|
|
Synthesis and evaluation of transdermal permeation enhancers based on terpenes
Kopečná, Monika ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Monika Kopečná Synthesis and evaluation of transdermal permeation enhancers based on terpenes Transdermal drug delivery has many advantages over the conventional routes of administration. It could make a treatment of some diseases more acceptable for patients. Other advantage is a possibility of easy interruption of treatment in case of problems. And profit comes also from the fact that the drug doesn't pass through the gastro-intestinal tract, so it avoids the first-pass effect and doesn't irritate this tract, too. But majority of drugs cannot cross the skin in sufficient amounts. To enable permeation of more drugs through the human skin, substances called transdermal permeation enhancers are used among others, some natural terpenes and amino acid derivatives such as dodecylester of 6-(dimethylamino)hexanoic acid (DDAK) are potent permeation enhancers (1) (2). The purpose of my work was to combine these potent enhancers and prepare esters of 6-(dimethylamino)hexanoic acid with selected terpenes (menthol, citronellol, linalool, farnesol and borneol) and determine their permeation-enhancing activity in vitro using two model drugs (theophylline and hydrocortisone), human skin and Franz diffusion cell. DDAK was able to increase skin flux of theophylline and hydrocortisone 23 and 37 times,...
|
|
|
Design and synthesis of new potentially antibacterial active compounds
Vosátka, Rudolf ; Vinšová, Jarmila (advisor) ; Imramovský, Aleš (referee) ; Hrabálek, Alexandr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of: Department of Organic and Bioorganic Chemistry Candidate: Mgr. Rudolf Vosátka Supervisior: prof. RNDr. Jarmila Vinšová, CSc. Consultant: PharmDr. Mgr. Martin Krátký, Ph.D. Title of Doctoral Thesis: Design and synthesis of new potentially antibacterial active compounds Tuberculosis (TB) and its resistant forms are one of the most often causes of death worldwide. It is therefore a matter of interest for many scientific groups, as well as a notable global risk of increasing resistance of bacteria and fungi, which must also be dealt with. The introduction of doctoral thesis deals with the TB in terms of epidemiology, pathogenesis, Mycobacterium tuberculosis and its current treatment, as well as its resistance problems. This work also present four basic structures, which then form the basic building blocks for the experimental part. It is triclosan, a direct inhibitor of mycobacterial enoyl-ACP reductase, antimicrobial highly effective salicylanilides, isoniazid as one of the most important antituberculotic drugs and p-aminosalicylic acid, which is a second line antituberculotic agent. The experimental part deals with variations of these structures leading to biological response, respectively antimycobacterial, antibacterial,...
|
|
|
Substituated Poly(ethylene Glycols) as Drugs Carriers
Pravda, Martin ; Hrabálek, Alexandr (advisor) ; Dittrich, Milan (referee) ; Kalendová, Andrea (referee)
The aim of this dissertation thesis was preparation of drug delivery systems for polyene antimycotics, especially amphtoricin B(AmB). Series of pH-sensitive conjugates of AmB with substituated poly(ethylene glycols) (PEG) have been synthesized and characterized for this purpose. The intermediate PEGs possess a 1,4-disubstituted benzene ring with aldehyde group at the end of the chain. The benzene ring is connected with PEG at its 4-position (with respect to the aldehyde group) by various functional groups (ether, amide, ester). Reaction of terminal aldehyde group of the substituted PEGs with AmB gave conjugates containinga pH-sensitive imine linkage, which can be presumed to exhibit antimycotic effect at sites with lowered pH value. The stability of prepared conjugates under the different physiological conditions was studied. Phosphate buffers (pH = 7,4 or 5,5) were used as model media. Stability of conjugates in human blood plasma and human blood serum was examinated. The imine linkage is split to give free AmB with half-lives of 2-45 min. The rate of acid catalysed hydrolysis depends upon substitution of the benzene ring; however, it does not depend on molecular weights ofthe PEGs used. The conjugates with ester linkage undergo enzymatic splitting in human blood plasma and/or blood serum at pH 7.4...
|
|
| |
|
|
Asymetrically substituted ureas as a skin permeation enhancers
Šíma, Martin ; Hrabálek, Alexandr (advisor) ; Vávrová, Kateřina (referee)
PharmDr. Martin Šíma Asymetrically substituted ureas as a skin permeation enhancers ABSTRACT: Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium-5-(dodecyloxycarbo-nyl)pentylcarbamate, T12) is a highly effective skin permeation enhancer. In this rigorous thesis, T12 analogs with urea function group replacing the ester one were synthetised, and evaluated in vitro as skin permeation enhancers on excised porcine skin, using theophiline as a model drug. The results were expressed by an enhancing ratio and compared with biological activity of T12 and its analogs from previous studies (alkane, ketone, amide, carbamate, and carbonate). Similarly to analogs from previous studies, there was a significant decrease in the enhancing potency. The results thus show that the ester group in the molecule of T12 is essential for its extraordinary effect.
|
|
|
Five-members N-heterocycles as potential antituberculotics
Sychra, Pavel ; Hrabálek, Alexandr (advisor) ; Kuneš, Jiří (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Pavel Sychra Supervisor: prof. PharmDr. Alexandr Hrabálek, CSc. Title of diploma thesis: Five-members N-heterocycles as potential antituberculotics Tuberculosis is widespread infectious disease predominantly caused by Mycobacterium tuberculosis. According to World Health Organization, 10.4 million new cases of tuberculosis and 1.8 million deaths from tuberculosis were registered worldwide only in 2015. In the previous work of our group it was found that 2,5- and 1,5-disubstituted tetrazoles and 2,5-disubstituted oxadiazoles bearing 3,5-dinitrobenzylsulfanyl fragment exhibited outstanding antimycobacterial activities. The aim of this work was to modify these lead structures by removing the methylsulfanyl linker and to prepare a series of 3,5-dinitrophenyl tetrazole and oxadiazole derivatives. Firstly, we prepared a series of 2- and 1-benzyl-5-(3,5-dinitrophenyl)-1H-tetrazoles by the reaction of 5-(3,5-dinitrophenyl)-1H-tetrazole with diversely substituted benzyl halide. In another part, we dealt with the preparation of tetrazole derivatives containing saturated nitrogen heterocycle. At first, it was necessary to prepare alkylating agents, which have been subsequently used for alkylation...
