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Synthesis of thiazolidine-2,4-dione derivatives as potential drugs I
Dušková, Anna ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Title of diploma thesis: Synthesis of thiazolidine-2,4-dione derivatives as potential drugs I Student: Anna Dušková Supervisor: PharmDr. Marta Kučerová, Ph.D. The theoretical part of this diploma thesis summarizes the biological activity of thiazolidine- 2,4-dione derivatives, focused mainly on their antibacterial, antimycobacterial and antifungal effects. The theoretical part shows that thiazolidine-2,4-dione derivatives are substances that have great potential to become good candidates for new drugs that are needed to be obtained due to the growing bacterial resistance to existing drugs. Thiazolidine-2,4-dione derivatives are already used in clinical practice as oral antidiabetics - pioglitazone and rosiglitazone. In the experimental part, I dealt with a three-step synthesis of (2,4-dioxothiazolidin-3-yl) acetic acid derivatives, which, however, was not succesful to prepare except for one product. This was followed by the synthesis of thiazolidine-2,4-dione derivatives, which consisted of the Knoevenagel condensation of thiazolidine-2,4-dione with aromatic and heterocyclic aldehydes, in which we managed to obtain a total of eight products. All substances were characterized...
Synthesis and evaluation of N-pyridylbenzamides as potential antimicrobial compounds
Suchánková, Eliška ; Zitko, Jan (advisor) ; Nováková, Veronika (referee)
SYNTHESIS AND EVALUATION OF N-PYRIDYLBENZAMIDES AS POTENTIAL ANTIMICROBIAL COMPOUNDS Eliška Suchánková Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic The derivatives of N-pyridylbenzamide were designed and synthesized to be in vitro tested for antimycobacterial activity against Mycobacterium tuberculosis H37Ra, M. smegmatis, M. aurum and in vitro cytotoxicity in HepG2 cells. These compounds are pyridinyl analogues of previously prepared N-pyrazinylbenzamides that have shown a significant in vitro antimycobacterial activity. The title compounds were synthesized by acylation of aminopyridine or chloropyridine-2-amine by selected benzoyl chlorides. Final compounds were described by elementary analysis, melting point, 1 H and 13 C spectra and IR spectroscopy. Generally, prepared compounds possess lower antimycobacterial activity than previously tested N-pyrazinylbenzamides. However, there are some cases, in which the derivatives of pyridine were more effective compared to the derivatives of pyrazine; mainly against M. smegmatis. The best antimycobacterial activity was proved for derivatives of 2-amino-6-chloropyridine and substituted benzoyl chloride, corresponding with higher lipophilicity of these compounds;...
Derivatives combining the fragment of pyrazinamide and 4-aminosalicylic acid as antimycobacterial compounds
Šlechta, Petr ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Petr Šlechta Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: MSc. Ghada Basem Bouz, Ph.D. Title of diploma thesis: Derivatives combining the fragment of pyrazinamide and 4-aminosalicylic acid as antimycobacterial compounds According to WHO, tuberculosis (TB) is the leading cause of death from a single infectious organism worldwide and the number of cases with drug resistant TB is still increasing, creating the need for new antituberculotics. Therefore, we report design, synthesis and antimicrobial evaluation of a series of hybrid compounds combining different pyrazinamide derivates and p- aminosalicylic acid as potential antituberculotic agents. The compounds were prepared by mixing different pyrazinecarboxylic acids, after activation by 1,1'-carbonyldiimidazole, with p- aminosalicylic acid in dimethylsulfoxide as a solvent. Obtained compounds were in vitro tested for their antimycobacterial activity against M. tuberculosis H37Rv, M. tuberculosis H37Ra and four other mycobacterial strains. Prepared compounds were also in vitro screened for antibacterial, antifungal, and cytotoxic (HepG2) activity. Most compounds showed antimycobacterial activity in range of...
