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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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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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Compounds combining pyrazinamide and p-aminosalicylic acid fragments as potential antituberculars II
Žák, Ondřej ; Zitko, Jan (advisor) ; Miletín, Miroslav (referee)
COMPOUNDS COMBINING PYRAZINAMIDE AND P-AMINOSALICYLIC ACID FRAGMENTS AS POTENTIAL ANTITUBERCULARS II ŽÁK ONDŘEJ Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic A series of new compounds combining pyrazinamide and p-aminobenzoic acid was prepared and in vitro tested for antimycobacterial activity against M. tuberculosis, M. avium, M. kansasii, M. aurum and M. smegmatis. Previously prepared 4-(5-chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (R1 = OH) exerted micromolar activity against M.tuberculosis and low in vitro cytotoxicity in HepG2 cells. Para-Aminosalicylic acid (PAS) has significant antitubercular properties based on its resemblance to p-aminobenzoic acid and interference with the folate pathway in mycobacteria. To assess the role of the PAS fragment, we designed and prepared derivatives with modified substitution on the phenyl ring (R1 ). Further modification was the exchange of 5-Cl on the pyrazine core for (alkyl)amino substituent (JZ-OZ), which was a successful modification in previous series. Final compounds were described by melting point, elementary analysis, IR spectroscopy and 1 H, 13 C NMR. Changing the PAS fragment, when we removed or replaced the OH-group at position 2, the antimycobacterial...
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Compounds combining pyrazinamide and p-aminosalicylic acid fragments as potential antituberculars II
Žák, Ondřej ; Zitko, Jan (advisor) ; Miletín, Miroslav (referee)
COMPOUNDS COMBINING PYRAZINAMIDE AND P-AMINOSALICYLIC ACID FRAGMENTS AS POTENTIAL ANTITUBERCULARS II ŽÁK ONDŘEJ Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic A series of new compounds combining pyrazinamide and p-aminobenzoic acid was prepared and in vitro tested for antimycobacterial activity against M. tuberculosis, M. avium, M. kansasii, M. aurum and M. smegmatis. Previously prepared 4-(5-chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (R1 = OH) exerted micromolar activity against M.tuberculosis and low in vitro cytotoxicity in HepG2 cells. Para-Aminosalicylic acid (PAS) has significant antitubercular properties based on its resemblance to p-aminobenzoic acid and interference with the folate pathway in mycobacteria. To assess the role of the PAS fragment, we designed and prepared derivatives with modified substitution on the phenyl ring (R1 ). Further modification was the exchange of 5-Cl on the pyrazine core for (alkyl)amino substituent (JZ-OZ), which was a successful modification in previous series. Final compounds were described by melting point, elementary analysis, IR spectroscopy and 1 H, 13 C NMR. Changing the PAS fragment, when we removed or replaced the OH-group at position 2, the antimycobacterial...
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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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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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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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