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Synthesis and biological evaluation of tacrine-amantadine derivatives
Král, Jan ; Opletalová, Veronika (advisor) ; Holas, Ondřej (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jan Král Supervisor: doc. RNDr. Veronika Opletalová, Ph.D. Consultant: PharmDr. Jan Korábečný, Ph.D. Title of diploma thesis: Synthesis and biological evaluation of tacrine-amantadine derivatives Alzheimer's disease (AD) is a fatal neurodegenerative disorder of brain. Nowadays there is only paliative treatment available, which can be further subdivided into two groups: acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist. Donepezil, rivastigmine and galantamine represents AChEIs currently available for AD treatment. Tacrine is the first AChEIs to be approved for AD treatment, however, it was withdrawn from the market due to its side effects, especially due to its hepatotoxicity. 7-Methoxytacrine (7-MEOTA) is less toxic tacrine derivative preserving pharmacological profile of tacrine. This diploma thesis describes synthesis of multifunctional 7-MEOTA- amantadine derivatives as potential drugs to confront AD. Using Ellmanʼs method, we have established their efficacy to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. All new synthesized hybrids from 7-MEOTA- amantadine family proved to be better...
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Polymeric stabilizers maintaining the supersaturation solubility of itraconazole nanocrystals after dissolution process
Kubačková, Jana ; Holas, Ondřej (advisor) ; Paraskevopoulos, Georgios (referee)
Title of thesis: Polymeric stabilizers maintaining the saturation solubility of itraconazole nanocrystals after dissolution process Author: Jana Kubačková Department: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Specialized supervisor: Assoc. Prof. Leena Peltonen, Ph.D. The increase of bioavailability of poorly water soluble drugs is still an issue. One of the techniques improving aqueous drug substance solubility, and consequently enhancing bioavailability, is formation of nanoparticles. However, the bioavailability is determined by the concentration of the dissolved drug achieved at the time of absorption. This fact emphasizes the importance of the maintenance of the high solubility until the absorption area is reached. Sufficiently stabilised nanocrystalline drugs offer a solution to this problem. In this thesis, the solid nanoparticle formations of an antifungal agent itraconazole (ITZ) are presented. Wet milling was employed to create the nanosuspension stabilised by binary mixture of stabilisers or by a single stabiliser. An aggregation inhibitor Poloxamer 407 (F127) in the combination with a polymeric precipitation inhibitor hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP) at different ratios, or a single precipitation inhibitor, were utilised. The...
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Molecular modeling study of potential mycobacterial enoyl-reductase inhibitors
Slovák, František ; Holas, Ondřej (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Diplomate: František Slovák Supervisor: PharmDr. Ondřej Holas, Ph.D. Title of Diploma Thesis: Molecular modeling study of potential mycobacterial enoyl ACP reductase inhibitors. Tuberculosis is a worldwide spread infectious disease. The biggest problem of our time are completely and multi resistant strains of Mycobacterium tuberculosis that do not respond to currently known drugs. The main reason for high resistance and drug resistance is a bacillus composition of its cell wall. It contains a high proportion of mycolic acids. The synthesis of mycolic acids takes several steps. The final step is a catalytic reduction by enzyme enoyl - ACP reductase ( InhA ). This work was focused on finding new potential substances that would be able to inhibit this enzyme. There were used methods of computing and molecular modeling to search these substances. Adjusting of crystallographic structures ran in the program Maestro and docking in the MOE program. Over the 30 000 thousand molecules from the ZND (Zinc Natural Derivates) were tested by molecular docking on 3 crystallographic structures of InhA enzyme. 8 of these molecules were selected from this amount because their...
