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Derivatives of boronic acids as potential drugs I.
Koucká, Kateřina ; Kučerová, Marta (advisor) ; Zitko, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Kateřina Koucká Supervisor: PharmDr. Marta Kučerová, Ph.D. Consultant: PharmDr. Petr Šlechta Title of diploma thesis: Derivatives of boronic acids as potential drugs I. The thesis includes the design, synthesis, and biological evaluation of boronic acid derivatives. These derivatives were prepared as hybrid compounds containing an amide linker, combining mainly pyrazinoic acids with 4-aminophenylboronic acid. Pyrazinamide is used as 1st line antituberculosis drug and 4-aminophenylboronic acid is a bioisoster of 4-aminobenzoic acid, which is a crucial precursor in the folate pathway. Bioisosteric replacement of the carboxylic group with boronic acid could afford the ability of the compounds to form a reversible covalent bond toward a potential biological target. The presented compounds were synthesized in a two-step reaction. The first step was the condensation of 4-aminophenylboronic acid pinacol ester with different derivatives of (hetero)aryl carboxylic acids, that underwent previous activation. The second step was the deprotection of boronic acid pinacol ester to obtain free boronic acids derivatives. The obtained compounds were screened for their in vitro...
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Synthesis and evaluation of potential antitubercular agents based on nitro aromates
Delong, Jakub ; Krátký, Martin (advisor) ; Kučerová, Marta (referee)
The goal of the master's thesis was the synthesis and assessment of potential molecules against tuberculosis based on aromatic compounds containing nitro groups. The thesis reviews tuberculosis and its therapy, in the theoretical part, followed by well-know and new nitro group containing antibiotics. The experimental part reports multitep synthesis from parent compounds - substituted benzoic acid, pyruvic acid and variously substituted anilines, which were evaluated for their antimycobacterial activity. The core structure of the prepared compound molecules is N-phenyl-2-[2-(3,5- dinitrobenzoyl)hydrazinylidene]propanamide, which was variously substituted on the benzene ring of N-phenylpropanamide. In case of four compounds, one nitro group was switched to the trifluoromethyl group. Yields varied from 7 to 72 % and their minimum inhibitory concentrations (MIC) ranged from 4 to more than 1000 µmol/l. N-(4-Bromphenyl)-2-[2-(3,5- dinitrobenzoyl)hydrazinylidene]propanamide proved to be the most effective derivate. Key words Antibiotics, antimycobacterial activity, 3,5-dinitrobenzohydrazide, nitro group, synthesis, tuberculosis
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Synthesis and evaluation of benzoxaborole derivatives as potential antimicrobial compounds
Needle, Adam Anthony ; Kučerová, Marta (advisor) ; Demuth, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Adam Anthony Needle Supervisor: PharmDr. Marta Kučerová, Ph.D. Consultant: PharmDr. Petr Šlechta Title of diploma thesis: Synthesis and Evaluation of Benzoxaborole Derivatives as Potential Antimicrobial Compounds It has been revealed, that benzoxaborole moiety can exert OBORT (oxaborole tRNA trapping) mechanism leading to protein synthesis cessation in microorganisms. This work focused on the synthesis and primary in vitro evaluation of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol- 6-yl)(hetero)aryl-2-carboxamide series. The compounds were prepared by reaction between activated (hetero)aryl carboxylic acid and 6-amino group of benzoxaborole moiety via amidic bond formation. Ten compounds were successfully prepared and tested in vitro against clinically important strains of bacteria, fungi and mycobacteria. Noticeable activity against several mycobacterial strains was revealed and the human cell cytotoxicity screening showed low toxicity. This outcome could originate in differences between active sites of human and mycobacterial target enzyme. This series of substances showed selective antimycobacterial properties and may streamline the search for novel...
