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Development of New Potential Antimycobacterial Active Agent Based on the Group of Salicylanilides
Monreal Férriz, Juana ; Vinšová, Jarmila (advisor) ; Opletalová, Veronika (referee) ; Polanc, Slovenko (referee)
Salicylanilides are an important class of aromatic compounds with a wide range of pharmacological activities, such as antibacterial, antifungal and anti-inflammatory, among others. Furthermore; several studies reported their potent antimycobacterial effect. Their activity results from multiple mechanisms. They are therefore interesting compounds for medicinal chemists. As phenolic- containing drugs, we hypothesised that a prodrug approach will make possible the improvement of the pharmaceutical, pharmacokinetic and/or pharmacodynamic properties of salicylanilides. This thesis describes the development of new potential antimycobacterial active agents based on this group that have shown interesting antimycobacterial activity against Mycobacterium tuberculosis, and some atypical strains. As the starting point for our research, the different strategies used in order to overcome the limited bioavailability of phenolic drugs were reviewed. Then new potentially antibacterial active prodrugs of salicylanilides, particularly N-benzyloxycarbonyl-ester and alkyl-carbamate derivatives of salicylanilide, active against M. tbc., MDR-TB strains or non-TB strains such as M. avium and M. kansasii, were prepared. Finally the physicochemical and pharmacokinetic properties of the most active synthesised compounds were...
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Synthesis and cytostatic activity of 3,5-disubstituted pentenolides analogous to gelastatin
Pavlík, Jan ; Pour, Milan (advisor) ; Starý, Ivo (referee) ; Dvořák, Dalimil (referee)
Within the framework of this thesis, a large series of 5-(acyloxymethyl)-3-aryl-5,6- dihydro-2H-pyran-2-ones was prepared and their cytostatic activity investigated. The key steps in the preparation of the compounds were alkylation of esters of substituted phenylacetic acids with 2-iodomethyl-5,5-dimethyl-1,3-dioxane, followed by cyclization to furnish a saturated lactone into which a double bond was introduced in the next step. Some of the target compounds displayed interesting cytostatic activity (IC50 < 10 µmol/L) against a panel of standard cell lines including both leukemic cells and those derived from solid tumours. The activity against colorectal carcinoma HT29 cell line, which is otherwise resistant against the standard combination of cytostatic agents used in the treatment of these tumours is especially remarkable. In the next part, the development of the synthesis of the 5-alkylidene analogues of these compounds, which are also analogous to bioactive natural products, such as the gelastatins and CR377, is described. Successful strategy is based on the use of 2-iodo allylic alcohols as the starting materials, which are converted into the target 3-substituted-5-alkylidene pentenolides via an array of Pd-catalyzed reactions, including Sonogashira coupling with methyl propiolate,...
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Phosphinoferrocene conjugates of selected amino acids
Tauchman, Jiří ; Štěpnička, Petr (advisor) ; Růžička, Aleš (referee) ; Dvořák, Dalimil (referee)
A series of chiral phosphinoferrocene amides was prepared by the condensation either of 1'- (diphenylphosphino)ferrocene-1-carboxylic acid (Hdpf) or its planar-chiral 1,2-isomers and amino acid methyl esters in the presence of peptide coupling agents. The resulting phosphinoamides were tested as ligands in Cu-catalyzed asymmetric conjugate additions of diethylzinc to chalcones and in Pd-mediated asymmetric allylic substitution reactions of 1,3- diphenylallyl acetate with the respective nucleophile (alkylation, amination and etherification). The catalytic tests were focused on an optimization of the reaction parameters (solvent, temperature, base, metal/ligand ratio) and on survey of various substrates. Compounds based on Hdpf proved to be better ligands in both catalytic reactions than their planar chiral analogues. In order to rationalize the influence of the ligand structure on the reaction course and also to interpret the catalytic results, several model complexes were prepared and structurally characterized. Other three series of non-chiral complexes were prepared from the corresponding (η6 - arene)ruthenium(II) precursor and Hdpf-glycine conjugates; the neutral complexes of the type [(arene)RuCl2(Hdpf-Gly(R)-κP)] (arene = benzene, p-cymene, hexamethyl-benzene; R = OMe, NH2, OH) as well as two...
