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Synthesis of Tetrahydroacridine Inhibitors of Acetylcholinesterase
Korábečný, Jan ; Opletalová, Veronika (advisor) ; Vinšová, Jarmila (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Jan Korábečný Supervisor Assoc. prof. RNDr. Veronika Opletalová, Ph. D. Title of Doctoral Thesis Synthesis of tetrahydroacridine inhibitors of acetylcholinesterase Cholinesterase inhibitors have beneficial effects on cognitive, functional, and behavioural symptoms of Alzheimer's disease (AD). Up to date, they represent the only drugs approved by U.S: Food and Drug Administration for AD treatment. These include donepezil, rivastigmine and galantamine. Apart from the above mentioned cholinesterase inhibitors memantine is used for AD treatment as well, acting as N methyl- D-aspartate antagonist drug. Tacrine (9-amino-1,2,3,4-tetrahydroacridine) was the first cholinesterase inhibitor to obtain a marketing authorisation in symptomatic treatment of AD. However, its several side effects (hepatotoxicity and gastrointestinal discomfort) limited tacrine broader usage. Novel tacrine derivatives are extensively investigated in endeavour to find less toxic compounds with "multi-target directed ligand" profile affecting more pathological mechanisms. As a part of these research efforts, 7-methoxytacrine (7-MEOTA) has been prepared as a less toxic derivate compared to tacrine...
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Substituted benzoxazoles - synthesis and biological activity
Opálka, Lukáš ; Vinšová, Jarmila (advisor) ; Vávrová, Kateřina (referee)
There were 14 compounds prepaired, including 7 Schiff bases and 7 substitued benzoxazoles. The compounds were characterised by 1 H NMR, 13 C NMR, IR, TLC and by melting point. All the new compounds aren't described in Reaxys or in Chemical Abstracts, so they can be considered as original compounds. The reaction was done in two steps. First, the Schiff base was made by the condensation of proper aminophenol and benzaldehyde and in second step, the Schiff base was cyclized by lead (IV) acetate.
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Design of New Antibacterial Active Molecules
Vavříková, Eva ; Vinšová, Jarmila (advisor) ; Opletalová, Veronika (referee) ; Čižmáriková, Růžena (referee)
The main task of the thesis was a design and synthesis of new potential antimycobacterial active molecules. Presently, the appearance of MDR-TB strains is alarming and the development of new therapeutical agents is necessary. The work is divided into two parts; first one is related to aminopolysaccharide chitosan and its connection with appropriate antimycobacterial drugs or dyes, second part is concerned with modifications of current antituberculotics. Due to the structure and physico-chemical properties, chitosan has been found as an interesting drug carrier in biomedicinal chemistry. It is used in drug delivery system with control release of the drug in the target cells or tissues. The component of the first part of the thesis was to review molecular modelling of chitosan, especially its usage as a prodrug or carrier in a field of antibacterial, antitumor and antioxidant activity. Derivatives of chitosan linked with the first or second line antituberculotics were prepared for the purpose of decreasing hepatotoxicity of used drugs. Their antimycobacterial activity against M. tbc., M. avium and M. kansasii was 125 µg/mL for all strains. Unexpectedly, O-carboxymethyl chitosan as an intermediate showed better MIC against M. tbc. and M. avium. It means that biological activity of chitosan derivatives...
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Synthesis of benzoxazoles with potential antituberculous activity
Kadeřávková, Zuzana ; Imramovský, Aleš (referee) ; Vinšová, Jarmila (advisor)
There were 18 compounds prepared.-nine Schiff bases and nine 2-substitued 5,7-di- tertbenzoxazoles. The compounds were characterized by 1H NMR a 13C NMR spectra, IR and UV spectra, TLC and melting point. All novel compounds except the 2-(2- hydroxybenzylidenamino)phenol45 and 2-(benzo[d]oxazole-2-yl)phenol46 are not described in Beilstein Handbuch der Organischen Chemie database and in Chemical Abstracts. The compounds can be considered to be original. 2-Amino-4,6-di-tert-butylphenol was obtained by reduction and conversion of 3,5-di-tertbutyl- 1,2-benzoquinone. Schiff bases were generated by the reaction of 2-amino-4,6-ditert- butylphenol with appropriate aromatic aldehydes. Final compounds (2-substitued 5,7- di-tert-benzoxazoles) were prepared through cyclization of Schiff bases under (AcO)4Pb catalysis in glacial acetic acid.
