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Preparation and evaluation of new potential antimicrobial drugs and prodrugs
Imramovský, Aleš ; Vinšová, Jarmila (advisor) ; Kríž, Miroslav (referee) ; Pazdera, Pavel (referee)
5. SUMMARY This thesis deals with the synthesis of antimicrobial active compounds from the group of salicylanilide derivates that were found to be highly antituberculosis active compounds against atypical and resistant strains of Mycobacterium tuberculosis. These derivates served as the starting substances for the synthesis of prodrugs of acetic acid and amino acid esters, with the aim to reduce toxicity and to optimize physico-chemical properties and transport to the site of action. The second group under investigation was new modifications of some contemporary antituberculosis drug (isoniazide and pyrazinamide), the combination of either of these two compounds with second active molecule through an easily splitting methane bridge, which together could serve as depot forms, after release of both parts they may act as synergists. The outcomes of a literary search, that forewent synthesis, were published as survey articles in scientific papers. They deal with: a) cyclization forms of prodrugs (paper I), b) salicylanilides and their research trends (paper II) and c) isoniazide, its mechanism of activity and structure modifications published till now (paper V). The main scope of the thesis is experimental parts whose results were parcially published and belong to enclosed articles (paper III, IV and VI)....
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HPLC methods for measuring benzocaine and its degradation products in Herplex gel
Kajfoszová, Renáta ; Vinšová, Jarmila (advisor) ; Kastner, Petr (referee)
Benzocaine as a main active substance in the Herplex gel, Galex d.d. used for healing of fever blister is treated as a local anaesthetic. According to European Pharmacopoeia titration method for determination of benzocaine is applied in the pharmaceutical industry. However its degradation products (determination of p-nitrobenzoic acid ethylester (EPNB) and p- aminobenzoic acid (PABA)) are not described in pharmacopoeias (neither Ph. Eur nor USP). Two high performance liquid chromatography methods with UV detection were developed for determination of benzocaine and both degradation products (p-nitrobenzoic acid ethylester and p-aminobenzoic acid). Procedures for extraction of these active from the Herplex gel were developed too. Optimum results were obtained with a column Eclipse XDB - C 18 (4.6 x 150 mm, 5 µm) and a mobile phase comprising glacial acetic acid solution (10%, v/v) and methanol. Injection volume was set to 10 µml and temperature to 40 ˚C. Other conditions used in methods varied. The first method for benzocaine and EPNB was set to flow rate 2 ml/min, detection time 30 min and mobile phase was carried as a gradient profile programme whereas the second method for PABA was set to flow rate 1 ml/min, detection time 10 min and glacial acetic acid solution and methanol in the rate of 90 :...
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Derivates of 5-methylpyrazine-2-carboxylic Acid as Potential Drugs
Mistríková, Katarína ; Doležal, Martin (advisor) ; Vinšová, Jarmila (referee)
Title of rigorous thesis: Derivates of 5-methylpyrazine-2-carboxylic acid as potential drugs Introduction of rigorous thesis is about tuberculosis, its occurence in the world, drug resistence, pathogenesis, diagnosis, prevention and treatment, about used and developed drugs. Further, I describe methods of carboxylic acid amides preparation, schemes of reactions and six prepared anilides. These are characterized by melting temperature, elemental analysis, IR, 1 H and 13 C NMR spectroscopy. Synthetized compounds were tested in vitro for antituberculotic, antifungal and herbicidal activity. Also values of lipophilicity log P and log K were gained. Relationship between biological activity, chemical structure and lipophilicity of prepared substances was evaluated.
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Study of Interactions between API and Excipients in Solid Drug Formulation
Oktábec, Zbyněk ; Vinšová, Jarmila (advisor) ; Pekárek, Tomáš (referee)
CHARLES UNIVERSITY IN PRAGUE PHARMACEUTICAL FACULTY IN HRADEC KRÁLOVÉ DEPARTMENT OF ANORGANIC AND ORGANIC CHEMISTRY Rigorous Thesis Study of interactions between API and excipients in solid drug formulation Mgr. Zbyněk Oktábec A drug formulation usually consists of an active pharmaceutical ingredient(s) - API(s) - combined with excipients that have been added to the formulation: 1. to facilitate its preparation 2. to ensure the required stability of the drug in the formulation during the manufacturing process 3. during the storage 4. to function as a drug delivery system 5. many others The interactions in formulations can influence pharmaceutical and biopharmaceutical properties, such as physical and chemical stability, dissolution rate, and total bioavailability, of the final dosage form. This thesis dealt with the preparation of binary mixtures of API and excipients and their analyses. The preparation of binary mixtures was in correlation with formulation process. The following analyses proceeds by Fourier transform near-infrared spectroscopy (FT-NIR), which is a fast andnon-destructive analytical technique that offers many advantages for a broad range of applications. Main topic was to observe the possible interaction of API and excipients and/or to describe the polymorphism of the API,...
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Synthesis of antimicrobial active anilides
Kozic, Ján ; Imramovský, Aleš (referee) ; Vinšová, Jarmila (advisor)
This work is talking about antimycobacterial salicylanilides and their thioxo analogues. In the introduction of this work there is a short review of biological activities of salicylanilides and description of mechanism of their action against bacterials. In details are analysed relationships between the structure and activity. There are compared antibacterial and antimycobacterial modifications of molecule of salicylanilide. The following part of this work brings the synthesis of five salicylanilides, their characteristics and the results of antimycobacterial activity. Unexpected is the relatively high activity of methoxyderivates. There is analysed also the other possibilities of synthesis of salicylanilides. Keywords: salicylanilides, antimycobacterial compounds, antituberculotics activity, relationship between the structure and activity
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Development of New Potential Antimycobacterial Active Agent Based on the Group of Salicylanilides
Monreal Férriz, Juana ; Vinšová, Jarmila (advisor) ; Opletalová, Veronika (referee) ; Polanc, Slovenko (referee)
Salicylanilides are an important class of aromatic compounds with a wide range of pharmacological activities, such as antibacterial, antifungal and anti-inflammatory, among others. Furthermore; several studies reported their potent antimycobacterial effect. Their activity results from multiple mechanisms. They are therefore interesting compounds for medicinal chemists. As phenolic- containing drugs, we hypothesised that a prodrug approach will make possible the improvement of the pharmaceutical, pharmacokinetic and/or pharmacodynamic properties of salicylanilides. This thesis describes the development of new potential antimycobacterial active agents based on this group that have shown interesting antimycobacterial activity against Mycobacterium tuberculosis, and some atypical strains. As the starting point for our research, the different strategies used in order to overcome the limited bioavailability of phenolic drugs were reviewed. Then new potentially antibacterial active prodrugs of salicylanilides, particularly N-benzyloxycarbonyl-ester and alkyl-carbamate derivatives of salicylanilide, active against M. tbc., MDR-TB strains or non-TB strains such as M. avium and M. kansasii, were prepared. Finally the physicochemical and pharmacokinetic properties of the most active synthesised compounds were...
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