|
|
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...
|
|
|
Creation and analysis of in-house database of pyrazine derivatives with potential antimicrobial activity
Kebakuile, Legae Gomolemo Boemo ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
In the early phases of drug design and development, scientists must overcome many challenges involved in identifying potential drug-like or lead-like compounds. This has led to the need of creating large sets of chemical data which will aid in improving the identification of pharmacophores and active compounds. Various scientific fields especially pharmacology, medicinal chemistry and biochemistry have begun to employ the use of computer sciences to aid in the screening for potential leads with more specificity with regards to drug-like compounds' or substances' bioactivity. The emphasis of this project was to create a database containing a collection of pyrazine compounds synthesized overtime in the Faculty of Pharmacy (Charles University, Hradec Kralove) with the aim of having anti-mycobacterium (and possible antibacterial and antifungal) activity, and further utilize this database to predict certain pharmacokinetic and bioavailability properties. This project seeks to demonstrate how certain molecular descriptors can be used as reliable chemoinformation to determine the likeliness or possibility of developing a lead-like or drug-like compound by utilizing computer software. An in-house database of 623 compounds saved in SMILES format was created and used in demonstrating quantitative...
|
|
|
Synthesis of BODIPY derivatives for photodynamic therapy
Rydrych, Milan ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Milan Rydrych Supervisor: Prof. PharmDr. Petr Zimčík, PhD. Name of the thesis: Synthesis of BODIPY dyes for photodynamic therapy Borron-dipyromethene dyes (BODIPYs) have been used since the 1990s for their photostability, high absorption coefficients and fluorescence quantum yields. Recently, a modification of the structure using the heavy atom effect was discovered, where high quantum yields of singlet oxygen were also achieved. This fact helped creating a family of compounds with the potential for use in photodynamic therapy (PDT). Previously described BODIPY preparations for PDT are limited by poor solubility in polar environments. This study provides an overview of current synthetic options and basic structure-effect relationships. In the experimental part of the work, three styryl disubstituted substances were prepared with λmax (absorption maximum) at wavelengths in near infrared region with good quantum yields of singlet oxygen and very good photostability. In addition to the target compounds, three 3,5- dialkoxy substituted benzaldehyde derivatives were prepared and characterized as precursors for the final compounds. Finally, the already published synthetic...
|
|
|
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.
|
|
|
Creation of a virtual library of synthetic compounds for practical use in a molecular modelling study
Vávrová, Jitka ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Jitka Vávrová Supervisor: PharmDr. Marta Kučerová, Ph.D. Title of Diploma Thesis: Creation of a virtual library of synthetic compounds for practical use in a molecular modelling study Drug development is a process requiring the analysis of a large amount of data.Creating a virtual library of synthesized compounds provides access to primary data concerning structure, results of biological activity studies, and molecular descriptors necessary for drug- like prediction. Chemical databases are usually used in virtual screening, which is a modern strategy of Computer Assisted Drug Design (CADD). Molecular docking is one of the methods. Microsoft Excel was used to create the database, which includes different structural types, e.g., pyrazine, rhodanine, thiazolidin-2,4-dione, and 1,2,4-oxadiazole derivatives prepared in the research group Design and Development of New Antimicrobial Agents. Molecules are available in a spreadsheet containing all compounds in a line-notation ready-to- dock format. To demonstrate this database's actual usage, a molecular modelling study was performed using the software Molecular Operating Environment (MOE). This study...
|
|
|
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...
|
|
|
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...
|
|
|
Pyrazine derivatives as a potential drugs
Molnárová, Marie ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical analysis Student: Mgr. Marie Molnárová Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Co-advisor: PharmDr. Ondřej Janďourek, Ph.D. Title of rigorous work: Pyrazine derivatives as a potential drugs Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Tuberculosis is a global problem because it is the most common cause of death among infectious diseases. The complication of therapy is the rise of multiresistant and extremely resistant strains. The synthesis of novel substances is focused to gain safer and active drugs. This work is focused on the synthesis of pyrazine derivatives in which substitution of pyrazine cycle with various substituents is used. It follows up the research which is established at the Department of Pharmaceutical Chemistry, Pharmaceutical Faculty in Hradec Králové. The pyrazinamide is the first line antituberculotic drug. The previous studies proved that substitution of pyrazine ring with various substituents can increase the antituberculotic and/or antifungal activity. In this work it is used aminodehalogenation reaction, the 2-chloropyrazine, as a starting substance, reacts with ring-substitued benzylamine in microwave reactor. In this...
|
|
|
Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars
Žecová, Jana ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Jana Žecová Supervisor: PharmDr. Jan Zitko, Ph.D. Title of diploma thesis: Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars Tuberculosis is a severe infectious disease, which has been afflicting the human world population for centuries. It's figuring in the scale of the deadliest diseases as well as the occurring of strains resistant to therapy requires a serious approach to this problem and the research of new therapeutic means. Among the actual antituberculars figure two compounds, PZA and PAS. Pyrazinamide is a first line drug, and its derivatives are subject of the research in the Department of Pharmaceutical chemistry and Pharmaceutical analysis. Structurally similar to 4-aminobenzoic acid, PAS is a second line antitubercular, which is again actual in the therapy of resistant form of TBC. This diploma thesis treats about possibilities of the use of compounds combining fragments of PZA and 4-aminobenzoic acid as potential antituberculars. Furthermore, this thesis evaluates the influence of PAS fragment in the derivatives prepared with this antimycobacterial purpose. The theoretical part describes the actual state of...
|
guest ::
RSS feed.