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Synthesis of Ortho-Condensed Nitrogen Heterocycles Using Gold Complexes
Makaj, Petr ; Matouš, Petr (advisor) ; Kuneš, Jiří (referee)
5 ABSTRACT Charles University, Faculty of Pharmacy in Hradci Králové Department of Organic and Bioorganic Chemistry Candidate: Petr Makaj Supervisor: PharmDr. Petr Matouš, Ph.D Title of Thesis: Synthesis of Ortho-Condensed Nitrogen Heterocycles Using Gold Complexes This diploma thesis is focused on the preparation of pyridopyridine derivatives using gold-catalyzed cyclizations. The synthesis is based on MBS-protected propargylamine, which after substitution with aryl using Sonogashira coupling reacts with tert-butyl (3- oxopent-4-ynyl)carbamate to form substituted 1,5-enyne. The enyne thus prepared then undergoes cycloisomerization using tris(2- furanyl)phosphinegold(I)chloride as a catalyst to form pyridopyridine. Substances with this scaffold can be further used to synthesize potentially biologically active structures. Keywords: gold catalysis, cyclization, pyridopyridine derivatives, 1,8-naphthyridine derivatives
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Derivatives of Amaryllidaceae alkaloids and their biological activity: Derivatives of maritidine
Moravcová, Markéta ; Cahlíková, Lucie (advisor) ; Kuneš, Jiří (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Markéta Moravcová Supervisor: prof. Ing. Lucie Cahlíková, Ph.D. Title of diploma thesis: Derivatives of Amaryllidaceae alkaloids and their biological activity: derivatives of maritidine The object of this diploma thesis was the preparation a pilot series of semisynthetic derivatives and screenink of their biological activities. Ten aromatic esters of maritidine were prepared. The compounds were identified by LC-MS, HR-MS, NMR analysis, and optical rotation. All prepared analogues matridine were screened for in vitro inhibitory activity against hAChE and hBuChE. Most of the derivatives were inactive, only the 3-O-(4-ethylbenzoyl)maritidine derivative showed moderate activity against hBuChE with IC50 = 67.01 ± 3.12 μM. Two derivatives maritidine, 3-O-(3,5-dimethylbenzoyl)maritidine and 3-O-(3,5- dimethoxybenzoyl)maritidine, were tested for their antimycobacterial activity. The substances showed promising antimycobacterial activity against Mtb H37Ra strain (MICs = 7.81 and 15.625 µg/ml). These two derivatives maritidine were tested against different strains of microorganisms. 3-O-(3,5-dimethylbenzoyl)maritidine showed antimicrobial activity against Staphylococcus aureus (MIC =...
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Structural modification of haemanthamine
Babcová, Jitka ; Cahlíková, Lucie (advisor) ; Kuneš, Jiří (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Jitka Babcová Supervisor: prof. Ing. Lucie Cahlíková, Ph.D. Title of diploma thesis: Structural modification of haemanthamine The object of this diploma thesis was to prepare several derivates of alkaloid haemanthamine. Twelve aromatic esters of haemanthamine and two ethers were prepared. Compounds were identified by MS, NMR analysis and optical rotation and screened for their biological activities. Ten prepared derivates were screened for in vitro inhibitory activity againts hAChE and hBuChE. All derivates were considered inactive (IC50 ˃ 10 µM). Twelve derivates of haemanthamine were tested for thein antimycobacterial aktivity, using rifampicin as a standard. The most interesting antimycobacterial potencial against Mtb H37Ra strain has shown 11-O-(4-pentylbenzoyl)haemanthamine (MIC = 3,91 µg/ml), against M. aurum: 11-O-(4-tercbutyllbenzoyl)haemanthamine, 11-O-(1-naftoyl)haemanthamine a 11-O-(4-butylbenzoyl)haemanthamine (MICs = 7,81 µg/ml), against M. avium: 11-O-(4-pentylbenzoyl)haemanthamine, 11-O-(4-hexylbenzoyl)haemanthamine (MICs = 31,25 µg/ml), against M. kansasii: 11-O-(4-pentylbenzoyl)haemanthamine (MIC = 3,91 µg/ml), 11-O-(4-hexylbenzoyl)haemanthamine (MIC = 7,81...
