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Development of a reliable test system for purinergic P2X3 receptors
Tomanová, Šárka ; Doležal, Martin (advisor) ; Pourová, Jana (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Šárka Tomanová Supervisors: Prof. PharmDr. Martin Doležal, Ph.D., Prof. Dr. Christa Elisabeth Müller Title of diploma thesis: Development of a reliable test system for purinergic P2X3 receptors Purinergic P2X3 receptor is a ligand-gated ionotropic channel that occurs in all mammalian tissues. The highest occurrence has been observed in central and peripheral nervous system and smooth muscles, where P2X3 receptors participate in pathological disorders such as visceral and neurophatic pain, inflammatory reactions and psychiatric disorders. Compounds capable of blocking P2X3 receptor activity could be therefore used as potential drugs for treatment of these states. P2X3 receptor belongs to fast- desensitizing ionotropic channels, which makes the measurement of its activity very difficult. It was described that one point S15V mutation, in which the amino acid serine in a position 15 is replaced by amino acid valine, slows down the desensitization rate and the signal becomes easily measurable. This simple mutation may be used as an effective tool for characterization of insufficiently explored P2X3 receptor. The P2X3 S15V receptor DNA was inserted into retrovirus and,...
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Derivatives of pyrazine as potential antituberculars (preparation and study of biological properties)
Janďourek, Ondřej ; Doležal, Martin (advisor) ; Farsa, Oldřich (referee) ; Musílek, Kamil (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Candidate Mgr. Ondřej Janďourek Supervisor Prof. PharmDr. Martin Doležal, Ph.D. Consultant PharmDr. Jan Zitko, Ph.D. Title of Doctoral Thesis Derivatives of pyrazine as potential antituberculars (preparation and study of biological properties) This work is focused on pyrazine derivatives with the structural relationship to pyrazinamide (PZA) and with the potential antitubercular effect. In the introduction, there are summarized theoretical findings about tuberculosis (TBC), its epidemiology and primarily the development of resistance to current pharmacotherapy. Brief overview of known antituberculars, novel compounds and auspicious molecules in clinical trials is outlined. PZA, which is counted among the first line antitubercular agents, is widely described due to its cardinal role in this thesis. PZA possible mechanisms of action are described together with its pharmacological profile. Finally, brief summary of already prepared derivatives of PZA is stated. Practical part of this thesis is focused on synthesis of three starting compounds (5-chloro-6-methylpyrazine-2,3-dicarbonitrile; 3-chloropyrazine-2-carboxamide; N-benzyl-3-chloropyrazine-2-carboxamide) that were...
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Derivatives of pyrazinecarboxylic acid as potential antituberculotics (synthesis and biological evaluation)
Vaňásková, Barbora ; Doležal, Martin (advisor) ; Zimčík, Petr (referee) ; Malík, Ivan (referee)
Charles University in Prague, Faculty of Pharmacy v Hradci Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Barbora Vaňásková Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Title of Doctoral Thesis: Derivatives of pyrazinecarboxylic acid as potential antituberculotics (synthesis and biological evaluation) This doctoral thesis deals with searching for potential antituberculotic drugs derived from pyrazinecarboxylic acid. Thesis contains theoretical part, in which problematics of tuberculosis, factors hindering the effectiveness of treatment (development of resistance and HIV coinfection) and current therapeutic practice are outlined. An individual chapter is devoted to the composition of the mycobacterial cell wall. A brief overview of first-line and second-line antituberculars as well as drugs newly introduced into the clinical practice and promising derivatives in various phases of preclinical and clinical trials is further stated. Special attention is dedicated to pyrazinamide, current theories dealing with mechanism of action of this first-line antituberculotic drug and to ribosomal protein S1, a specific target of pyrazinecarboxylic acid. A summary of pyrazinamide derivatives with antimycobacterial activity published since 2011 is listed for...
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Synthesis and in vitro testing of tacrine-troloxic derivatives as potential inhibitors of acetylcholinesterase
Ondřejíček, Aleš ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Aleš Ondřejíček Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Supervisor specialist: PharmDr. Jan Korábečný, Ph.D. Title of Diploma thesis: Synthesis and in vitro testing of tacrine-trolox derivatives as potential inhibitors of acetylcholinesterase Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves gradual loss of episodic memory and impairment of cognitive functions. Characteristic histopathological hallmarks of AD are neuritic plaques and neurofibrillary tangles present in brain tissue as well as deterioration of cholinergic neurotransmission. Currently there are only two classes of drugs used for the treatment of AD. The first group represents inhibitors of acetylcholinesterase (AChEI), whereas the second only memantin, NMDA receptor antagonist. The aim of the thesis was to synthesize three series of tacrine - trolox derivatives. In particular derivatives of trolox with tacrine, 7-methoxytacrine and 6- chlorotacrine, which were connected by various linkers. To determine the therapeutical potential of new compounds Ellman method was used and results were compared with tacrine, 7-methoxytacrine and 6-chlorotacrine as standards. The...
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Design and Synthesis of Hybrid Compounds Based on Tacrin/Resveratrol Derivatives
Jeřábek, Jakub ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...