Design, synthesis and evaluation of pyrazinamide derivatives as potential antimicrobial compounds II
Kučerová, Lucie ; Zitko, Jan (advisor) ; Miletín, Miroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Lucie Kučerová Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: PharmDr. Martin Juhás Title of diploma thesis: Design, synthesis and evaluation of pyrazinamide derivatives as potential antimicrobial compounds II Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex and is currently one of the most common causes of death from an infectious disease. Treatment of tuberculosis is long-term, combined and controlled to prevent resistance. Resistance is very serious and therefore treatment is always performed with more antituberculars at the same time. Finding new drugs and improving existing ones is a constant part of research. In the theoretical part I tried to summarize information about tuberculosis, its causative agent, diagnostics, possible prevention and treatment strategy. I have described the most commonly used antituberculars, especially the first- line antituberculars - pyrazinamide, from which the derivatives synthesized in my work are based. In the experimental part I described the procedures and reactions used for synthesis of the new compounds, which were formed by combining pyrazinamide with various amino acids. In this...
Design, synthesis and biological evaluation of 2,3-disubstituted pyrazines
Kerda, Marek ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Supervisor: Assoc. Prof. PharmD. Jan Zitko, PhD. Author: Marek Kerda Title of diploma thesis: Design, synthesis and biological evaluation of 2,3-disubstituted pyrazines This thesis deals with problem of tuberculosis. In a theoretical part are summarized information and knowledge about tuberculosis, nowadays epidemiology and drugs used in current treatment. There are also described drugs in the different stage of clinical trials and could be used for treatment of tuberculosis in the future. Searched information were used from accessible learning materials and in articles in online databases as Web of Science and PubMed. There are also summarized basic methods of computer design of new drugs. In practical part of this thesis was focus on novel inhibitor of prolyl-tRNA synthetase, which is based on structure of pyrazinamide. There was prepared in silico virtual library of pyrazine-based new potential ligands. Related docking to the structure of human prolyl t-RNA (pdb: 5VAD) and the bacterial version of this enzyme (pdb: 2J3M) and evaluation was performed in Molecular Operating Environment (Chemical Computing Group, Canada). From the results were predicted some of the relations between structure and activity. Virtual library of the...
Modulation of pKa of the recognition moiety of azaphthalocyanine sensors
Čermáková, Veronika ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Veronika Čermáková Supervisor: Assoc. Prof. Petr Zimčík, Ph.D. Title of Diploma Thesis: Modulation of pKa of the recognition moiety of azaphtalocyanine sensors Azaphthalocyanines (AzaPc) are macrocyclic compounds containing a large system of conjugated double bonds that enables them to absorb light in the red part of the spectrum that is promising in biological applications. They are characterized by intense red fluorescence as one of the relaxation pathways of the excited state after absorbing a photon. The fluorescence of AzaPc substituted with a phenol moieties on the periphery can be switched ON/OFF depending on the pH of the environment and the pKa of the phenolic group. In basic medium, the molecule occurs as phenolate and undergoes intramolecular charge transfer between the phenolate group (a donor) and the electron- deficient macrocyclic core (an acceptor). As a consequence of this process, the fluorescence is quenched. Switching between ON/OFF states in phenol-substituted AzaPc is dependent on the proton concentration and thus can be utilized in pH sensing. The aim of this work was to synthesize derivatives of phenol-substituted AzaPcs whose pKa is...
Amidoxime derivatives as synthetic intermediates and potential drugs
Hariková, Michaela ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Title of diploma thesis: Amidoxime derivatives as synthetic intermediates and potential drugs Student: Michaela Hariková Supervisor: PharmDr. Marta Kučerová, Ph.D. In the theoretical part of this diploma thesis, biological effects of N-hydroxykarbimidoylchlorides and amino derivatives are summarized. In addition, biologically active compounds which are synthesized from N-hydroxykarbimidoylchlorides, in particular the compounds containing isoxazole. In the experimental part, the procedures used for the synthesis of amidoxime derivatives are described. Initial compounds for the synthesis of N-hydroxykarbimidoylchlorides were the corresponding alkylated amidoximes available at the Department of Pharmaceutical Chemistry and Pharmaceutical Analysis or prepared by radical alkylation of pyrazinecarbonitrile followed by conversion to amidoxime. From the N-hydroxykarbimidoylchloride, an amino derivative was subsequently prepared. All prepared compounds were characterized by melting point, NMR and IR spectra. The purity of the substances was checked by TLC and elemental analysis. The prepared derivatives were tested in vitro for their antibacterial, antimycobacterial and antifungal activity.
