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Synthesis and Biological Evaluation of Selected Polysubstituted Furanones
Kratochvíl, Jiří ; Pour, Milan (advisor) ; Opletalová, Veronika (referee)
The aim of this thesis was to prepare 5-(benzyloxymethyl)-3-(4-bromophenyl)-2,5- dihydrofuran-2-one derived from cytostatically active 5-alkoxymethyl-3-(4-bromophenyl)- 2,5-dihydrofuran-2-ones. However, none of the three proposed synthetic procedures led to the target molecule. Next we focused on the preparation of a series of 5-bis(acetyloxymethyl)-3- aryl-4-phenyl-2,5-dihydrofuran-2-ones with different aryl substitution derived from the antibacterially, antifungally and cytostatically active 5-bis(acetyloxymethyl)-3- (4-bromophenyl)-4-phenyl-2,5-dihydrofuran-2-one. The aim was to explore a relationship between aryl substitution in position 3 and biological activity of the compounds. The spectrum of products was also enriched by 5-acetyloxymethyl-3-aryl-4-phenyl-2,5-dihydrofuran-2-ones. In conclusion aryl substitution leads to a significant decrease or vanishing of the antibacterial, antifungal and cytostatic effects with the exception of 5-acetyloxymethyl-3-aryl-4-phenyl-2,5- dihydrofuran-2-ones, in which marginal antifungal (Absidia corymbifera), antibacterial (Staphycoccus aureus a Staphylococcus epidermidis) and significant cytostatic (L1210, HeLa S3, CCRF-CEM, IC50 < 5 µmol.l-1 ) activities were found.
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Preparation and evaluation of potential drugs inhibiting mitochondrial enzymes
Benek, Ondřej ; Musílek, Kamil (advisor) ; Patočka, Jiří (referee) ; Opletalová, Veronika (referee)
Preparation and evaluation of potential drugs inhibiting mitochondrial enzymes Summary in English Alzheimer's disease (AD) is the most common cause of senile dementia worldwide. Despite being subject to intensive research, the pathogenic mechanisms of AD are still not fully understood and consequently an effective treatment is yet to be developed. Although the aetiology of AD is still unknown, a build-up of amyloid-beta peptide (Aβ) is considered to play an important role in disease progression. The original amyloid cascade hypothesis proposed that insoluble extracellular plaques were responsible for the majority of Aβ toxicity. This hypothesis has since been refined, as recent data indicates that soluble intracellular oligomers are now responsible for the majority of Aβ induced toxic effects. The mitochondrial dysfunction also plays an important role in the pathophysiology of AD. Aβ was detected inside mitochondria and several mitochondrial proteins were found to interact directly with Aβ. Such interactions can affect a protein's function and cause damage to the mitochondria, which finally results in progression of AD. The background for the experimental part of this dissertation thesis was literature review summarizing current knowledge on mitochondrial proteins directly interacting with Aβ in order to...
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Synthesis of Precursors for Biologically Active Lactones II
Finková, Lenka ; Kučerová, Marta (advisor) ; Opletalová, Veronika (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Chemistry and Drug Control In the theoretical part of the diploma paper there are summarized antiviral effects of butenolides isolated from natural resources as well as substances obtained by synthesis. Methyl-(E)-2,3-dibromacrylate has been synthesized within the scope of the experimental work as a precursor for methyl-(E)-2-brom-5-subst.phenylpent-2-en-3- ynoates which have been obtained by Sonogashira coupling with different alkynes. Syntheses of some derivates have been optimized by modification of reaction conditions. Methyl-(E)-2-brom-5-subst.phenylpent-2-en-3-ynoates can be used as starting compounds for synthesis of potential biological active lactones.
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Synthesis and biological evaluation of novel tacrine-tryptophan derivatives
Jarošová, Michaela ; Opletalová, Veronika (advisor) ; Zitko, Jan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Drug Control Student: Michaela Jarošová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Consultant: PharmDr. Jan Korábečný, Ph.D. Title of thesis: Study and biological evaluation of new tacrine-tryptophan derivatives Alzheimer's disease (AD) is a chronic neurodegenerative disease with characteristic histopathological changes in the brain. It is the most common cause of dementia. There is about 7.4 million people affected by AD in Europe today. In connection with aging of the population a significant increase of patients affected by the disease can be expected in the coming years. The cause of neural tissue damage is aggregated amyloid β (Aβ), which disrupts neurons by creating glial hem with consequent inflammatory processes. Hyperphosphorylated τ-protein causes neuronal damage intracellularly by forming so-called neurofibrillary tangles. This leads to macroscopically visible brain atrophy and loss of neurons. Current AD pharmacotherapy is based on influencing the cholinergic system. Acetylcholinesterase inhibitors (AChEIs) - rivastigmine, donepezil and galanthamine are used for this purpose. Memantine, antagonist of N-methyl-D-aspartate receptors (NMDA) has been approved for the...
