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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...
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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...
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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...
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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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Pyrazinamide derivatives as potential antimicrobial compounds
Čečetková, 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 of 5-alkylpyrazine-2-carboxylic acid as potential anti-infectives
Halířová, Martina ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
DERIVATIVES OF 5-ALKYLPYRAZINE-2-CARBOXYLIC ACID AS POTENTIAL ANTI-INFECTIVES HALÍŘOVÁ MARTINA Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic In our previous study, we have demonstrated that 5-alkylamino-N- phenylpyrazine-2-carboxamides with longer alkyl chain (C5-C8) exerted micromolar growth inhibition activity against M. tuberculosis H37Rv. We speculated that the long alkylamino chain could facilitate the penetration of lipophilic mycobacterial cell envelope. To test this hypothesis, we performed the amino to methylene isosteric exchange and designed a series of 5-alkyl-N-phenylpyrazine-2-carboxamides. 5- Alkylpyrazine-2-carboxylic acids (5-Ak-POA) were prepared by homolytic alkylation of commercially available pyrazine-2-carbonitrile by respective alkanoic acid, followed by hydrolysis of the carbonitrile group. Final derivatives were prepared by CDI mediated coupling of 5-Ak-POA with corresponding aniline at RT. Final compounds were described by melting point, elementary analysis, IR spectroscopy and 1 H, 13 C NMR. Then they were tested in vitro for antimycobacterial activity against M. tuberculosis H37Rv and several non-tuberculous mycobacterial strains. Several compounds exerted MIC of 3.13-6.25 µg mL-1 ....
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Interactions of metal nanoparticles with microorganisms
Bubáková, Eliška ; Beranová, Jana (advisor) ; Zikánová, Blanka (referee)
This thesis deals with metal nanoparticles and their antibacterial effects. Nanotechnologies have been paid intensive attention both in scientific and public area. Some metal nanoparticles possess provable antibacterial potential. Nowadays, when the growing resistance of pathogenic bacteria represents an important issue, metal nanoparticles could be one of the potential solutions to the problem. Interactions of metal nanoparticles with bacteria have however not yet been fully understood. It is also evident that their effects depend on various physical and biological factors. The cytotoxicity of nanoparticles to eukaryotic organisms has not been explored in depth either. These all are the reasons why the practical use of nanoparticles has still many limitations. This thesis summarizes information available on the topic of bactericidal effects of metal nanoparticles.
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Antibacterial effect of plant oils containing medium-chain fatty acids
Laloučková, Klára ; Skřivanová, Eva (advisor) ; Rondevaldová, Johana (referee)
This diploma thesis focuses on antibacterial effect of plant oils containing medium-chain fatty acids (MCFA). The minimum inhibitory concentration (MIC) of eight chosen plant oils was defined as the mode of the lowest concentrations that were able to reduce the bacterial growth of 13 pathogenic and 6 beneficial intestinal strains of bacteria by 80 %. Coconut (Cocos nucifera), palm, red palm and palm kernel (Elaeis guineensis), Cuphea (C. lanceolata and C. ignea), babassu (Attalea speciosa, syn. Orbignya speciosa), tucuma (Astrocaryum vulgare), and muru-muru (Astrocaryum murumuru) oils were selected. Their antibacterial activity was tested towards following bacteria: Bifidobacterium animalis, B. longum, Campylobacter jejuni, Clostridium perfringens, Enterococcus cecorum, Escherichia coli, Lactobacillus acidophilus, L. fermentum, Listeria monocytogenes, Salmonella enteritidis, S. infantis, S. typhimurium and Staphylococcus aureus. To identify the fatty acids composition of tested oils a gas chromatography was used. Consequently, the MIC of each oil towards all the bacteria was determined by a broth-microdilution test in 96-well microtitration plates. The essentiality of cleavage of selected oils by lipase was observed, in order to activate their antibacterial effect. None of the tested oils exhibited any potential to inhibit the growth of Gramnegative bacterial strains even after cleavage. Furthermore palm and palm red oil did not exhibit any antibacterial action towards any of the tested bacterial strains. The strongest antibacterial activity was observed in tucuma oil, that inhibited C. perfringens by MIC=0.14 mg/ml. Other oils inhibited the growth of C. perfringens in concentrations from 0.25 to 4.5 mg/ml. The growth of E. cecorum was inhibited by coconut, babassu, Cuphea, palm kernel, muru-muru and tucuma oil in MIC range between 1.12 - 4.5 mg/ml. The only compound active against L. monocytogenes was Cuphea oil (MIC 1.12 mg/ml). Oils that were able to inhibit the growth of S. aureus strain showed MIC from 0.56 to 2.25 mg/ml (coconut, babassu, Cuphea, palm kernel, muru-muru and tucuma oil). Undetected susceptibility of B. animalis, B. longum, L. acidophilus and L. fermentum bacterial strains to tested oils was evaluated as a positive effect. According to the foregoing statements, it can be concluded that the plant oils containing MCFA show antibacterial effect towards Grampositive strains of bacteria after their cleavage by lipase. No showed influence to beneficial intestinal microflora can be a big advantage.
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Plants traditionally used in the Czech Republic for their antimicrobial properties: An overview and comparison with scientific studies
Ježková, Pavlína ; Nový, Pavel (advisor) ; Houdková, Markéta (referee)
The use of plants in medicine and folk medicine is probably as old as humanity itself. Medicinal plants have accompanied human throughout the stages of its historical development and herbs were the first medicines which human met. Healing herbs were the most accessible and often only therapeutic agent.
In the first part of the thesis, the information about the history of medicinal plants, natural method of therapy, phytotherapy, biologically active substances of plant and about antimicrobial agents are summarized. Some specific cases of plants with antimicrobial activity are also listed.
The second part presents data obtained by comparing data on the traditional use of plants for their antimicrobial activity in folk medicine to scientific data available from the Web of Science database. The traditional use of plants was investigated according to data from the most comprehensive Czech herbarium of medicinal plants from Jiří Janča and Josef Antonín Zentrich. From a total of 363 plants, 207 species whith presumable antimicrobial activity were selected from the herbarium,. For these plants were subsequently searched and evaluated all records from scientific databases mentioning their antimicrobial activity.Sbsequently, all records on these species mentioning their antimicrobial activity were searched on the scientific database and evaluated.
After the comparison and evaluation of the data gathered about the initial 207 species, 31 plants, which should exhibit antimicrobial effects according to the aforementioned herbals but scientific records are confirmed unsatisfactorily or not at all, were selected. This group of plants can serve as the basis for future research to confirm or refute their antimicrobial activity.
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