|
|
Oxadiazoles as potential drugs
Dzámová, Pavlína ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Candidate: Pavlína Dzámová Supervisor: PharmDr. Marta Kučerová, Ph. D. Title of diploma thesis: Oxadiazoles as Potential Drugs Due to the increasing resistence of bacteria and fungi against conventional drugs, it is imperative to design and develop new antibacterial or antifungal agents. In the theoretical part of this diploma thesis,I focused on the biological activities of 1,2,4- oxadiazoles, that are known as the compounds with promising future in this direction. They are very important heterocyclic compounds with various bioactivities, such as tyrosine kinase inhibition, muscarinic agonism, histamine H3 antagonism, anti- inflammatory, antitumoral, antimicrobal and monoamine oxidase inhibition. Methodical part resumes the most important procedures for the preparation of 1,2,4-oxadiazoles. In the experimental part of this study, six new oxadiazole derivates have been synthesized. 5-Methyl-3-pyrazin-2-yl-1,2,4-oxadiazoles variably alkylated in position 5 of the pyrazine ring resulted from cyclization of corresponding pyrazin-2- karboximidamides with acetanhydride. Starting compounds for cyclization were available in our laboratory. In case of absence, they were prepared by radical alkylation of pyrazincarbonitrile and by...
|
|
|
Synthesis of arylsufanyl phthalocyanines and their aza-analogues
Málková, Anna ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
8 3. ABSTRACT Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Anna Málková Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Title of Thesis: Synthesis of arylsulfanyl phthalocyanines and their aza-analogues. Phthalocyanines (Pcs) and their aza-analogues (AzaPc), chemical substances used in photodynamic therapy, are characterized by interesting photophysical properties which may substantially vary in dependence on the character of peripheral substituents. For example, sum of singlet oxygen and fluorescence quantum yields reaches typically a value of 1 for Mg and Zn complexes while is significantly decreased for metal-free derivatives. It has been suggested from several previous experiments that this effect can be influenced by bulkiness of the peripheral substituents. The aim of this work was the synthesis of bulky 2,6-diphenylphenylsulfanyl substituted Pcs and AzaPcs with subsequent study of their photophysical properties. The synthesis started from 2,6-diphenylphenol, a commercially available substance, which was converted to corresponding O-carbamothioate with dimethylcarbamoylchloride. Isomeric S-carbamothioate was prepared using Newman-Kwart rearrangement at high temperatures and then reduced to corresponding...
|
|
|
Preparation and testing of bisquarternary pyridinium reactivators of acetylcholinesterase
Leblochová, Hana ; Opletalová, Veronika (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Hana Leblochová Consultant Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis Preparation and testing of bisquarternary pyridinium reactivators of acetylcholinesterase Within this rigorous thesis, 21 new potential bisquarternary pyridinium AChE reactivators were prepared and their reactivation abilities on dichlorvos and paraoxon inhibited AChE were determined in vitro. Pralidoxime (2-PAM), obidoxime, asoxime (HI-6), trimedoxime (TMB-4), methoxime (MMC), K027 and K203 were used as reference compounds as they are known to be able to partially reactivate paraoxon and dichlorvos inhibited AChE. The experimental data showed that 6 compounds were able to achieve reactivation parameters recommended for in vivo testing on dichlorvos inhibited hAChE and 8 compounds on paraoxon inhibited hAChE. The compounds (9), (19), (20) and (21) seem to be very promising reactivators since they were able to reactivate hAChE inhibited by both pesticides. Based on in vitro results the structure activity relationships for newly prepared compounds were determined. Compounds having an oxime group in the 2- and 4- position to the pyridinium ring, the 1,4-phenyldimethylenyl or...