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The impact of an injection drug administration on an oxidative stress development in laboratory Guinea pig model
Kračmarová, Alžběta ; Mokrý, Milan (advisor) ; Holas, Ondřej (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate Msc. Alžběta Kračmarová Consultant assoc. prof. Miroslav Pohanka, RNDr, PhD. Title of Thesis The impact of an injection drug administration on an oxidative stress development in laboratory Guinea pig model Injections of drugs are considered to be standard procedures used in experimental work with laboratory animals. Laboratory rodents are sensitive to a way of handling. For this reason stress caused by the injection leads to alteration of various physiological processes. Rise of body temperature, tachycardia, elevated or declined blood glucose level or oxidative imbalance may influence results in disparate experiments. Aim of our experiment was to clarify an impact of intramuscular injection on development of an oxidative imbalance. The laboratory Guinea pigs were sacrificed one hour after the intramuscular injection of saline solution. After that, blood and selected organs were collected. Ferric reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), carbonylated proteins, superoxide dismutase activity and glutathione reductase activity as markers of oxidative state and caspase 3 activity as marker of apoptosis were measured in the tissue homogenates....
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Colorimetric assay based on immobilized acetylcholinesterase for the determination of efficiency of inhibitors used in pharmacotherapy
Drobík, Oto ; Opletalová, Veronika (advisor) ; Holas, Ondřej (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Mgr. Oto Drobík Consultant Assoc. Prof. Veronika Opletalová, Ph.D. Title of Thesis Colorimetric assay based on immobilized acetylcholinesterase for the determination of efficiency of inhibitors used in pharmacotherapy. There is a large number of substances belonging to acetylcholinesterase (AChE) inhibitors that are used in agriculture, for example as insecticides or pesticides. They are also used as nerve paralytic agents for military purposes. Some of them have been applied in treatment of diseases such as myasthenia gravis or Alzheimer's disease. Within the thesis, AChE was successfully immobilized on the bottom of a 96 well microplate, using gelatine. By means of a colorimetric method, the reaction conditions were optimized; the resistance of the immobilized AChE against the washout was also tested. Furthermore, an inhibition rate of AChE by solvents was determined and kinetic parameters of an enzymatic reaction were evaluated. Tacrine and pyridostigmine were tested as representatives of AChE inhibitors. A long-term stability test of the immobilized AChE was further performed. The results that have been achieved indicate that the method described is...
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Molecular modeling study of potential acetylcholinesterase inhibitors .
Kratochvíl, Jakub ; Holas, Ondřej (advisor) ; Marek, Jan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradci Králové Department of: Pharmaceutical chemistry and drug control Consultant: PharmDr. Ondřej Holas, Ph.D. Student: Jakub Kratochvíl Title of Thesis: Molecular modeling study of potential acetylcholinesterase inhibitors. This diploma thesis deals with an utilization of molecular docking to confirm the ability to inhibit acetylcholinesterase and butyrylcholinesterase in several substances. Well known AChE inhibitors (donepezil, tacrine, galanthamine, huperzine A) were chosen as ligands binding to active site of the enzyme. Their activity was confirmed. Other substances with certain inhibition potential were studied and in most cases the potential was proven. Structures of cholinesterases from human body and Torpedo californica were used for studies. The experimental part was carried out on a computer using a molecular modeling software: MGL Tools, PyMOL, Chimera and Autodock Vina.
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Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors
Šebl, René ; Zimčík, Petr (advisor) ; Holas, Ondřej (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND DRUG CONTROL Name: René Šebl Supervisor: Doc. PharmDr. Petr Zimčík,Ph.D Title of the thesis: Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors The topic of my thesis was synthesis of azaphtalocyanines containing pyrazinopyrazine units. These molecules have been published only in few publication till now. Since these molecules are extended by one pyrazine nucleuson each unit, their extended conjugation leads to an increased absorption in the higher regions of the absorption spectrum. In the first step, I focused on the synthesis of precursors for subsequent cyclotetramerization. Starting compound for the preparation of various precursors was 6,7- dichloropyrazino [2,3-b] pyrazine-2,3-dicarbonitrile. It underwent nucleophilic substitution leading to products substituted with various substiuents attached via heteroatoms such as oxygen or nitrogen. Another option is the condensation of 5,6-diaminopyrazine-2,3- dicarbonitrile with appropriate diketon. This attempt did not lead to the successful preparation of the precursor. The precursors were subsequently cyclotetramerized to corresponding macrocycles. We succeeded only with one precursor...