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Development of selective agonists of adenosine receptors optimization of the synthetic procedures to obtain 2-chloropurine and analogues
Mimochodková, Lenka ; Vinšová, Jarmila (advisor) ; Špulák, Marcel (referee)
CONCLUSION This thesis describes the synthesis of nucleosides and their analogues that are of enormous importance. They are an established class of clinically useful medicinal agents, possessing antiviral and anticancer activity. From a chemical point of view, in this work, we focus on the synthesis of adenosine and nucleoside analogues. In the adenosine nucleoside series the purine base was altered at the 2- and N6-position. In the method developed by Vorbrüggen, the glycosidic bond formation is driven by the use of 2,6- dichlorpurine and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose in combination with strong Lewis acids, like trimethylsilyl trifluoromethanesulfonate and a base diazabicyclo [5.4.0]undec-7- ene. This Vorbrüggen coupling reaction is the reference in nucleoside synthesis and provides a highly reproducible method for 2,6-dichloro-9H-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine formation in high yield (86 %) with reliable and predictable stereochemistry, i.e. orientation of the glycosidic bond. Displacement of the 6-chloro atom in 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose with ammonia or isobutylamine, followed by deprotection, produced the 2-chloroadenosine and the 2- chloro-N6-isobutyladenosine. 2-Chloroadenosine and 2-chloro-N6-isobutyladenosine are used as a starting material for...
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Synthesis of antimicrobial active anilides and their sulphur analogues
Oktábec, Zbyněk ; Vinšová, Jarmila (advisor) ; Macháček, Miloš (referee)
CHARLES UNIVERSITY IN PRAGUE PHARMACEUTICAL FACULTY IN HRADEC KRÁLOVÉ DEPARTMENT OF ANORGANIC AND ORGANIC CHEMISTRY Diploma Thesis Synthesis Of Antimicrobial Active Anilides and Their Sulphur Analogues Zbyněk Oktábec Implementation of tert-butyl group into the molecule of benzoxazoles leads to enhancement of lipophility and therefore better penetration through lipoid mycobacterial cell-wall. Several derivates had shown 100-90 % activity in concentration 6,25 μg/ml against Mycobacterium tuberculosis H37Rv in our series of 5,7-di-tert-butyl-benzoxazoles substituted in position No. 2 with aromatic substituent. Metabolism of benzoxazoles probably includes the opening of their structure. The goal of this thesis is to synthesize substituted N-(3,5-di-tert-butyl-2-hydroxyphenyl)benzamides and pyridinecarboxamides, their so-called "open forms". These structures could be also considered as "reversed salicylanilides" which have also a significant antitubercular activity. The first step of the synthesis of these analogues is preparation of 2-amino-3,5-di-tert- butylphenol. It was prepared by reaction of 3,5-di-tert-butylbenzo-1,2-quinone with ammonia and following reduction by NaBH4. Resulting DTB-aminophenol has been condensed with appropriate aromatic or heteroaromatic acids, while PCl3 in chlorobenzene was...
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Synthesis of salicylanilide prodrugs
Krátký, Martin ; Vinšová, Jarmila (advisor) ; Imramovský, Aleš (referee)
KRÁTKÝ, Martin. Synthesis of Salicylanilide Prodrugs. Hradec Králové: Faculty of Pharmacy of Charles University, 2008. 75 pp. Diploma Thesis. This diploma thesis is concerned with synthesis of antibacterial prodrugs based on esters of salicylanilides with amino acids. First there are characterized prodrugs and their importance and then biological activities and application of salicylanilides. The main goal of this work was the synthesis of prodrugs of salicylanilides amino acids esters. Some synthesized compounds were evaluated especially for their activity against atypical Mycobacteria strains. These compounds possess antimycobacterial activity, but it is lower than initial salicylanilide 5-chloro- N-(3-chlorophenyl)-2-hydroxybenzamide. This diploma thesis acknowledges rearrangement after N-deprotection and α-amino group liberation of N-protected amino acids esters with salicylanilides to furnish diamides. The diamide was esterified by Z-amino acids (L-phenylalanine and glycine). These obtained esters were N- deprotected and the amino group was liberated. After this liberation there was described rearrangement to furnish probably triamides, analogously to furnishing of diamides. There are discussed two possible mechanisms of rearrangement - with forming of seven-membered benzoxazepinedione rings...
