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Quinazoline derivatives as compounds with potential bronchodilatory effect III
Abo El Dahabová, Mona ; Špulák, Marcel (advisor) ; Vinšová, Jarmila (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Mona Abo El Dahabová Supervisor: PharmDr. Marcel Špulák, Ph.D. Title of diploma thesis: Quinazoline derivatives as compounds with potential bronchodilatory effect III Asthma and COPD are serious diseases worldwide, that are mostly medicated with agents possessing bronchodilatory activity. Based on our previous research, I did prepare quinazoline derivatives via changing the structure of (-)vasicinone, which showed promising bronchodilatory activity. The reactions took place mainly by the mechanism of nucleophilic substitution, which is characterized with binding of the nucleophile to the appropriate molecular target. During my diploma thesis, I have isolated the quinazoline derivatives in the form of a tertiary amine and a quaternary ammonium salts. For most of the prepared substances, I determined their bronchodilatory activity at ex vivo rat trachea, which indicated possible direction of the structure modifications of the original compounds. Keywords: Asthma, COPD, muscarine receptors, (-)vasicinon, quinazolines, bronchodilatory activity.
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Synthesis of mouse CAR receptor analogs
Jirsová, Michala ; Špulák, Marcel (advisor) ; Palát, Karel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Ing. Michala Jirsová Supervisor: PharmDr. Marcel Špulák Ph.D. Title of thesis: Synthesis of mouse CAR receptor analogs This diploma thesis is focused on the synthesis of potential mouse CAR receptor agonists. Prepared compounds resulted from the structural changes of the template molecule TCPOBOP, when one of the two pyridine rings was removed from the structure and the phenyl moiety was substituted by both electron donor and acceptor functional groups. The syntheses were carried out on the basis of nucleophilic aromatic substitution starting from 2,3,5-trichloropyridine and appropriately substituted phenol. A series of twenty derivatives were prepared and their potential agonism/antagonism against the mouse CAR receptor was determined. Five of the tested substances showed a weak activation effect, furthermore, potential inhibitory activity was observed for the other three substances. These prepared compounds were tested on the HepG2 cell line, and their possible effect on selected bacteria, mycobacteria and fungal strains was also investigated to verify potential toxicity. Activity was observed in only one mycobacterial strain, Mycobacterium kansasii. Keywords: CAR receptor, pyridine,...
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Synthesis of mouse CAR receptor analogs
Jirsová, Michala ; Špulák, Marcel (advisor) ; Palát, Karel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Candidate: Ing. Michala Jirsová Supervisor: PharmDr. Marcel Špulák Ph.D. Title of thesis: Synthesis of mouse CAR receptor analogs This diploma thesis is focused on the synthesis of potential mouse CAR receptor agonists. Prepared compounds resulted from the structural changes of the template molecule TCPOBOP, when one of the two pyridine rings was removed from the structure and the phenyl moiety was substituted by both electron donor and acceptor functional groups. The syntheses were carried out on the basis of nucleophilic aromatic substitution starting from 2,3,5-trichloropyridine and appropriately substituted phenol. A series of twenty derivatives were prepared and their potential agonism/antagonism against the mouse CAR receptor was determined. Five of the tested substances showed a weak activation effect, furthermore, potential inhibitory activity was observed for the other three substances. These prepared compounds were tested on the HepG2 cell line, and their possible effect on selected bacteria, mycobacteria and fungal strains was also investigated to verify potential toxicity. Activity was observed in only one mycobacterial strain, Mycobacterium kansasii. Keywords: CAR receptor, pyridine,...
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Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid
Šůs, Jan ; Roh, Jaroslav (advisor) ; Špulák, Marcel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Student: Mgr. Jan Šůs Supervisors: Assoc. Prof. PharmDr. Jaroslav Roh, Ph. D. Title of rigorosum thesis: Synthesis of cardioprotective ion chelators derived from diethylenetriaminepentaacetic acid Anthracyclines (ANTs) such as doxorubicin or daunorubicin are widely used anticancer drugs. However, their administration is associated with high risk of cardiotoxicity. Chronic ANT cardiotoxicity is characterized by dilated cardiomyopathy, with subsequent development of left ventricular contractile dysfunction and congestive heart failure. It is supposed that the complexation of ANTs with intracellular iron ions leads to the formation of reactive oxygen species, which causes serious tissue damage especially in myocardium. However, recent studies showed that the mechanism of action is more complex and the inhibition of topoisomerase IIβ (TOP2β) may play a crucial role. The only drug preventing cardiotoxicity of ANTs with established clinical efficacy is dexrazoxane (DEX). The mechanism of action of DEX is not fully elucidated, it probably involves either chelation of intracellular ions by its metabolite ADR-925 (Fig. 1) or the inhibition of TOP2β by the parent compound. Fig. 1. Dexrazoxane and its...