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Derivatives of Rhodanine as Potential Drugs III
Kalafutová, Stanislava ; Opletalová, Veronika (advisor) ; Zimčík, Petr (referee)
Diploma thesis Rhodanine derivatives as potential drugs III. Stanislava Kalafutová In the first part of the diploma thesis there is generally written about different types of tuberculosis in the various aspects as ethiology, pathogenesis and pharamacotherapy. The second part is focused on the newly tested potential antituberculotic drugs. Especially in the third part there are mentioned different drug targets of these promising antituberculotics. Finally the fourth part of the theoretical introduction briefly summarizes currently used drugs in the treatment of this infectous disease. The experimental work deals with number of synthesis of following compounds: 5-(3-bromobenzylidene)-2-thioxo-1,3-thiazolidine-4-one, 5-(2- bromobenzylidene)-2-thioxo-1,3-thiazolidine-4-one, 5-(3-chlorobenzylidene)-2- thioxo-1,3-thiazolidine-4-one, 5-(2-chlorobenzylidene)-2-thioxo-1,3-thiazolidine- 4-one, 5-(4-fluorobenzylidene)-2-thioxo-1,3-thiazolidine-4-one, 5-(3- fluorobenzylidene)-2-thioxo-1,3-thiazolidine-4-one, 5-(2-fluorobenzylidene)-2- thioxo-1,3-thiazolidine-4-one, 5-(pyridine-4-ylmetylidene)-2-thioxo-1,3- thiazolidine-4-one, 5-(pyridine-3-ylmetylidene)-2-thioxo-1,3-thiazolidine-4-one, 5-(furane-2-ylmetylidene)-2-thioxo-1,3-thiazolidine-4-one. All synthesized compounds were tested for an antifungal and antibacterial...
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Issues of the Cholinesterase Inhibition by the Selected Organophosphorous Pesticides In Vitro
Lázenská, Helena ; Opletalová, Veronika (advisor) ; Kuča, Kamil (referee)
QUESTIONS OF THE IN VITRO INHIBITION OF CHOLINESTERASES BY SELECTED ORGANOPHOSPHORUS PESTICIDES Helena Lázenská Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic. The aim of this study was to describe organophosphorus inhibitors paraoxone, DDVP and DFP from the aspect of the kinetics of their reaction with human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), to find IC50, and to test the in vitro potency of five selected oximes (pralidoxime, methoxime, trimedoxime, obidoxime and HI-6) to reactivate AChE and BuChE inhibited by three mentioned organophosphorus inhibitors. The inhibition of AChE and BuChE was performed by incubation with organophosphorus inhibitors at a convenient concentration and such time, that would result in about 90% activity of an enzyme. A solution of a reactivator at a final concentration 1 μM or 10 μM was added to an enzyme, after 10 min of reactivation, a solution of a substrate - acetylthiocholine-iodide or butyrylthiocholine-iodide was added, and the activity of an enzyme was measured by the spectrophotometric Ellman's method. The experiment was performed at 25 žC, pH 7,4 and in a 0,1 M phosphate buffer. According...
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The relationship between structure and activity of potential reactivators of acetylcholinesterase I.
Holas, Ondřej ; Opletalová, Veronika (advisor) ; Pohanka, Miroslav (referee)
The realtionship between structure and activity of potencial reactivators of acetylcholinesterase Organophosphorus compounds (OPC) are used as agricultural pesticides and in industry as fire retardants or plastificators. For military use there have been developed nerv agents (NA, e.g. tabun, sarin, somna, VX). The toxicity of these compounds is based upon phosphorylation or phosphonylation at the serine hydroxy group (Ser200) of the active site of the acetylcholinesterase. The current standard treatment consists of administration oxime reactivators in combination with anticholinergic drug (preferably atropin). Unfortunately, none from the currently used oximes is sufficiently effective against all types of the OPCs. The aim of this study is determination of the relationship between structure and activity of new reactivators against paraoxon inhibited AChE in vitro and comparison with currently available substances. For evaluation of reactivation activity has been chosen standard in vitro test using rat brain homogenate
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Pyrazine derivatives as potential drugs VI.
Servusová, Barbora ; Doležal, Martin (advisor) ; Opletalová, Veronika (referee)
Title of diploma thesis: Pyrazine derivates as potential drugs VI. Review of tuberculosis therapy and modern research were presented in this diploma thesis. Six novel compounds substituted anilides pyrazine-2-carboxylic acid character were synthesized. Products were characterized by melting points, TLC, IR, 1 H and 13 C NMR. This set was put through in vitro biological evaluation. Log P and Clog P were also calculated. These values were put into the structure-activity relationships of prepared compounds.
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Synthesis, biological evaluation and in silico study of 7-MEOTA-donepezil inhibitors of cholinesterases
Čábelová, Pavla ; Opletalová, Veronika (advisor) ; Kučerová, Marta (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Pavla ábelová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Supervisor specialist: PharmDr. Jan Korábe ný, Ph.D. Title of diploma thesis: Synthesis, biological evaluation and in silico studies in the series of novel 7-methoxytacrine-donepezile like compounds Alzheimer's disease (AD) is an irreversible neurodegenerative disorder of the brain characterized clinically by loss of memory, deterioration of activities of daily living and cognition. The pathological hallmarks of AD include neuritic plaques composed of extracellularly stored fibrils of amyloid- peptide, intracellular deposits of hyperphosphorylated tau and neurotransmitter deficits. The aim of the study was to design and synthesize 7-methoxytacrine-donepezil-like compounds as potential inhibitors of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8). New compounds consist of 7-methoxytacrine representing less toxic derivative of tacrine and benzylpiperazine moiety corresponding to donepezil fragment. To determine the potential of new derivatives, AChE and BChE inhibitory activities of the new molecules were assessed in vitro according to the method of Ellman et al....
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