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Synthesis of thiazolidine derivatives as potential drugs
Makovská, Kateřina ; 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: Synthesis of thiazolidine derivatives as potential drugs Student: Kateřina Makovská Supervisor: PharmDr. Marta Kučerová, Ph.D. The theoretical part was focused on the literature research on the biological activity of derivatives 2-thioxothiazolidine-4-one (rhodanine) and its oxygen isostere thiazoli- dine-2,4-dione. There was mainly the antibacterial, antimycobacterial, and antifungal activity of variously substituted rhodanine and thiazolidine-2,4-dione derivatives repor- ted. These derivatives seem to be suitable candidates for the development of new drugs Within the experimental part, an in silico study on molecular docking of a larger series of rhodanine and thiazolidine-2,4-dione derivatives prepared in this work and earlier was performed with MurD ligase of E. coli as a potential bacterial target. On the whole, seventeen syntheses were performed in the laboratory using the Kno- evenagel condensation of thiazolidine-2,4-dione or rhodanine with various aldehydes, nine reactions with the aim to obtain thiazolidine-2,4-dione derivatives and eight reacti- ons withe the goal to get rhodanine derivatives. Eleven reactions afforded successfully six...
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Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity III
Rahi, Fahim - Joe ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
Univerzita Karlova Farmaceutická fakulta v Hradci Králové Katedra farmaceutické chemie a farmaceutické analýzy Kandidát: Fahim Joe Rahi Vedoucí: doc. PharmDr. Jan Zitko, Ph.D. Název diplomové práce: Návrh, syntéza a hodnocení heterocyklických sloučenin s potenciální antimikrobní aktivitou III Nadužívání antibiotik vedlo k alarmujícímu nárůstu rezistence. Akutní potřeba antibiotik s novým mechanismem účinku vedla náš výzkum k nalezení slibných nových sloučenin prostřednictvím studie HIT-SAR. Cílená struktura byla inspirována nedávnou publikací. Naše sloučeniny mají navíc methylenový můstek mezi heterocyklem a benzenovým kruhem. Tento methylenový můstek zvyšuje flexibilitu struktury, což může zlepšit interakční potenciál sloučenin. Obecně lze říci, že methylenový můstek nezlepšil antimikrobiální vlastnosti zamýšlených sloučenin. V některých případech byla antimikrobiální aktivita významně snížena ve srovnání s publikovanými sloučeninami. MIC nebyla dostatečná k provedení dalšího mikrobiologického testování.
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Synthesis of new antimitotic agents
Hoppová, Martina ; Kučerová, Marta (advisor) ; Miletín, Miroslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Martina Hoppová Supervisors: PharmDr. Marta Kučerová, Ph.D.; Dr. Rafael Peláez Lamamie de Clairac Arroyo Title of diploma thesis: Synthesis of new antimitotic agents Cancer is one of the main causes of death all around the world and therefore the development of new chemotherapeutic drugs is one of the major areas of pharmaceutical research. The effort is to obtain an agent that would be highly effective, target the neoplastic tissue, and have advantageous pharmacological properties and minimum side effects. Rapid proliferation is one of the main features of cancerous growth, thus influencing mitosis as the phase of cell division may be a convenient way for cancer treatment. Tubulin is a protein, which rapidly polymerizes into microtubules and again depolymerizes and beside others it forms mitotic spindle during mitosis, and according to its important role, tubulin is an attractive target for antitumoral agents. Many drugs inhibiting polymerization or stabilizing already formed microtubules are actually in clinical practice, and research regarding new antimitotics interacting with tubulin is going on at the same time. Such an example is natural combretastatin A-4...
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Synthesis of novel 5,6-disubstituted derivatives of uracil as potential drugs
Vu, Lien Phuong ; Kučerová, Marta (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Vu Lien Phuong Supervisors: PharmDr. Marta Kučerová, Ph.D. Tanja Bruun, M.Sc. (Pharm.) Prof. Jari Yli-Kauhaluoma Title of diploma thesis: Synthesis of novel 5,6-disubstituted derivatives of uracil as potential drugs In this thesis, uracil was used as the core structure given its many biological activities that were reported such as antitumor, antiviral, antibiotic, hypoglycemic, diuretic and many others. The work was focused on the preparation of new 5,6- disubstituted uracil derivatives as potential biologically active agents. 2,4,6-Trichloropyrimidine was used for the preparation of 6-chlorouracil that was condensed with phenols or anilines to give the respective 6-phenoxyuracils and 6- phenylaminouracils. These intermediates were then modified in position 5 to give the final products. For this very challenging last step, various alkylating and acylating agents were used, e.g. Vilsmeier reagent, alkylchlorides, chloroacetyl chloride, ethyl chlorooxoacetate and ethyl bromoacetate. In the end, ethyl bromoacetate gave the most promising results affording four novel 5,6-disubstituted uracil derivatives. During the experimental work it was found that pH of water used...