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Benzodiazines as compounds with potential bronchodilatory effect
Ježková, Věra ; Špulák, Marcel (advisor) ; Nováková, Veronika (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Věra Ježková Consultant: PharmDr. Marcel Špulák, PhD. Title of Thesis: Benzodiazines as compounds with potential bronchodilatory effect The most active compounds from previous screening contained (piperidine-1-yl)propyl moiety attached to quinazoline or quinoxaline rings. The goal of this project was to introduce hydroxyl into the three-membered carbon linker with a possibility of further modification. The synthesis was carried out employing the reaction of commercially available quinazolinone and racemic epichlorohydrin leading to epoxide which undergoes nucleophilic attack resulting in hydroxyquinazolinones. Similarly, this reaction sequence was applied on quinoxalinone. However, the attempts with sulphur analogue of quinazolinone and quinoxalinone failed. All prepared compounds have been evaluated for their bronchodilatory activity. The results indicated similar level of bronchodilatory effect as their precursors, except one with cyclohexylamine ring, which showed higher bronchodilatory effect.
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Quinazoline derivatives as compounds with potential bronchodilatory effect
Šašková, Jaroslava ; Špulák, Marcel (advisor) ; Kuneš, Jiří (referee)
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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Use of the NMR spectroscopy for structural analysis of the plant metabolites
Maříková, Jana ; Kuneš, Jiří (advisor) ; Špulák, Marcel (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Jana Maříková Supervisor: doc. PharmDr. Jiří Kuneš, CSc. Title of Thesis:Use of the NMR spectroscopy for structural analysis of the plant metabolites This diploma thesis is based on the structure determination of unknown compounds. These compounds, plant alkaloids, have been carried out of Fumaria officinalis L. (Fumariaceae) and Nerine bowdenii (Amaryllidaceae) at the Department of Pharmaceutical Botany and Ecology of the Faculty of Pharmacy in Hradec Králové. After that, some of them were passed to the NMR laboratory, requesting a structure determination. The goal of this diploma thesis was the sample identification of three unknown substances by NMR analysis. The unknown compounds were identified on the basic of the NMR experiments (1 H NMR, 13 C NMR, gHSQC, gHMBC, gCOSY, NOESY). Then the structures were compared with the data provided in the subject publications.
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Synthesis of substituted arylguanidines as potential drugs IX.
Vidrna, Ondřej ; Palát, Karel (advisor) ; Špulák, Marcel (referee)
Charles university in Prague Faculty of Pharmacy in Hradec Králové Department of Anorganic and Organic Chemistry Candidate: Ondřej Vidrna Supervisor: PharmDr. Karel Palát, CSc Title of diploma thesis: Synthesis of substituted arylguanidines as potential drugs IX. The increasing incidence of diseases caused by fungal and mycotic pathogens, many of which acquire resistance to available antifungal substances, causes the need for a search for new molecules inhibiting their growth. The worldwide research is focused on substances derived from guanidine which were found to be potentially active against many strains of fungi and bacteria. Faculty of Pharmacy in Hradec Králové has been researching these substances for many years. The aim is to get the most active compounds from the group of substituted arylguanidines and find a structure-activity relationships effect of these substances. In this study the seven previously undescribed molecules were synthesized: 1-(4- methyl-2-octylsulfanyl)phenylguanidinium nitrate, 1-(4-methyl-2-dodecylsulfanyl) phenylguanidinium nitrate, 1-(4-methyl-2-dodecylsulfanyl)phenyl-3,3-dimethylguanidine, octyl-(4-methyl-2-nitrophenyl)sulfide, 5-methyl-2-(octylsulfanyl)aniline, dodecyl-(4-methyl-2- nitrophenyl)sulfide and 5-methyl-2-(dodecylsulfanyl)aniline. Three of them were...
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New derivatives of combretastatine
Horký, Pavel ; Pour, Milan (advisor) ; Špulák, Marcel (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Pavel Horký Consultant: Prof. RNDr. Milan Pour, Ph.D. Title of Thesis: New derivatives of combretastatine Four 3,4-diaryl-2,5-dihydrofuran-2-ones analogous to cytostatic combretastatines were prepared within this Diploma Thesis. Their preparation was based on the bromination of substituted acetophenones and subsequent esterification of the resultant bromo derivatives with p-bromophenylacetic acid. The esters obtained were subsequently cyclized in an intramolecular aldol process to yield 3,4-diarylfuranones, out of which one compound was further converted to 5-hydroxymethyl and 5,5-bis(hydroxymethyl) derivatives. Two compounds were subjected to screening for cytostatic activity, and evaluated as inactive.
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Use of the NMR spectroscopy for structural analysis of the secondary metabolites isolated from Berberis vulgaris L.
Hordějčuková, Anežka ; Kuneš, Jiří (advisor) ; Špulák, Marcel (referee)
Charles Univeversity in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chenistry Candidate: Anežka Hordějčuková Supervisor: doc. PharmDr. Jiří Kuneš, CSc. Title of Thesis: The use of NMR spectroscopy for structural analysis of secondary metabolites isolated from Berberis vulgaris L. This diploma thesis deals with determination of unknown substances structure. A great many alkaloids from the plant Berberis vulgaris from the Berberidaceae family has been isolated in the Department of Pharmaceutical Botany and Ecology at the Faculty of Pharmacy in Hradec Králové. Some of them were passed to the NMR laboratory, requestig a structure determination. The aim of this thesis was to identify three unknown chemical formulas isolated from the plant Berberis vulgaris with the help of NMR analysis. The unknown compounds were determined on the basis of NMR experiments (1 H NMR, 13 C NMR, gHSQC, gHMBC, gCOSY, NOESY).
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