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Macroporous indium tin oxide as a potential platform for bioanalytical applications
Špirková, Zuzana ; Doležal, Martin (advisor) ; Kučera, Radim (referee)
Charles Univesity in Prague, Faculty of Pharmcy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate: Zuzana Špirková Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Consultant: Assist. Prof. Gulnara Safina, Ph.D. Title of thesis: Macroporous indium tin oxide as a potential platform for bioanalytical applications Blood glucose monitoring is an essential tool in diabetes mellitus diagnosis. Therefore new strategies have been developed to improve the performance of glucose sensing devices. In this thesis the suitability of macroporous indium tin oxide (ITO) electrodes for construction of third-generation glucose biosensors was investigated. As a biosensing part in sensor cellobiose dehydrogenase from Corynascus thermophilus (CtCDH) immobilized onto ITO platform was used. Several immobilization strategies based on physical adsorption, electrostatic bindings of the enzyme to the surface functionalized with polythyleneimine (PEI) and cross-linking with glutaraldehyde (GA) were studied in order to achieve reasonable sensitivity and stability of the biosensor. The morphology/topography and elemental composition of the enzyme modified surface were examined by scanning electron microscopy (SEM), energy-dispersive X- ray spectroscopy (EDX), X-ray photoelectron spectroscopy...
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Preparation of phenyl derived benzothiazoles as potential ABAD modulators
Chřibek, Matěj ; Doležal, Martin (advisor) ; Kučerová, Marta (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Matěj Chřibek Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Title of Thesis: Preparation of phenyl derived benzothiazoles as potential ABAD mo- dulators Alzheimer's disease (AD) is neurodegenerative disease, which is characterized by progressive cognitive decline. Characteristic symptoms are memory loss, change of behaviour and personality. The pathological hallmarks of AD are senile plaques and neurofibrillary tangles of hyperphosphorylated τ protein. Currently there is no causal treatment, because the aetiology stays unexplained, despite of intensive research. Nowadays, the hypothesis assumes that soluble form of amyloid-β (Aβ) is asso- ciated with toxic effects inside the cells, among others in mitochondria. There are many intracellular proteins, which interact with Aβ, such as amyloid binding alcohol dehydrogenase (ABAD). Interaction Aβ-ABAD with consequent alteration of ABAD function has been shown to cause mitochondrial dysfunction, consequently leading to the cell death. Therefore, inhibition of Aβ-ABAD along with ABAD inhibition seems as a potential pharmacological target. 1 The aim of this thesis was to synthesize substituted benzothiazole ureas as...
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Prodrug structures to improve the drug delivery of anti-cancer agents
Králová, Vendula ; Doležal, Martin (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Vendula Králová Supervisor: Prof. PharmDr. Martin Doležal, Ph.D Specialized supervisor: Kristiina Huttunen, Ph.D Title of diploma thesis: Prodrug structures to improve the drug delivery of anti- cancer agents Cancer belongs to the most widespread diseases in the world, and we can expect that it will remain among the deadliest illnesses in the future. For this reason, scientists have put enormous efforts into researching new drugs, which would stop this growing trend. Nowadays, pharmaceutical research is focused mainly on the development of targeted treatment of oncological diseases, which aims at specific structures on the surface or in the core of the tumorous cells. This treatment is limited only to a precisely targeted group of tumors, and it usually leaves healthy cells unharmed. Through clinical studies, many new medications have been developed, and they show high efficiency in the treatment of various types of cancer. However, their success is constrained by drug resistance, which has become a significant obstacle to their use. The topic of this thesis is the synthesis of new anticancer drugs and their prodrugs. These prodrugs were prepared in such a way that they would...
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Pyrazine derivatives as potential drugs IV.
Valášek, Ondřej ; Doležal, Martin (advisor) ; Opletalová, Veronika (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Tutor - specialist: PharmDr. Jan Zitko, Ph.D. Candidate: Ondřej Valášek Title of diploma thesis: Pyrazine Derivatives as Potential drugs IV. Even in the year 2016, tuberculosis is still worldwide problem which is addressed by many national and supra-national organizations trying to eliminate it. It burdens the most developing countries which don't usually have the opportunity to access the potential of modern medicine to its full extent. In relation to ineffective treatment, there grows prevalence of tuberculosis, which can't be managed by standard treatment. There is an urgent need to find new compounds and change structures of current antituberculars, which will help us defeat multi-drug resistant M. tuberculosis. The objective of my work was to find out the influence of inversion of the amidic group in derivatives of pyrazin-2-carboxylic acid (-CO-NH- to -NH-CO-) and their efficacy and toxicity. In the theoretical part I focused on resuming all the basic facts about tuberculosis and its causing agent, about possibilities in prevention and diagnostics as well as the antituberculars, both used and currently tested, which can help us in the future. In the experimental part I wrote down the reactions and procedures, which were used...
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Tacrine-benzothiazole derivatives in Alzheimer's disease
Svobodová, Lucie ; Kučerová, Marta (advisor) ; Doležal, Martin (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Lucie Svobodová Supervisor: PharmDr. Marta Kučerová, Ph.D. Consultant: Mgr. Eugenie Nepovimová Title of Diploma Thesis: Tacrine-Benzothiazole Derivatives in Alzheimer's Disease Therapy Alzheimer's disease (AD) is a progressive fatal neurodegenerative disorder and the most common type of dementia. It is manifested by a variety of neuropsychiatric symptoms such as memory loss, visuospatial deficits etc. Ethiology of the disease has a multifactorial character and is not well known. Among the major pathological features belong: presence of extracellular amyloid plaques, intracellular aggregates of hyperphosphorylated tau protein and neuronal loss, especially loss of cholinergic neurons. Also the oxidative stress of the neuronal cells contributes to the pathophysiology of the disease. As AD is influenced by multiple factors, the main strategy in treatment is hitting multiple targets in the brain as well. Such drugs are denoted as multi-target-directed ligands (MTDLs) and they affect different molecular abnormalities of AD. Within this work, we would like to bring out new tacrine - benzothiazole hybrids combining tacrine with the amino benzothiazole moiety. Linkers of...
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