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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...
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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...
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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...
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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...
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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...
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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...
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Pyrazinamide derivatives as potential antimicrobial compounds
Martinková, Martina ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
Charles University, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical analysis Candidate: Martina Čečetková Supervisor: PharmDr. Jan Zitko, Ph.D. Title of Diploma Thesis: Pyrazinamide derivatives as potential antimicrobial compounds Even in 21st century, tuberculosis still remains a serious and global health threat. Tuberculosis is one of the 10 most common causes of death, the most burdened are developing countries, but this disease infects up to 1/3 of population worldwide. Due to ineffective treatment of tuberculosis in developing countries, the prevalence of tuberculosis which does not respond to standard treatment is increasing. It is necessary to develop new drugs effective against multidrug-resistant tuberculosis and prevent further spread of the disease. The design of final structures is based on previously synthesized molecule 6- chloro-N-(4-(4-fluorophenyl)thiazol-2-yl)pyrazine-2-carboxamide, which structure comes from first line antitubercular pyrazinamide (PZA) and 4-arylthiazol-2-amine scaffold with formerly identified antimycobacterial activity. This starting compound exhibits high activity against M. tuberculosis described by MIC = 0,78 µg/mL and low cytotoxicity. The object of study was to determine effect of substitution...
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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...
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Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers
Kollár, Jan ; Zimčík, Petr (advisor) ; Mosinger, Jiří (referee) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Jan Kollar Supervisor: prof. PharmDr. Petr Zimcik, Ph.D. Advisor: doc. PharmDr. Veronika Novakova, Ph.D. Doctoral Thesis: Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers Phthalocyanines (Pcs) and their aza-analogues (e.g. tetrapyrazinoporphyrazines, TPyzPzs) represent a promising group of organic dyes with interesting photophysical properties (strong absorption in area 650-750 nm, strong singlet oxygen production) highly suitable for the use in photodynamic therapy (PDT) of cancer. However, they have also some drawbacks lowering their potential use in PDT (low solubility in water, strong tendency to aggregate). The topic of my dissertation thesis closely follows the topic of my diploma thesis, during which TPyzPz with sixteen carboxylate groups in rigid arrangement was prepared and in which we have disclosed strong negative effect of low pH and serum proteins on photodynamic activity. In the first part of this thesis I prepared new zinc TPyzPz with eight sulfonate groups on periphery, which was characterised by good solubility in water. Sulfonates were chosen as stronger acids than carboxylic groups, so they were...
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Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers
Kollár, Jan ; Zimčík, Petr (advisor) ; Mosinger, Jiří (referee) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Jan Kollar Supervisor: prof. PharmDr. Petr Zimcik, Ph.D. Advisor: doc. PharmDr. Veronika Novakova, Ph.D. Doctoral Thesis: Synthesis of anionic phthalocyanines as potential photodynamic active photosensitizers Phthalocyanines (Pcs) and their aza-analogues (e.g. tetrapyrazinoporphyrazines, TPyzPzs) represent a promising group of organic dyes with interesting photophysical properties (strong absorption in area 650-750 nm, strong singlet oxygen production) highly suitable for the use in photodynamic therapy (PDT) of cancer. However, they have also some drawbacks lowering their potential use in PDT (low solubility in water, strong tendency to aggregate). The topic of my dissertation thesis closely follows the topic of my diploma thesis, during which TPyzPz with sixteen carboxylate groups in rigid arrangement was prepared and in which we have disclosed strong negative effect of low pH and serum proteins on photodynamic activity. In the first part of this thesis I prepared new zinc TPyzPz with eight sulfonate groups on periphery, which was characterised by good solubility in water. Sulfonates were chosen as stronger acids than carboxylic groups, so they were...
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