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The repair of DNA damage induced with suphur mustard and its relationship to the cytotoxicity
Jílková, Martina ; Vopršalová, Marie (advisor) ; Herink, Josef (referee)
The aim of this study was to investigate the induction and repair mechanisms of DNA damage caused by sulphur mustard in specific cell lines and their relationship to cytotoxicity of sulphur mustard. Sulphur mustard is a chemical warfare agent of the blistering agent category, which can be misused in local conflicts, terrorist attacks and during liquidation of its storage. Sulphur mustard is an alkylating agent, which interacts with a wide range of cellular macromolecules including DNA, RNA and proteins. Sulphur mustard forms single - strand breaks, monofunctional guanine and adenine adducts, as well as interstrand cross-links involving the two guanines in interaction with DNA. This study is aimed at cross-links. We used the Single Cell Gel Electrophoresis (SCGE, comet assay) for their detection. It is a method of evaluation of single cells ambeded in agarose. It is used for detection of DNA single strand breaks in a single cell. In our modification of the method we determined cross-links, which make the alkaline DNA unwinding impossible. That is why we had to induce a standard number of single strand breaks in DNA by styreneoxide (at a certain concentration and exposure time) before the comet assay. We studied DNA repair mechanisms of specific DNA lesions using specific cell lines with clearly...
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Application of gas chromatography for determination of drug residuals
Sýkora, Richard ; Lisá, Hana (referee) ; Vávrová, Milada (advisor)
Analgesics are nowadays widely used group of drugs in human and also in veterinary medicine. Residuals of these drugs enter surface waters via discharges from the waste water treatment plants as the result of insufficient efficiency of their removal during cleaning process. In this bachelor thesis the possibilities of the analgesics residuals determination in waters using derivatization followed by gas chromatography with mass spectrometric detection were experimentally evaluated. Individual derivatization procedures were compared too. Several derivatization agents were tested and experimental parameters for selected analgesics were optimized (reaction time and temperature, amount of derivatizing agent). Further, several procedures of isolation of target compounds from water based on Solid Phase Extraction were verified. In all cases, gas chromatography with TOF-based mass spectrometric detection acts as final analytical method.
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Interspecies Comparison of Plasma Protein Binding of Recently Prepared Radopharmaceuticals
Drymlová, Petra ; Lázníček, Milan (advisor) ; Trejtnar, František (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Petra Drymlová Consultant: Prof. PharmDr. Ing. Milan Lázníček, CSc Title of thesis: Interspecies comparison of plasma protein binding of recently prepared radiopharmaceuticals. Plasma protein binding is one of the parameters, which significantly influence pharmacokinetics of drug. The aim of this thesis was to determine binding of three potential radiopharmaceuticals to the proteins of human, bovine, rabit and rat plasma by the method of equilibrium dialysis at 37řC. Concretely these compounds were bifunctional chelating agent 111In-DTPA-oxn, the derivative of commonly used chelate DTPA, and two labelled receptor specific peptides- somatostatin analog 177Lu-DOTA-NOC and gastrin derivative 111In-DOTA-MG-1. The results shows that plasma protein binding of 111In-DTPA-oxn is very low and pharmacokinetically unimportant as at the standard compound 111In-DTPA. Plasma protein binding of somatostatin derivative 177In-DOTA-NOC is between 30,0- 41,4 % and increases in order: bovine < rabbit < human < rat plasma. Statistically significant difference to human plasma was found only at bovine plasma. Plasma protein binding of peptide 111In- DOTA-MG-1 was found very low and in spite of...
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Antituberculosis Agents and Their Antimicrobial Effects.
