National Repository of Grey Literature 7 records found  Search took 0.02 seconds. 
Application of amines for the preparation of chiral cyclic compounds
Formánek, Bedřich ; Veselý, Jan (advisor) ; Kočovský, Pavel (referee) ; Soural, Miroslav (referee)
Organocatalysis, along with catalysis by metal complexes or enzymes, has become one of the very useful tools of asymmetric synthesis. Different activation modes or their combinations into sequences (domino reactions) enable effective access to enantiomerically enriched complex substances. The objective of this work was the preparation of chiral molecules from simple precursors activated by amine-based organocatalysts. In particular, we were focused on a study of asymmetric allyl substitution of Morita-Baylis-Hillman carbonates and two-component domino reactions on sulfur-containing heterocycles. The thesis deals with the organocatalytic allyl amination of Morita-Baylis-Hillman carbonates with aromatic amines catalyzed by β-isocupreidine. The corresponding allylic amines were obtained in high yields (90-96%) with moderate enantiomeric excess. It was possible to get substances of high optical purity (ee 82-99%) by recrystallization of selected products. Furthermore, the developed method was applied in the preparation of enantiomerically enriched β-lactams, which represent valuable precursors, for example, in the synthesis of the drug Ezetimibe. The second part of the work is focused on stereoselective cyclization reactions comprising selected sulfur heterocycles. Although the cyclization reaction of...
Design, synthesis and evaluation of novel inhibitors of class II PI4Ks and RIPK2/3 kinases
Misehe, Mbilo ; Nencka, Radim (advisor) ; Soural, Miroslav (referee) ; Baszczyňski, Ondřej (referee)
Synthetic kinase inhibitors are chemical tools to investigate cellular roles of kinase enzymes and, potentially, find new treatments for various diseases that are connected with their dysregulated expressions and activities. This thesis focuses on two projects that were devoted to design, synthesize and evaluate novel compounds as kinase inhibitors. In a first project, employing structure-based docking methods, novel 7-aryl- or 7-heteroaryl-substituted 4-aminoquinazoline-6-carboxamide compounds were developed as inhibitors of class II phosphatidylinositol 4-kinases (PI4K2A/2B). A simple synthetic approach enabled the preparation and the functionalization of the 4-aminoquinazoline scaffold in six steps. Enzymatic evaluation for activity and selectivity against PI4Ks (i.e., PI4K2A and class III PI4Ks) highlighted several compounds with low micromolar potency and good selectivity against PI4K2A. Moreover, the binding mode of the new compounds in the conserved ATP-binding sites of class II PI4Ks was corroborated by X-ray crystallography. This suggests the applied rationale of the design can be a strategical option to obtain more potent and selective PI4K class II inhibitors, to conduct additional investigations on these kinases. In a second project, novel 4,6- and 4,6,7-substituted quinazoline...
Novel quinazoline derivatives with biological activity
Brožová, Zuzana Rania ; Pour, Milan (advisor) ; Miletín, Miroslav (referee) ; Soural, Miroslav (referee)
Faculty of Pharmacy in Hradec Králové, Charles University Department of Organic and Bioorganic Chemistry Candidate: Mgr. Zuzana Rania Brožová Supervisor: prof. RNDr. Milan Pour, Ph.D. Title of Doctoral Thesis: Novel quinazoline derivatives with biological activity This thesis is divided into two parts, both dealing with the synthesis of novel quinazoline derivatives and evaluation of their biological activity. The first part is focused on the synthesis of bronchodilatory active derivatives derived from vasicinone as a lead compound and 3-[3-(piperidin-1-yl)-propyl]-3,4- dihydroquinazoline-4-one and 4-[3-(piperidin-1-yl)-propylsulfanyl]-3,4-dihydroquinazoline-4- one, the most active derivatives from our previous work. The derivatives were subsequently tested on isolated rat trachea and their bronchodilatory activity was evaluated. Their toxicity, in vivo activity, mechanism of action and the relationships between structure and activity (SAR) were also investigated. The second part deals with the synthesis of novel derivatives of 2,4-disubstituted quinazoline and their testing for affinity to nuclear constitutive androstane receptor (CAR). This work follows up on the previous random discovery that 2-(3-methoxyphenyl)quinazoline- 4-ol is a promising CAR agonist which own activity comparable to that of...
