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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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Issues of the Cholinesterase Inhibition by the Selected Organophosphorous Pesticides In Vitro
Lázenská, Helena ; Opletalová, Veronika (advisor) ; Kuča, Kamil (referee)
QUESTIONS OF THE IN VITRO INHIBITION OF CHOLINESTERASES BY SELECTED ORGANOPHOSPHORUS PESTICIDES Helena Lázenská Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic. The aim of this study was to describe organophosphorus inhibitors paraoxone, DDVP and DFP from the aspect of the kinetics of their reaction with human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), to find IC50, and to test the in vitro potency of five selected oximes (pralidoxime, methoxime, trimedoxime, obidoxime and HI-6) to reactivate AChE and BuChE inhibited by three mentioned organophosphorus inhibitors. The inhibition of AChE and BuChE was performed by incubation with organophosphorus inhibitors at a convenient concentration and such time, that would result in about 90% activity of an enzyme. A solution of a reactivator at a final concentration 1 μM or 10 μM was added to an enzyme, after 10 min of reactivation, a solution of a substrate - acetylthiocholine-iodide or butyrylthiocholine-iodide was added, and the activity of an enzyme was measured by the spectrophotometric Ellman's method. The experiment was performed at 25 žC, pH 7,4 and in a 0,1 M phosphate buffer. According...
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Oximes as Drugs
Švehlová, Jana ; Opletalová, Veronika (advisor) ; Miletín, Miroslav (referee)
Name: Jana Švehlová Title: Oximes as Drugs Thesis Charles University in Prague, Faculty of Pharmacy in Hradec Králové Programme: Pharmacy This thesis aims at the processing data about existing and potential drugs of the oximes and amidoximes groups. First section contains information on existing drugs; second section focuses on the potential chemicals from the groups of oximes and amidoximes For the most part, oximes have been used as acetylcholinesterase-reactivating agents. The oxime group is contained in the structure of the macrolide antibiotic roxithromycin (RX) and also in the structure of some cephalosporin antibiotics of the second, third and fourth generation. Another representative of oximes used in pharmacotherapy is the antidepressant fluvoxamine, a selective serotonin reuptake inhibitor (SSRI). Potential pharmaceuticals influencing the cardiovascular system include istaroxime and its analogues which are positively inotropic. Formamidoxime, acetohydroxamic acid and formamidoxime function as nitric oxide donors and certain oximes may reduce cholesterol levels in blood. Oximes, whose molecules contain 5-benzyl-2,4-thiazolidinedione, and newer oximes in which the thiazolidinedione has been substituted with α-substituted β-phenylpropionic moiety may be used for treating diabetes. Oximes...
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In vitro reactivation of cholinesterases previously inhibited by pesticides
Drtinová, Lucie ; Opletalová, Veronika (advisor) ; Vlček, Vítězslav (referee)
In vitro reactivation of choliesterases after pesticides inhibition Organophosphate pesticides are toxic substances supplied commercially as insecticides in order to protect agricultural commodities, for suppression of epidemic events etc. The use of pesticides in the Czech Republic is strongly regulated by law similarly as in the whole EU. The regulation is aimed at monitoring and regulating the use of products containing toxic pesticides. In this diploma work, I measured the efficacy of previously synthesized oxime reactivators using the standard spectrophotometric method and multi-channel spectrophotometer. After experimental testing, the ability of selected pesticides to inhibit acetylcholinesterase (AChE) was assessed. I choose tree pesticides that are capable of binding to AChE without any metabolic activation. It was paraoxon ethyl, paraoxon methyl, and DFP. Subsequently, I experimentally observed the ability of 78 selected oximes reactivators to restore AChE activity in vitro. I proved that the DFP inhibited AChE can be reactivated with high efficacy using monopyridinium reactivators but bispyridinium reactivators are also suitable. In contrast to DFP, paraoxon ethyl as well as paraoxon methyl inhibited AChE was reactivated with only bispyridinium reactivators. Number of oxime groups isn not...
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