Novotná, Eva ; Waisser, Karel (advisor) ; Kvasničková, Eva (referee) ; Lešetický, Ladislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Organic and Inorganic Chemistry Candidate: Mgr. Eva Petrlíková Supervisor: Prof. RNDr. Karel Waisser, DrSc. Title of Doctoral Thesis: Antituberculosis Agents and Their Antimicrobial Effects. The dissertation focuses on the preparation of antimycobacterially active compounds. Some of the prepared compounds were also screened for the in vitro antibacterial and antifungal activity. The prepared compounds included sulfur derivatives of 3-benzyl-2H-1,3-benzoxazine- 2,4(3H)-diones, N-(pyridylmethyl)salicylamides, sulfur derivatives of 3-(4-alkylphenyl)- 2H-1,3-benzoxazine-2,4(3H)-diones, N-benzylthiosalicylamides, benzaldehyde- Sbenzylisothiosemicarbazones, salicylaldehyde-S-benzylisothiosemicarbazones, derivatives of 1,2-bis(9H-fluoren-9-ylidene)-N,N'-diarylethane-1,2-diamine, and hybrid molecules of cholesterol and terpenes. The highest antimycobacterial activity was exerted by 3-benzyl-2H-1,3-benzoxazine- 2,4(3H)-dithione and 3-(3,4-dichlorobenzyl)-2H-1,3-benzoxazine-2,4(3H)-dithione, 3-(4- secbutylphenyl)- 7-methyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-one, N-(4-methylbenzyl) thiosalicylamide and 4-methyl-N-(4-methylbenzyl)thiosalicylamide. Salicylaldehyde- S-(4-chlorobenzyl)isothiosemicarbazone was the most active...
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Analysis of amino acids and polyamines by HPLC and CZE
Kubíčková, Anna
(EN) This work is focused on two specific classes of amines. First group comprises of cyclic polyaminocarboxylates from the DOTA (1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid) family, which are important reaction intermediates in magnetic resonance imaging (MRI) contrast agent synthesis. In the development of new contrast agents, carboxyl groups are very often protected with tert-butyl ester groups. Among these derivatives, tBu3DO3A is of the highest importance. Therefore, reverse-phase high performance liquid chromatographic (RP-HPLC) and non- aqueous capillary zone electrophoretic (CZE) methods were evaluated for qualitative and quantitative analysis of tBu3DO3A (1,4,7,10-tetraazacyclododecan-1,4,7- tris(tert-butylacetate) and two typical reaction by-products, i.e. tBu4DOTA (1,4,7,10- tetraazacyclododecan-1,4,7,10-tetrakis(tert-butylacetate) and tBu2DO2A (1,4,7,10- tetraazacyclododecan-1,4-bis(tert-butylacetate). These optimized methods were successfully applied to monitoring of real reaction mixtures during synthesis of a new MRI contrast agent. No further sample pretreatment was necessary. In the second part of the thesis, proteinogenic amino acids and polyamines were used as model analytes for development of a new post-column solid-phase reactor suitable for on-line derivatization...
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Comaprison of effectivness of quarternary amonium salts on different microbes.
Pulcová, Denisa ; Jílek, Petr (advisor) ; Voxová, Barbora (referee)
We tried to compare antimicrobial effectiveness of Benzalkonium bromide with various lengths of alkyl chains fixed in effective cationic section of the molecule in this dissertation. We worked with homologues that had the alkyl chain length 12, 14 and 16 carbon atoms and also with the mixture of homologues mixed in ratio 1 : 1 : 1. We were comparing the antimicrobial effectiveness against the members of G+, G- bacteria, torula, fungi and spores. We used agents from the Czech collection of microorganisms of the Natural science faculty of the Masaryk University Brno. Namely they are: Staphylococcus aureus, Escherichia coli, Proteus vulgaris, Serratia rubidaea, Pseudomonas aeruginosa, Candida albicans, Aspergillus niger and Bacillus subtilis. We determined MIC, MBC, MBC/N and MBC-B by the help of suspense micromethod for all strains except the fungi and spores members. Concerning the Aspergillus niger and Bacillus subtilis we determined only the MBC. This was executed by the standard suspension method. The results of effective concentrations of particular tests are mentioned in g/100ml. The antimicrobial effectiveness in the MIC test was nearly identical for all tested preparations. Concerning the bacterial strain of Staphylococcus aureus and Escherichia coli all homologues and also a mixture proved...
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