(4-chlorbenzylidene)-2-thioxothiazolidin-4-one. This substance shows some inhibition effect on Trichosporon asahii (MIC/IC80/12 h = 62.5 μmol.l-1 ), Trichophyton mentagrophytes (MIC/IC80/72 h = 15.62 μmol.l-1 ), Aspergillus fumigatus (MIC/IC80/12 h = 15.62 μmol.l-1 ) and Absidia corymbifera (MIC/IC80 /12 h = 15.62 μmol.l-1 ). The inhibition activity of these compounds on Mycobacterium tuberculosis wasn't found sufficient for further investigation. The strongest...
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Derivatives of Rhodanine as Potential Drugs I
Kešetovičová, Diana ; Opletalová, Veronika (advisor) ; Kučerová, Marta (referee)
Diploma thesis title: RHODANINE DERIVATIVES AS POSSIBLE THERAPEUTICS I. Author: Diana Kešetovičová ABSTRACT The raise of microbial resistance towards commonly used antimicrobial agents enhances the need for new active substances with novel modes of action. Rhodanine (2-thioxo-1,3-thiazolidin-4-one) represents a structural motif that has not yet been applied in any antimicrobial drug. Rhodanine derivatives have already been described as substances possessing a wide spectrum of biological activity. Within this diploma thesis, condensation products of rhodanine and 3-(2- hydroxyethyl)-rhodanine with ortho-, meta- and para-substituted nitro- benzaldehydes have been prepared. The reaction was carried out in water- alcoholic medium using NH4OH/NH4Cl as a catalyst. The antifungal and antimycobacterial properties of these derivatives and their inhibitory activity on photosynthetic processes were then evaluated. A medium antifungal activity against C. albicans, T. asahii, T. mentagrophytes and A. fumigatus have been observed with the N-unsubstituted derivatives, while the N-substituted derivatives were inactive. The antimycobacterial properties of the tested compounds were not high enough (inhibition of at least 90% in the primary test) to undergo further studies. The antimycobacterial activity of the N-substituted...
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Synthesis of precursors for biologically active lactones IV.
Bémová, Hana ; Kuča, Kamil (referee) ; Opletalová, Veronika (advisor)
Charles University in Prague, Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Drug Control SYNTHESIS OF PRECURSORS FOR BIOLOGICALLY ACTIVE LACTONES IV. Rigorous Thesis Hana Piskacova A high width of biological activity of natural or synthetic unsaturated five membered lactones from the family of furan-2(5H)-ones, is the main reason why to synthesize new substances of this structure. The introductory part of the thesis deals with antineoplastic natural compounds of this type. Except of antitumour activity some unsaturated five membered lactones exhibit antifungal, antiviral, antibacterial effects, or inhibit the synthesis of cholesterol, for example. The experimental project is an extension of my diploma thesis concerned with the synthesis of precursors for lactones. These precursors - methyl (E)- and (Z)-2-bromo-5- (subst.)arylpent-2-en-4-ynoates - were prepared by Sonogashira couplings. The parent substances for couplings were arylethynes (1-ethynyl-4-(methoxymethoxy)benzen, 1-ethynyl-2-nitrobenzene, 3-ethynylaniline, 2-ethynylpyridine) and methylesters of dihalogenated prop-2-enoic acid. The dominant products of the couplings were β-monoalkynylated esters, apart from them side products of homocouplings were obtained. Reactions of E-methylesters of dihalogenated...
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Synthesis and Biological Evaluation of Selected Polysubstituted Furanones
Kratochvíl, Jiří ; Opletalová, Veronika (referee) ; Pour, Milan (advisor)
The aim of this thesis was to prepare 5-(benzyloxymethyl)-3-(4-bromophenyl)-2,5- dihydrofuran-2-one derived from cytostatically active 5-alkoxymethyl-3-(4-bromophenyl)- 2,5-dihydrofuran-2-ones. However, none of the three proposed synthetic procedures led to the target molecule. Next we focused on the preparation of a series of 5-bis(acetyloxymethyl)-3- aryl-4-phenyl-2,5-dihydrofuran-2-ones with different aryl substitution derived from the antibacterially, antifungally and cytostatically active 5-bis(acetyloxymethyl)-3- (4-bromophenyl)-4-phenyl-2,5-dihydrofuran-2-one. The aim was to explore a relationship between aryl substitution in position 3 and biological activity of the compounds. The spectrum of products was also enriched by 5-acetyloxymethyl-3-aryl-4-phenyl-2,5-dihydrofuran-2-ones. In conclusion aryl substitution leads to a significant decrease or vanishing of the antibacterial, antifungal and cytostatic effects with the exception of 5-acetyloxymethyl-3-aryl-4-phenyl-2,5- dihydrofuran-2-ones, in which marginal antifungal (Absidia corymbifera), antibacterial (Staphycoccus aureus a Staphylococcus epidermidis) and significant cytostatic (L1210, HeLa S3, CCRF-CEM, IC50 < 5 µmol.l-1 ) activities were found.
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Transport of ion channel blockers across the blood-brain barrier in vitro
Leblochová, Hana ; Opletalová, Veronika (advisor) ; Štaud, František (referee)
Transport of ion channel blockers across the blood-brain barrier in vitro Diploma thesis, 2010 Hana Leblochová Abstract Six different substances blocking ion channels were chosen (verapamil, diltiazem, nifedipine, phenobarbital, memantine, amantadine) for the purpose of this work. All these substances are routinely used in clinical practice and it is well known that adverse effects on the central nervous system can occur during therapy with them. Therefore, both single and group transport studies were carried out to investigate and compare the transport abilities of chosen ion channel antagonists to penetrate the BBB and to find out the interference between them. The required data for each substance used in single and group studies were determinated using the Transwell BBB in vitro model based on EVC304 cell line. Diazepam and carboxyfluorescein were used as internal standards for normalization of permeability data. According to the obtained data from single studies nifedipine as drug acting in periphery passes the BBB faster than internal standard diazepam (acting in CNS) and much more faster than other ion channel blockers acting in periphery, too. In clinical practice it can mean that nifedipine used for concrete clinical problem can have more CNS adverse effects in comparison to verapamil or diltiazem....
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Preparation of New Acetylcholinesterase Reactivators with an Amidoxime Functional Group and Their In Vitro Testing
Zemek, Filip ; Opletalová, Veronika (advisor) ; Jun, Daniel (referee)
1. SUMMARY Originally organophosphorus compounds were used as pesticides. Unfortunately, their irreversible inhibition of AChE was discovered, and they were widely misused as warfare agents. Presently, there is not a reactivator good enough to reverse completely irreversible inhibition of AChE. Thus, especially for military purposes, it is very important to look for better reactivators. As the reactivators can both reactivate inhibited AChE and inhibit the intact AChE, they have also been tested as potential therapeutics for Alzheimer's disease. New modification of oxime group with -NH2 was tried for better reactivation or inhibition results compared to widely used conventional drugs. Also monoquartenary and bisquartenary modifications were tested for possible improvement in activity. Wide range of substances was synthesized, which differed in homologous unit -CH2-. Thus substances with short aliphatic side chains, with partly hydrophilic properties, and those with long chains with mainly liphophilic properties as well as bisquarternary derivatives with various linking chains between two pyridininum centers were prepared and tested. Unfortunately these modifications did not prove to have any positive effect on activity or on inhibition. Some substances have shown mild reactivation possibility or inhibited...
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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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