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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...
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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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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...
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Enzyme tests with immobilized acetycholinesterase for the anti-Alzheimer's disease drugs characterization
Dulinová, Miriama ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical chemistry and drug control Consultant: prof. PharmDr. Martin Doležal, Ph.D. Supervisor specialist: pplk. prof. RNDr. Miroslav Pohanka, Ph.D., DSc. Student: Miriama Dulinová Title of diploma Thesis: Enzyme assays with bound cholinesterase to characterize drugs for Alzheimer's disease. Alzheimer's disease is a progressive and irreversible neurodegenerative brain disease, which is globally connected with the most common cause of dementia. The pathophysiology of the disease is not yet fully understood. Treatment of this disease is for the time being only symptomatic and is represented by inhibitors of the acetylcholinesterase. The acetylcholinesterase inhibitors are at present practically the only active substances that mitigate the effects of the Alzheimer's disease. In this thesis, we have investigated the ability to inhibit already known AChE inhibitors (rivastigmine, donepezil, galantamine, tacrine), that have been tested for their activity. We tested the effectiveness of the inhibitors with loose acetylcholinesterase (via the reference method) and subsequently with the immobilised acetylcholinesterase in clear gelatine, but also with added netted agents. (glutaraldehyd, EDC). For the purposes of our...
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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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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.
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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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Amidoximes as synthetic intermediates and potential drugs II.
Oravcová, Dominika ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Diploma thesis Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Dominika Oravcová Supervisor: PharmDr. Marta Kučerová, Ph.D. Title of the thesis: Amidoximes as synthetic intermediates and potential drugs II. Diploma thesis is focused on amidoxime derivates, specifically their esters. In the theoretical part, biological activities of amidoxime esters are described, particularly their antibacterial and antiprotozoal activity. Experimental part contains preparation of seven amidoxime esters. The syntheses afforded three N'-acetoxypyrazine-2-carboximidamides and four N'-pivaloyloxypyrazine-2-carboximidamides. Products prepared in this thesis have not yet been described in any literature. All prepared esters were characterized by their melting points and spectra - IR and NMR. Purity of these compounds was confirmed by elemental analysis. Biological activity of these esters was also tested, to check their antibacterial and antifungal abilities. Four substances showed mild activity against M. tuberculosis. Other biological tests did not show any activity.
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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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