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Synthesis and biological evaluation of tacrine-amantadine derivatives
Král, Jan ; Opletalová, Veronika (advisor) ; Holas, Ondřej (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jan Král Supervisor: doc. RNDr. Veronika Opletalová, Ph.D. Consultant: PharmDr. Jan Korábečný, Ph.D. Title of diploma thesis: Synthesis and biological evaluation of tacrine-amantadine derivatives Alzheimer's disease (AD) is a fatal neurodegenerative disorder of brain. Nowadays there is only paliative treatment available, which can be further subdivided into two groups: acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist. Donepezil, rivastigmine and galantamine represents AChEIs currently available for AD treatment. Tacrine is the first AChEIs to be approved for AD treatment, however, it was withdrawn from the market due to its side effects, especially due to its hepatotoxicity. 7-Methoxytacrine (7-MEOTA) is less toxic tacrine derivative preserving pharmacological profile of tacrine. This diploma thesis describes synthesis of multifunctional 7-MEOTA- amantadine derivatives as potential drugs to confront AD. Using Ellmanʼs method, we have established their efficacy to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. All new synthesized hybrids from 7-MEOTA- amantadine family proved to be better...
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In silico screening of SIRT6 inhibitors
Kučera, Tomáš ; Doležal, Martin (advisor) ; Holas, Ondřej (referee)
Title: In silico screening of SIRT6 inhibitors Author: Tomáš Kučera Department: Department of Pharmaceutical Chemistry and Drug Control Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Specialized supervisor: Maija Lahtela-Kakkonen, Ph.D. Abstract: SIRT6 is called NAD-dependent protein deacetylase sirtuin-6 and it is a member of sirtuin protein family. It modulates acetylation of histone H3 (clinically important Lys9 and Lys56). The SIRT6 enzyme is an interesting drug target because of its role in DNA replication, glycolysis and inflammation - that is why the design of SIRT6 inhibitors is relevant in context of diabetes mellitus, arthritis and cancer. The aim of the work was to identify small molecules to inhibit deacetylase activity of SIRT6 using methods of computational chemistry and molecular modeling. We tried to find new lead structures with possibility to be optimized in next phases of the drug discovery process. The 9 known inhibitors and crystal structure of SIRT6 (PDB code 3K35) were used as input data during the modeling. Pharmacophoric and chemical similarity searches were selected from the group of ligand-based methods and molecular dock- ing from the group of structure-based methods. The pharmacophore was defined after structural alignment of four known ligands and tested on set of...
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Modulation of acetylcholinesterase activity using different organic compounds
Vavrošová, Petra ; Opletalová, Veronika (advisor) ; Holas, Ondřej (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Petra Vavrošová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of thesis: Modulation of acetylcholinesterase activity using different organic compounds Acetylcholinesterase is a vital enzyme because of its ability to end a nerve impulse by decomposition of neurotransmitter acetylcholin. Inhibitors of cholinesterases have been used in many sectors, such as drugs, pesticides, or substances abused as biological weapons. Using chosen agents an existence of acetylcholinesterase inhibition was detected together with its rate and character. The detection was accomplished by the method of measuring the decrease of acetylcholinesterase activity. In this experiment some organic solvents, metal salts, and other agents like gelatine, tacrine or caffeine were used. Ellman's spectrophotometrical detection was used to determine the decrease of acetylcholinesterase activity. The data were evaluated by the graphical representation by Dixon and Boltzmann. In this experiment the acetylcholinesterase from electric eel was used. Results showed that many chosen agents have the ability to inhibit acetylcholinesterase and on the other hand many of them do not have this...
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