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Synthesis, study and structure activity relationships of antiinflammatory drugs derived from leukotriens
Junek, Richard ; Hartl, Jiří (advisor) ; Beneš, Luděk (referee) ; Kuchař, Miroslav (referee) ; Kuneš, Jiří (referee)
7 Summary A series of arylalkanoic acids derivatives bearing methyl(phenethyl)amino groups were prepared and their antileukotrienic activities involving LTB4 were evaluated. Regression analysis of the first group of derivatives of arylacetic acid has shown a strong dependence of these activities on lipophilicity for both LTB4 receptor binding and inhibition of LTB4 biosynthesis, parabolic relationships were derived. The values of slopes of the ascending linear parts of these dependences indicate various types of hydrophobic binding at the site of ligand interaction with relevant biomacromolecules. Regression analysis showed the slightly different parabolic dependences of this activity on lipophilicity of -methyl and -unsubstituted alkanoic acids derivatives. The relationship derived for -unsubstituted alkanoic acids extended by group of similar derivatives of arylacetic acids was without any change of regression coefficients and statistical criteria. It was concluded, that the most active compounds belong to 2-arylpropanoic acids derivatives with lipophilicity close to log Popt (= 6.98). The antiinflammatory effect of the compounds under study was evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis was followed. It can be stated that the...
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4'-alkylsalicylanilides with branched aliphatic chain and the corresponding derivatives of benzoxazinedions
Divišová, Hana ; Waisser, Karel (advisor) ; Kuneš, Jiří (referee)
Three problems of antimycobacterial compounds were solved in the work. a) It was synthesis of eight new halogenated 4' -alkylsalicylanilides with branched alkyl in position 4'. b) Synthesis of new halogenated 3-(4-alkylphenyl)-1,3-benzoxazin-2,4-(3H)-diones. ) with the branched alkyl on the phenyl. Seven new halogenated 3-(4-alkylphenyl)-1,3-benzoxazin-2,4-(3H)- diones were synthesized by reaction of salicylanilides and methyl choroformiate. All the compounds were screened in vitro against three different strains of mycobacterium. The results were not finished at the time of diploma work. We assume according hypothesis of professor Waisser that the activity of the new compounds will be very perspective. .
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The synthesis of the derivatives of 2-aryl-4-methylcyclopent-2-en-1-one with potential antifungal activity
Matoušová, Eliška ; Kuneš, Jiří (advisor) ; Hrabálek, Alexandr (referee)
THE SYNTHESIS OF THE DERIVATIVES OF 2-ARYL-4-METHYLCYKLOPENT-2-EN-1-ONE WITH POTENTIAL ANTIFUNGAL ACTIVITY Eliška Matoušová ABSTRACT Several series of compounds with potential antifungal activity related to a national product incrustoporine have been synthesized in last years. The aim of this thesis was to prepare the set of carbanalogues of incrustoporine (2-arylderivatives of 4-methylcyklopent-2-en-1-one) to find whether the substitution of oxygen atom in lactone group by methylen would have any influence on the activity. We found that the antifungal effect of these compounds was very low. It means that the lactone group is necessary for the activity. All the compounds was also tested for cytotoxic activity but they did not display any significant effect. Z O 2-subst.phenyl-4-methylcyklopent-2-en-1-one O O (-) incrustoporine
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Pyridine sulphides as antituberculotic active compounds
Sýkora, Lukáš ; Kuneš, Jiří (referee) ; Klimešová, Věra (advisor)
This diploma thesis is devoted to antituberculosis drugs research. A very briefly depicts of genus Mycobacterium, structure and composition of mycobacterial cell wall allowed here better process and determination of mechanisms of antituberculosis drugs targets. The synthesis selected derivates of pyridine sulfides: 4- (phenethylsulfanyl)pyridine-2-carbonitriles are the main aim of the diploma thesis. As well as a possible mechanism of action these substances is discussed. Thus a series of 4-(phenethylsulfanyl)pyridine-2-carbonitriles were synthesized. The structures were confirmed by IR spectra, NMR spectra and elementary analyses. Antimycobacterial activities these compounds were tested against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium kansasii. None of prepared substances exhibited activity (against M. tuberculosis) comparable to clinical used antituberculosis drugs. Significant activity was observed (in compare with isoniazide) against M. kansasii and M. avium.
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Use of NMR in structural analysis of natural products
Dohnalová, Hana ; Špulák, Marcel (referee) ; Kuneš, Jiří (advisor)
This Diploma work is dedicated to the determination of the structure of unknown substances. A large number of alkaloids was isolated from an Eschscholtzia Californica plant (Papaveraceae) at the Department of Pharmaceutical Botanic and Ecology of the Pharmaceutical Faculty in Hradec Králové. Some of them were passed to the Laboratory of the structure and interaction of the biological aktive molecules along with the request for the structure analysis.The main object of this Diploma work was the identification of three of unknown subjects by the help of NMR analysis. The structures of unknown substances were identified on the basis of the NMR experiments (1 H-NMR, 13 C-NMR, DEPT, ghmqc, ghsqc, ghmqfcops a dpfgnoe). These structures were confirmed based on the comparison with the data provided in the subject publications. Now identified substances belong to isochinoline alkaloids. Namely, it is scoulerine and retikuline. The third substance was not specified in the subject publication.
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Quinazoline derivatives as compounds with potential bronchodilatory effect
Šašková, Jaroslava ; Kuneš, Jiří (referee) ; Špulák, Marcel (advisor)
This diploma thesis describes the synthesis of quinazoline derivatives structurally derived from vasicine and vasicinone, alkaloids contained in a plant Adhatoda vasica. This plant has beed used for treatment of respiratory diseases in Ayurvedic medicine for more than 2000 years. First attempts to modify the structure of vasicinone revealed the fact that the ring C wasn't necessary for the bronchodilatory effect. Thus, we decided to cut this ring off resulting in the structure of quinazoline-4-ol. Using simple alkylation reactions, we prepared the first group of derivatives. One of these molecules, 4-dimethylaminoethoxyquinazoline, possesed a promising bronchodilatory activity. We modified its structure leading to the second series of derivatives containing 9 compounds. All prepared quinazolines were tested for their bronchodilatory effect by the classical experimental in vitro model of isolated rat trachea. Most of the synthesized derivatives displayed better bronchodilatory activity than theophyllin.
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Chalcones and their analogues as potential drugs.
Chlupáčová, Marta ; Hartl, Jiří (advisor) ; Kuneš, Jiří (referee) ; Čižmárik, Jozef (referee)
1 SUMMARY This dissertation thesis deals with searching for potential drugs, particularly with preparation and biological activity study of natural compounds derivatives - chalcones. The work includes preparation of intermediates - 5-alkylated pyrazin-2-carbonitriles and 1-pyrazinyl-2-ethanones. Substituted chalcones, several series of pyrazine analogues of chalcones and Michael adducts of chalcones with different thiols were prepared as final products. In this part of the work, known reaction methodologies were used. Products were identified by melting point, resp. boiling point, IR, NMR spectra. Their purity was checked by elemental analysis. In the case of liquids, elemental analysis could not be performed, and MS spectra were recorded instead. In total were prepared 22 intermediates (9 of them have been described in our department) 62 final products (19 of them have been already described) 1 by-product 57 Unknown compounds were prepared. Synthesis of 12 compounds was not successful. The final products were tested for their antimycobacterial, antifungal, antialgal, and antiaggregating effects. The chalcones were examined for the ability to inhibit one of the cysteine protease - papain and this part of the work continued in a preliminary kinetic study of reaction addition of chalcones with thiol-...
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