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Synthesis and study of supramolecular properties of azaphthalocyanines usable as sensors
Sikorová, Eliška ; Demuth, Jiří (advisor) ; Kučerová, Marta (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Eliška Sikorová Supervisor PharmDr. Jiří Demuth, Ph.D. Title of ThesisSynthesis and study of supramolecular properties of azaphthalocyanines usable as sensors Azaphthalocyanines are planar aromatic macrocycles that were derived from natural porphyrins. The basic skeleton consists of four isoindole units which are linked at positions 1 and 3 by azamethine bridges, resulting in an extensive system of conjugated double bonds that give these compounds unique optical and electrical properties. Azaphthalocyanines are widely used as industrial dyes, conductors, photosensitizers in photodynamic therapy, fluorescence quenchers or fluorescence sensors, etc. The compounds synthesized during this thesis can be used as an interesting type of sensors for sensing coordination analytes in solution. That is why this work deals with the study of the supramolecular properties of the synthesized compounds, in particular the ability to form J-dimer type aggregates, which are formed by coordination of the peripheral pyridyl nitrogen to the central zinc cation of the second azapthalocyanine. J-dimers resemble a "step-like" arrangement in contrast to the second type of...
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Synthesis of thiazolidine derivatives as potential drugs
Makovská, Kateřina ; 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: Synthesis of thiazolidine derivatives as potential drugs Student: Kateřina Makovská Supervisor: PharmDr. Marta Kučerová, Ph.D. The theoretical part was focused on the literature research on the biological activity of derivatives 2-thioxothiazolidine-4-one (rhodanine) and its oxygen isostere thiazoli- dine-2,4-dione. There was mainly the antibacterial, antimycobacterial, and antifungal activity of variously substituted rhodanine and thiazolidine-2,4-dione derivatives repor- ted. These derivatives seem to be suitable candidates for the development of new drugs Within the experimental part, an in silico study on molecular docking of a larger series of rhodanine and thiazolidine-2,4-dione derivatives prepared in this work and earlier was performed with MurD ligase of E. coli as a potential bacterial target. On the whole, seventeen syntheses were performed in the laboratory using the Kno- evenagel condensation of thiazolidine-2,4-dione or rhodanine with various aldehydes, nine reactions with the aim to obtain thiazolidine-2,4-dione derivatives and eight reacti- ons withe the goal to get rhodanine derivatives. Eleven reactions afforded successfully six...
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Growth and control of Pseudomonas aeruginosa in a multi-species biofilm
Hutlas, Andrej ; Kučerová, Marta (advisor) ; Konečná, Klára (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Cardiff University, School of Pharmacy and Pharmaceutical Sciences Study program: Pharmacy Candidate: Andrej Hutlas Consultants: PharmDr. Marta Kučerová, Ph.D. (Charles); Prof. Jean-Yves Maillard (Cardiff); BSc. Katarzyna Ledwoch Ph.D. (Cardiff) Biofilms are a default mode of growth for most bacteria. Microbes encapsulate themselves within a matrix, composed mainly of extracellular polymeric substances. A biofilm can be composed by multiple species. Matrix environment induces various physiological shifts, such as switch to dormant state or expression of biofilm-specific genes. Mature biofilm's heterogeneous, due to differences in spatial microbe distribution and spatial nutrient utilization across the matrix. Matrix provides many advantages to bacteria, like nutrient capture and transfer or protection against extreme conditions. Washbasin U-bend multi-species biofilms were investigated with a special focus on Pseudomonas aeruginosa. This opportunistic pathogen causes nosocomial infections, mainly in immunocompromised patients, with considerable health and socio-economic impacts. A link between sinks and environmental P. aeruginosa contamination has been established. Environmental decontamination may be an approach to lessen aforementioned...
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