|
|
|
Preparation of phenylcarbamoylpyrazine-2-carboxylic acid derivatives as potential antitubercular drugs
Janošcová, Petra ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Medicinal Chemistry and Drug analysis Consultant: PharmDr. Jan Zitko, Ph.D Student: Mgr. Petra Janošcová Title of Thesis: Preparation of phenylcarbamoylpyrazine-2-carboxylic acid derivatives as potential antitubercular drugs Tuberculosis still represents a major public health issue all over the world. The increasing number of newly detected multi-drug resistance cases indicates that there is an urgent need of discovery of new antituberculotics addressed towards new and specific targets. This is accompanied by the development of new and effective synthetic methods. This work provides an introduction to tuberculosis and its treatment. Furthermore it covers a microwave-assisted synthesis of organic acid esters and synthesis of pyrazinamide derivatives as potential antituberculotics whereas pyrazinamide is one of the most used antitubercular drugs nowadays. Series of substituted 3-(phenylcarbamoyl)pyrazine-2- carboxylic acid derivatives and their methyl esters were synthesized. Final products were characterized by 1 H and 13 C NMR and IR spectroscopy, elementary analysis was performed and melting point was measured. Lipophilic parameters log P and Clog P were calculated and log k was measured experimentally....
|
|
|
Synthesis and in vitro testing of tacrine-troloxic derivatives as potential inhibitors of acetylcholinesterase
Ondřejíček, Aleš ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Aleš Ondřejíček Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Supervisor specialist: PharmDr. Jan Korábečný, Ph.D. Title of Diploma thesis: Synthesis and in vitro testing of tacrine-trolox derivatives as potential inhibitors of acetylcholinesterase Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves gradual loss of episodic memory and impairment of cognitive functions. Characteristic histopathological hallmarks of AD are neuritic plaques and neurofibrillary tangles present in brain tissue as well as deterioration of cholinergic neurotransmission. Currently there are only two classes of drugs used for the treatment of AD. The first group represents inhibitors of acetylcholinesterase (AChEI), whereas the second only memantin, NMDA receptor antagonist. The aim of the thesis was to synthesize three series of tacrine - trolox derivatives. In particular derivatives of trolox with tacrine, 7-methoxytacrine and 6- chlorotacrine, which were connected by various linkers. To determine the therapeutical potential of new compounds Ellman method was used and results were compared with tacrine, 7-methoxytacrine and 6-chlorotacrine as standards. The...
|
|
|
Pyrazine derivatives as potential drugs IV
Janoutová, Alena ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Author: Alena Janoutová Supervisor: PharmDr. Jan Zitko, PhD. Title of diploma thesis: Pyrazine Derivatives as Potential Antituberculosis Drugs IV Drug research, potentially effective against tuberculosis, progress already for several years in the Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec Králové. This study is focused on new derivatives of pyrazinamide (PZA) prepared as potential antituberculars. PZA itself is a well-established first-line antitubercular agent and a constituent of all basic tuberculosis treatment regimens. The design of final compounds was based on the previously synthesized 5-alkylamino-N-phenylpyrazine-2-carboxamides1, which possessed promising in vitro antimycobacterial activity with MIC ranging from 0.78 to 3.13 µg/mL. The object of this study was to test the activity of derivatives with alkylamino chain modified with terminal phenyl, hydroxyl or methoxy group. Final compounds were prepared by nucleophilic substitution of chlorine with respective amines in refluxing EtOH. Reaction yields, after all purification steps, were 58-87%. Compounds were characterized by 1 H and 13 C NMR, IR, elementary analysis and...