Modulation of pKa of the recognition moiety of azaphthalocyanine sensors II.
Karlíková, Martina ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Martina Karlíková Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Title of diploma thesis: Modulation of pKa of the recognition moiety of azaphthalocyanine sensors II. Our research group recently developed the sensors based on azaphthalocyanine (AzaPc) core containing one or two phenolic groups as recognition moiety and because of them, the AzaPcs can be utilized as fluorescent sensors. The fluorescent state of the molecule depends on the pH of the environment and the pKa of the recognition moiety. The latter can be modified by altering the substituents on phenol. The formation of AzaPcs was initiated by the synthesis of their precursors. In most of the cases, the starting material was 4-hydroxyacetophenon that was modified by electrophilic substitution. The products were oxidized to corresponding vicinal ketoaldehydes using selenium dioxide and immediately condensed with diaminomaleonitrile to substituted pyrazine-2,3-dicarbonitriles. Synthesis were completed by the cyclotetramerization reaction of this dicarbonitrile with 5,6-bis(tert-butylsulfanyl)pyrazine-2,3-dicarbonitrile using magnesium butoxide as initiator. Six different congeners were obtained by this...
Derivatives of quinoxaline-2-carboxylic acid as potential antimicrobial compounds
Bouz, Sarah ; Zitko, Jan (advisor) ; Nováková, Veronika (referee)
(ENGLISH) Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Sarah Basem Bouz Supervisor: PharmDr. Jan Zitko, Ph.D. Title of diploma thesis: Derivatives of quinoxaline-2-carboxylic acid as potential antimicrobial compounds Despite the presence of well-established treatment plan, tuberculosis remains the number one killer of infections according to WHO. One of the reasons behind this failure in eradicating this infection is drug resistance. This fact potentiates worldwide efforts to develop new antituberculars. As part of our long-term research on pyrazine derivatives, we prepared a series of N-substituted quinoxaline-2-carboxamides, refer to fig. below. Quinoxaline-2-carboxylic acid was activated by oxalyl chloride and reacted with different anilines or benzylamines in the presence of pyridine at room temperature, overnight with stirring, and then obtained crudes were purified with flash chromatography. Final products were evaluated for in vitro antimicrobial activities against six mycobacterial strains, eight fungal stems, along with four gram positive and four gram negative bacteria of clinical importance. The most promising compound among all with broad spectrum of antimycobacterial activity (MICMtbH37Ra = 3.91...
Delineating pain and fear engrams in the prefrontal cortex
Ludínová, Kristýna ; Zitko, Jan (advisor) ; Herink, Josef (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Kristýna Ludínova Supervisor: PharmDr. Jan Zitko, Ph.D. External supervisors: Dr. Manfred Oswald, Prof. Dr. Rohini Kuner Title of diploma thesis: Delineating Pain and Fear Engrams in the Prefrontal Cortex Pain is a complex process associated with activation of various brain centres. According to evidence of imaging studies in humans and rodents the medial prefrontal cortex (mPFC) ranks amongst the brain area consistently activated during painful perception. The mPFC circuits underlies functionally-distinct processes, such as pain, emotional response, decision-making, attention amongst others. However, the precise contribution of mPFC in pain related function remains to be unknown. The aim of the study was to delineate how pain and fear are manifested at the cellular level within the regions of PFC. By employing activity dependent neuronal labelling we tested if cellular ensembles activated in pain and fear behaviours within the mPFC are distinct. We investigated a potential use of activity-dependent DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) expression in order to test for the functional role of PFC ensembles in pain and fear behaviour. Our...

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