|
|
|
Effect of ceramide acyl chain length on the skin permeabillity
Lorenc, Petr ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Ceramides that are present in stratum corneum (SC), the uppermost layer of the skin, are responsible for skin barrier function and thus for its permeability for drugs. Their role in the formation of skin barrier has been widely described; however, up to now, their structure-activity relationships have not been fully revealed. Previous studies suggested, that the ceramide acyl chain length is a key factor for the permeability of the skin barrier. The aim of this work was to study the influence of the length of ceramide acyl chain on the permeability of the skin barrier using short ceramides, sphingosine, phytoshingosine and ceramide 2 (NS). Short ceramide analogues contained sphingosine with 18 carbon atoms and the acyl chain ranging from 2 to 18 carbon atoms. Their influence on skin permeability was tested in vitro in Franz diffusion cells on dermatomed porcine skin using two model drugs - theophylline (TH) and indomethacin (IND). Donor samples were prepared as 5% (w/v) suspension of TH and 2.5% (w/v) suspension of IND with addition of 1% (w/v) ceramide in 60% (v/v) propylene glycol. Negative samples for the comparison of the fluxes and the drug concentrations contained 5% (w/v) suspension of TH and 2.5% (w/v) suspension of IND propylene glycol without the addition of ceramide. Phosphate buffer...
|
|
|
Synthesis of 5-substituted tetrazoles - a comparison of classical synthetic aproach with synthesis under microvawe activation
Gela, Petr ; Roh, Jaroslav (advisor) ; Hrabálek, Alexandr (referee)
1. Abstract Chemistry of 5-substituted tetrazoles has been the subject of intense investigation during last ten years. 5-substituted tetrazoles have found widespread use in many branches of industry, especially in pharmacy. In many cases, 5-substituted tetrazole present an optimal isosteric analogue of carboxylic group due to similar physico-chemical properties. The advantage of 5-substituted tetrazoles is their low metabolic degradability. One of the most important uses of 5-substituted tetrazoles are antihypertensives, antagonists of angiotensin II receptors, so called "sartans". Advance in synthesis of 5-substituted tetrazoles has occurred since the publication of W. G. Finnegan in 1958. In the following years numerous new methods have been published, originating from this work. The latest trend in chemistry of tetrazoles is microwave activation instead of conventional heating. In our work we focused on efficiency of microwave activation compared to conventional heating in several methods of the preparation of 5-substituted tetrazoles. We selected a preparation of 5-phenyl-1H-tetrazole from an easily available benzonitrile as the model reaction. Surprisingly, microwave irradiation did not result in a significant decrease in the reaction time or a higher yield. Furthermore, we aimed at preparation of...
|
|
|
Direct Activation of the C-H Bond in Tetrazoles
Lubojacký, Richard ; Pour, Milan (advisor) ; Hrabálek, Alexandr (referee)
Direct activation of C-H bond in tetrazoles Richard Lubojacký, 5th grade Supervisor: Prof. RNDr. Milan Pour, Ph.D. Department of Inorganic and Organic Chemistry, Faculty of Pharmacy in Hradec Králové Within the framework of this diploma thesis, direct arylation and alkenylation of 1- substituted tetrazoles at C5 was developed and optimized. An economical preparation of a range of 1,5-disubstituted tetrazoles was thus made possible. In these reactions, Pd-catalysis in the presence of CuI and Cs2CO3 was found as optimal. Contrary to similar reactions of imidazoles and purines, it was necessary to incorporate phosphine ligands in order to stabilize Pd - intermediates and prevent them from a premature decomposition into cyanamides. A library of 1,5-disubstituted tetrazoles with very promising yields has been prepared using this method.
|
|
|
Five-members N-heterocycles as potential antituberculotics
Sychra, Pavel ; Hrabálek, Alexandr (advisor) ; Kuneš, Jiří (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Pavel Sychra Supervisor: prof. PharmDr. Alexandr Hrabálek, CSc. Title of diploma thesis: Five-members N-heterocycles as potential antituberculotics Tuberculosis is widespread infectious disease predominantly caused by Mycobacterium tuberculosis. According to World Health Organization, 10.4 million new cases of tuberculosis and 1.8 million deaths from tuberculosis were registered worldwide only in 2015. In the previous work of our group it was found that 2,5- and 1,5-disubstituted tetrazoles and 2,5-disubstituted oxadiazoles bearing 3,5-dinitrobenzylsulfanyl fragment exhibited outstanding antimycobacterial activities. The aim of this work was to modify these lead structures by removing the methylsulfanyl linker and to prepare a series of 3,5-dinitrophenyl tetrazole and oxadiazole derivatives. Firstly, we prepared a series of 2- and 1-benzyl-5-(3,5-dinitrophenyl)-1H-tetrazoles by the reaction of 5-(3,5-dinitrophenyl)-1H-tetrazole with diversely substituted benzyl halide. In another part, we dealt with the preparation of tetrazole derivatives containing saturated nitrogen heterocycle. At first, it was necessary to prepare alkylating agents, which have been subsequently used for alkylation...
|
guest ::