|
|
|
Molecular modeling study of potential mycobacterial enoyl-reductase inhibitors
Slovák, František ; Holas, Ondřej (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Diplomate: František Slovák Supervisor: PharmDr. Ondřej Holas, Ph.D. Title of Diploma Thesis: Molecular modeling study of potential mycobacterial enoyl ACP reductase inhibitors. Tuberculosis is a worldwide spread infectious disease. The biggest problem of our time are completely and multi resistant strains of Mycobacterium tuberculosis that do not respond to currently known drugs. The main reason for high resistance and drug resistance is a bacillus composition of its cell wall. It contains a high proportion of mycolic acids. The synthesis of mycolic acids takes several steps. The final step is a catalytic reduction by enzyme enoyl - ACP reductase ( InhA ). This work was focused on finding new potential substances that would be able to inhibit this enzyme. There were used methods of computing and molecular modeling to search these substances. Adjusting of crystallographic structures ran in the program Maestro and docking in the MOE program. Over the 30 000 thousand molecules from the ZND (Zinc Natural Derivates) were tested by molecular docking on 3 crystallographic structures of InhA enzyme. 8 of these molecules were selected from this amount because their...
|
|
|
Synthesis of arylsufanyl phthalocyanines and their aza-analogues
Málková, Anna ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
8 3. ABSTRACT Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Anna Málková Supervisor: doc. PharmDr. Petr Zimčík, Ph.D. Title of Thesis: Synthesis of arylsulfanyl phthalocyanines and their aza-analogues. Phthalocyanines (Pcs) and their aza-analogues (AzaPc), chemical substances used in photodynamic therapy, are characterized by interesting photophysical properties which may substantially vary in dependence on the character of peripheral substituents. For example, sum of singlet oxygen and fluorescence quantum yields reaches typically a value of 1 for Mg and Zn complexes while is significantly decreased for metal-free derivatives. It has been suggested from several previous experiments that this effect can be influenced by bulkiness of the peripheral substituents. The aim of this work was the synthesis of bulky 2,6-diphenylphenylsulfanyl substituted Pcs and AzaPcs with subsequent study of their photophysical properties. The synthesis started from 2,6-diphenylphenol, a commercially available substance, which was converted to corresponding O-carbamothioate with dimethylcarbamoylchloride. Isomeric S-carbamothioate was prepared using Newman-Kwart rearrangement at high temperatures and then reduced to corresponding...
|
|
|
Transformace Sylvestrovy matice a výpočet největšího společného dělitele dvou polynomů
Eckstein, Jiří ; Zítko, Jan (advisor) ; Tůma, Miroslav (referee)
In this thesis we study the computation of the greatest common divisor of two polynomials. Firstly, properties of Sylvester matrices are considered as well as their role in computation. We then note, that this approach can be naturally generalized for several polynomials. In the penultimate section, Bézout matrices are studied as an analogy to the Sylvester ones, providing necessary comparison. Extension for more than polynomials is presented here as well. Algorithms corresponding to the individual approaches are presented as well. Finally, the algorithms are implemented in MATLAB and are compared in numerical experiments. Powered by TCPDF (www.tcpdf.org)
|
|
|
Pyrazine derivatives as potential drugs IV
Janoutová, Alena ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Author: Alena Janoutová Supervisor: PharmDr. Jan Zitko, PhD. Title of diploma thesis: Pyrazine Derivatives as Potential Antituberculosis Drugs IV Drug research, potentially effective against tuberculosis, progress already for several years in the Department of Pharmaceutical Chemistry and Drug Control Faculty of Pharmacy in Hradec Králové. This study is focused on new derivatives of pyrazinamide (PZA) prepared as potential antituberculars. PZA itself is a well-established first-line antitubercular agent and a constituent of all basic tuberculosis treatment regimens. The design of final compounds was based on the previously synthesized 5-alkylamino-N-phenylpyrazine-2-carboxamides1, which possessed promising in vitro antimycobacterial activity with MIC ranging from 0.78 to 3.13 µg/mL. The object of this study was to test the activity of derivatives with alkylamino chain modified with terminal phenyl, hydroxyl or methoxy group. Final compounds were prepared by nucleophilic substitution of chlorine with respective amines in refluxing EtOH. Reaction yields, after all purification steps, were 58-87%. Compounds were characterized by 1 H and 13 C NMR, IR, elementary analysis and...
|
guest ::