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Synthesis of xanthone derivatives by microwave-assisted methods
Vrbata, Petr ; Macháček, Miloš (advisor) ; Vinšová, Jarmila (referee)
Synthesis of Xanthone Derivatives by Microwave-assisted Methods Petr Vrbata This diploma thesis deals with preparation of xanthone derivatives as inhibitors of growth of human cancer cell lines. A new methodology for synthesis of dihydropyranoxanthones 1 and 2, based on the usage of heterogeneous catalysis combined with microwave irradiation, was optimized. This allowed decreasing significantly the reaction time and improving yields. Along with this the Grover, Shah and Shah method (J. Chem. Soc. 1955, 3982) for synthesis of xanthone derivatives was improved due to usage of microwave heating. Using this method a new xanthone derivate 5,8,10-trihydroxy-7H-benzo[c]xanthen-7-on (3) was prepared. Its structure was verified by IR, 1 H NMR and 13 C NMR spectra. O O O OH O O O OH O OH OHO OH 1 2 3
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Picolinamide Derivatives of N-Methyl Valine as New Possible Chiral Organocatalysts in the Enantioselective Reduction of Aromatic Ketimines with Trichlorosilane
Bešťák, Petr ; Pour, Milan (advisor) ; Vinšová, Jarmila (referee)
N O 5, Cl3SiH (60%, 28%ee) HN PMP H MePh HN PMP MePh H R; 36% + S; 64% 1a 1aa 1ab NH O O O Ph NH PMP O O H Ph NH PMP O O H + (90%, 22%ee) R; 39% S; 61% 5, Cl3SiH 1b 1bb 1ba A N H O O N H N ON Ph Ph OH B O 5, Cl3SiH (49%; ee's unknown) OH OH + 2a 2aa 2ab O 5 (32%; ee's unknown ) OH OH + SiCl3, 3a 3aa 3ab N O O HN 5 N N O O HN 5a N O A Diploma Thesis Abstract : Picolinamide Derivatives of N-methyl Valine Used as New Possible Chiral Organocatalysts in the Enantioselective Reduction of Aromatic Ketimines with Trichlorosilane. Petr Bešťák, 5th grade Supervisor: Prof. RNDr. Milan Pour, Ph.D. Katedra anorganické a organické chemie, Farmaceutická fakulta UK v Hradci Králové Chiral substances have become popular for pharmaceutical industry recently, due to the differences between enantiomers' and racemate's efficiency and/or safety. Asymmetric organocatalysis is a perspective approach in the synthesis of chiral substances, used as new drugs or their synthons. No doubt that this way is cheaper and easier than methods using splitting a racemic mixture. This method was developed as an attractive alternative of transition metals-using procedures (with Pd, Ir, Ti), while completely excluding their toxicity, limited usage and high costs. Chiral reduction of N-aryl ketimines like 1a, 1b with trichlorosilane can be...
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The Influence of a Small Ball Facilitation on the Effect of Exercise after the Childbirth
Vinšová, Jarmila ; Prajerová, Květa (advisor) ; Malá, Michaela (referee)
Title of work: The Influence of a Small Ball Facilitation on the Effect ofExercise after the Childbirth Aims: To verify whether the aplication of a pelvic small ball facilitation after the childbirth has any influence on the correction of abdominal muscles diastasis and correction of pelvic floor disorders. Methods: It is a qualitative research in which the method of combinated experiment (extragroup and intragroup) was used. Ten participants took part in the research and were dividend by a lot into two groups A and B. The group A did the prescribed configuration of exercises during the period of the puerperium while the group B did the same exercises besides made the pelvic small ball facilitation. The own evaluation was based on differences between input and output kinesiology analysis. The results were processed in Microsoft Office Excel XP. Results: The frrst hypothesis was confirmed. The small ball facilitation supported the effectiveness of exercise. It was discovered that there was a complete correction of abdominal muscles diastasis in more cases in group B than in group A. The second hypothesis was also confrrmed. The correction of urinal incontinence was made in a shorter period of time in group B than in group A. The results of the research cannot be accepted as generally valid because...
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