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Synthesis of hydroxy derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione
Musilová, Jitka ; Macháček, Miloš (advisor) ; Kuneš, Jiří (referee)
Synthesis of hydroxy derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)- dione Jitka Musilová The thesis is concerned with the preparation of 16 cyclic analogues of hydroxy-salicylanilides, i.e. 3- phenyl-2H-1,3-benzoxazine-2,4(3H)-diones monosubstituted with a hydroxyl group on the heterocyclic ring. The starting hydroxysalicylanilides belonging to four series were synthesized by the microwave- assisted reaction of the respective hydroxysalicylic acid with aniline (unsubstituted or para- substituted by chlorine, methyl or methoxy groups) in the presence of phosphorus trichloride. Their treatment with ethyl-chloroformate afforded the expected 1,3-benzoxazine derivatives in 77 - 94 % yields. All compounds prepared were characterized by infrared and NMR spectroscopy and by elemental analysis. All the compounds were examined for antifungal activity in vitro against Candida albicans, C. tropicalis, C. krusei, C. glabrata, Trichosporon asahii, Trichophyton mentagrophytes, Aspergillus fumigates, and Absidia corymbifera, but none of these compounds was more active than ketoconazole. In general, parent hydroxysalicylanilides were more active than their cyclic counterparts.
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Synthetic studies of 3,5-disubstituted gamma-lactams
Coufalová, Klára ; Pour, Milan (advisor) ; Kuneš, Jiří (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Klára Coufalová Consultant: Prof. RNDr. Milan Pour, PhD. Title of Thesis: Synthetic studies of 3,5-disubstituted gamma-lactams The aim of my thesis was to synthesize lactam analogues of hydrolytically and enzymatically unstable 3,5-disubstituted five-membered lactone rings possessing an antifungal effect. I have tried to develop the preparation of 5-(acyloxymethyl)- -3-(4-methoxyfenyl)-1H-2,5-dihydropyrrol-2-one, however, even application of two reaction pathways did not (for now) successfully lead to the desired five-membered lactam ring.
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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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Synthesis of transdermal permeation enhancers on basis piperidine carboxylic acids derivatives II
Kořínek, Michal ; Hrabálek, Alexandr (advisor) ; Kuneš, Jiří (referee)
Synthesis of transdermal permeation enhancers on basis of piperidine carboxylic acids derivatives II. Michal Kořínek Supervisor: Doc. PharmDr. Alexandr Hrabálek, CSc. Transdermal permeation enhancers are substances facilitating penetration of drugs through the skin. They temporarily influence stratum corneum, the outermost protective layer of epidermis. Highly effective transkarbam 12 served as a model substance. The aim of my work was to find out the effect of cyclization on its enhancing activity. The following derivatives of piperidine-4-carboxylic acid esters were synthesized: 4-(decyloxycarbonyl)piperidinium bromide 4-(dodecyloxycarbonyl)piperidinium bromide 1-acetylpiperidine-4-carboxylic acid decyl ester 1-acetylpiperidine-4-carboxylic acid dodecyl ester 4-(decyloxycarbonyl)piperidinium 4-(decyloxycarbonyl)piperidine-1-carbamate 4-(dodecyloxycarbonyl)piperidinium 4-(dodecyloxycarbonyl)piperidine-1-carbamate These unknown substances were characterized by spectral methods. The biological activity of the prepared compounds was evaluated in vitro on porcine skin in modified Franz diffusion cell with theophylline as a model permeant. The amount of theophylline was measured by HPLC method with UV detection. The results showed a significant permeation-enhancing activity of both the carbamic acid salts and...
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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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Analysis of the structure of alkaloids using multidimensional NMR spectroscopy
Novák, Zdeněk ; Kuneš, Jiří (advisor) ; Šimůnek, Petr (referee) ; Šaman, David (referee)
This Thesis was focused on the structural analysis employing nuclear magnetic resonantion (NMR) of unknown natural substances, which were isolated at the Department of Pharmaceutical Botany and Ecology from the plants Berberis vulgaris L., Fumaria officinalis L. and Nerine bowdenii W. Watson. For this purpose, 1D (1 H NMR, 13 C NMR) and 2D (gCOSY, gHSQC, gHMBC, NOESY, …) NMR spectra were measured and interpreted. Isotopic induced effect was optimized for the determination of the constitutional isomers. To distinguish the possible stereoisomers Mosher method, chiral shift reagent, nuclear Overhauser effect, indirect spin-spin coupling and circular dichroism were used. The structures of forty- five alkaloids were determined including their absolute configuration. Ten of them have not been yet mentioned in the literature before.
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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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