Synthesis, Biological Profiling and Photophysical Properties of Polycyclic Hetero-Fused 7-Deazapurine Nucleosides
Yang, Chao ; Hocek, Michal (advisor) ; Soural, Miroslav (referee) ; Nencka, Radim (referee)
This thesis describes the synthesis, photophysical properties and biological profiling of several series of polycyclic hetero-fused 7-deazapurine nucleosides. Modified 7-deazapurine ribonucleosides display a variety of biological effects. Previously, small (hetero)aromatic rings-fused 7-deazapurine nucleosides show submicromolar cytostatic effects or antiviral activities. Thus, the two isomeric series of new benzothieno-fused deazapurine nucleosides were designed as the extended analogues to the cytotoxic thieno-fused nucleosides and hetero-analogues of antiviral naphtho-fused nucleosides. The goal of the first part of my work was to synthesize these target compounds. Key steps include Negishi coupling of zincated pyrimidine with iodobenzothiophene, thermal or photochemical cyclization, glycosylation and final diversification. The furyl and benzofuryl derivatives exerted moderate anticancer and anti-HCV activities. Most of the free nucleosides showed moderate to strong fluorescence, and the corresponding 2′-deoxyribonucleoside triphosphate was incorporated into modified DNA and their fluorescence properties were studied The tri- and tetracyclic fused nucleobases can be synthesized either by multistep heterocyclization approach or through cross-coupling of zincated pyrimidine with hetaryl halides,...
Synthesis of Neuraminidase binders suitable for theranostics
Berenguer Albiñana, Carlos ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza viruses cause respiratory illnesses which can vary in severity depending on the strain of the virus, as well as the age and health condition of the host. Influenza remains a major threat to public health due to its nature prone to suffer mutations. As a result, vaccines have to be reformulated annually and new strains may cause sporadic global pandemics. Furthermore, the recent emergence of resistant strains of the virus against the current standard of care (oseltamivir and zanamivir) underlines the need of novel anti-influenza therapeutics. The aim of this dissertation work is to contribute to the discovery of new anti-influenza inhibitors either by rational drug-design and optimization of oseltamivir structure, or by developing screening assays suitable for the discovery of novel inhibitors of the enzymes neuraminidase or RNA-polymerase. Scheme 1. Overview of the strategy used for the development of new anti-influenza therapeutics. The dashed arrows indicate the inhibitors that were converted into probes and their corresponding target enzymes Two main modification points were explored for the improvement of oseltamivir properties (Scheme 1); modifications at carbon C-3 aimed to overcome oseltamivir resistance caused by common mutations like H274Y, meanwhile modifications at carbon C-5...
Preparation of Influenza Neuraminidase and Polymerase Inhibitors
Zima, Václav ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza is an infectious disease caused by the influenza virus. This virus causes a severe viral infection that spreads easily from person to person in yearly pandemics. Vaccination is the most effective way to prevent the infection, however, due to the high rate in mutations of the virus, the vaccine needs to be often reformulated. Another option to combat influenza is based on administration of antiviral drugs. Clinical studies of isolated influenza strains ("avian flu" H5N1, 2004; "swine flu" H1N1, 2009) revealed resistance towards known influenza neuraminidase inhibitors (zanamivir, oseltamivir). The resistance is caused by structural changes close to the enzymatic site. This calls for the development of new neuraminidase inhibitors as well for development of inhibitors targeting different influenza enzymes. This Thesis is focused on design and synthesis of new inhibitors of influenza neuraminidase and RNA-dependent RNA polymerase, namely PA subunit and the assembly of PA-PB1 heterodimer enzymes (Scheme 1). Influenza neuraminidase inhibitors were prepared by C-5 derivatization of oseltamivir followed by subsequent extension of its structure with binders of 150-cavity. Binding potencies of new oseltamivir derivatives against two influenza strains were determined. The next part contributed to...
Synthesis of Neuraminidase binders suitable for theranostics
Berenguer Albiñana, Carlos ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza viruses cause respiratory illnesses which can vary in severity depending on the strain of the virus, as well as the age and health condition of the host. Influenza remains a major threat to public health due to its nature prone to suffer mutations. As a result, vaccines have to be reformulated annually and new strains may cause sporadic global pandemics. Furthermore, the recent emergence of resistant strains of the virus against the current standard of care (oseltamivir and zanamivir) underlines the need of novel anti-influenza therapeutics. The aim of this dissertation work is to contribute to the discovery of new anti-influenza inhibitors either by rational drug-design and optimization of oseltamivir structure, or by developing screening assays suitable for the discovery of novel inhibitors of the enzymes neuraminidase or RNA-polymerase. Scheme 1. Overview of the strategy used for the development of new anti-influenza therapeutics. The dashed arrows indicate the inhibitors that were converted into probes and their corresponding target enzymes Two main modification points were explored for the improvement of oseltamivir properties (Scheme 1); modifications at carbon C-3 aimed to overcome oseltamivir resistance caused by common mutations like H274Y, meanwhile modifications at carbon C-5...

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1 Soural, Martin
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