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Study of pyridine derivatives as potential antimycobacterial active drugs.
Nawrot, Daria Elżbieta ; Doležal, Martin (advisor) ; Musílek, Kamil (referee) ; Musiol, Robert (referee)
Univerzita Karlova, Farmaceutická fakulta v Hradci Králové Katedra Katedra farmaceutické chemie a farmaceutické analýzy Kandidát: Daria Nawrot Školitel: Prof. PharmDr. Martin Doležal, Ph.D. Název disertační práce: Studium derivátů pyridinu jako potenciálních antimykobakteriálních léčiv. Mimo období kdy tvořil COVID-19 největší hrozbu pro účinnost zdravotnických systémů na celosvětovém měřítku, zůstává tuberkuloza nejdůležitější příčinou úmrtí na infekční chorobu. Tato skutečnost, spolu se stoupající antibakteriální rezistencí, tvoří zásadní výzvu pro výzkum nových léčiv. Teoretická část tohoto komentáře krátce zvýrazňuje problematiku tuberkulozy a konkrétněji antimikrobiální rezistence. V experimentální části je vedena diskuze o návrhu, syntéze a biologickém hodnocení nových sloučenin zkoumaných během doktorského studia. Navržené sloučeniny byly připraveny a testovány na in vitro aktivitu proti vybraným mykobakteriálním kmenům (M. Avium, M. aurum, M. kansasii, M. smegmatis spolu s kmeny hlavního zájmu - Mtb H37Ra a H37Rv), osmi fungálním kmenům (Candida albicans, Candida krusei, Candida parapsilosis, Candida tropicalis, Aspergillus fumigatus, Aspergillus flavus, Absidia corymbifera, a Trichophyton interdigitale) a osmi bakteriálním kmenům (Staphylococcus aureus, Escherichia coli, Pseudomonas...
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Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease
Hroch, Lukáš ; Musílek, Kamil (advisor) ; Farsa, Oldřich (referee) ; Zimčík, Petr (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Lukáš Hroch Supervisor assoc. prof. PharmDr. Kamil Musílek, Ph.D. Title of Doctoral Thesis Inhibitors of mitochondrial enzymes as potential therapeutics for Alzheimer's disease There were about 50 million people living with dementia in 2015. It is expected that number of people living with dementia will reach 130 million by the year of 2050. Alzheimer's disease (AD) is one of the most common causes of dementia and it is estimated to account for about 60 80% of overall cases. Current symptomatic treatment only alleviates symptoms and delays progression of the disease. However, there is no effective treatment, which would address the underlying cause of AD. The extracellular depositions of insoluble amyloid beta peptide (Aβ) were thought to be a causative factor and main target for a long time. Yet, targeted treatment towards the reduction of extracellular Aβ depositions failed to show expected therapeutic merit. Later on, it has been shown that development of AD starts much earlier than any Aβ plaques or symptoms could be observed. With growing evidence of soluble Aβ in intracellular regions, main attention moved to investigations of Aβ within the cells. Aβ...
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Study of recognition moieties of sensoric azaphthalocyanines
Lochman, Lukáš ; Nováková, Veronika (advisor) ; Musílek, Kamil (referee) ; Kubát, Pavel (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Lukas Lochman Supervisor: Doc. PharmDr. Veronika Novakova, Ph.D. Advisor: Doc. PharmDr. Petr Zimcik, Ph.D. Doctoral Thesis: Study of recognition moieties of sensoric azaphthalocyanines Azaphthalocyanines (AzaPcs) are planar macrocyclic compounds with unique photophysical properties like absorption and emission over 650 nm and high quantum yields of fluorescence. Alkylamine substituted AzaPcs have been shown to undergo an ultrafast intramolecular charge transfer (ICT) which is responsible for efficient quenching of excited states (nonfluorescent OFF state). ICT occurs between donor (peripheral amine) and acceptor (macrocyclic core). Blocking of ICT leads to restoration of high fluorescence emission (fluorescent ON state) which is the competitive relaxation pathway. There are two known possible ways how to block ICT in AzaPcs sofar: By protonation of donor in pH sensitive AzaPc sensors or by coordination of metal cation into the recognition moiety resulting in cation sensitive AzaPc sensors. Above-mentioned properties predestinate AzaPcs to become new fluorescent sensors with good brightness and advantageous absorption and emission of red light deep...
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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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Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease
Červinková, Tereza ; Červený, Lukáš (advisor) ; Musílek, Kamil (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...
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Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease
Červinková, Tereza ; Červený, Lukáš (advisor) ; Musílek, Kamil (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...
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Preparation of quarternary cationic tenzides and their evaluation
Slavětinská, Lenka ; Doležal, Martin (advisor) ; Musílek, Kamil (referee)
Preparation of quarternary cationic tensides and their evaluation. Lenka Slavětinská This thesis was focused on a synthesis of three homological series of tensides. The analogues of N-phenylethyl-N,N-dimethyl-N-alkylammoniumbromide; 3-hydroxy-1-alkylpyridiniumbromide and 4-hydroxyiminomethyl-1-alkylpyridinium- bromide were prepared. All prepared structures were confirmed by the NMR, EA and ESI-MS analysis. Their critical micellar concentration (CMC) was measured by conductometry and the reduced CMC with increasing alkyl chain was proved. The concentration scale for the measurement of micellar catalysis of p- nitrophenylcaprylate and p-nitrophenylcaprate was based on CMC outcomes. Only more lipophilic tensides were used, because their higher reactivity with chosen substrates was expected.
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Alkylamino- Derivatives of Pyrazinamide as Potential Antituberculotic Drugs
Mlčoch, Michal ; Zitko, Jan (advisor) ; Musílek, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Michal Mlčoch Supervisor: Mgr. Jan Zitko, Ph.D. Title of candidate thesis: Alkylamino- derivatives of pyrazinamide as potential antituberculotic drugs This thesis is a result of intention to prepare potential effective derivatives from pyrazinamide (PZA) structure. These results contribute to enrichment of the research of new antituberculars (antiTBC) which has been carried out at the Dpt. of Pharmaceutical Chemistry and Drug Control at the Faculty of Pharmacy in Hradec Králové. The aim of the research to produce the new effective antituberculars is supported by the contemporary state of tuberculosis in the world. This state is closely described in this thesis. Despite of decreasing number of new cases in all six WHO regions, spreading of this infectious disease is not under the control. The main reason is a resistance formation of new mycobacterial strains which can cause hardly treatable cases. The prepared substances are PZA derivatives which represent one of the most important first line drugs for tuberculosis treatment. The latest research focused on mechanism of PZA showed new information which was included in this thesis. Furthermore, some...
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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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Synthesis of acetylcholinesterase reactivators and their evaluation against the intoxications caused by the organophosphorus inhibitors in vitro.
Musílek, Kamil ; Doležal, Martin (advisor) ; Beneš, Luděk (referee) ; Bajgar, Jiří (referee)
6. Summary The Ph.D. thesis is focused on a development of the novel acetylcholinesterase reactivators - the causal treatment for the intoxications caused by the organophosphorus inhibitors of cholinesterases. The background for an experimental work was a review article based on the published papers in the period 1990-2004. The experimental work was focused on a synthesis, a structural analysis and an in vitro evaluation of the novel acetylcholinesterase reactivators, which were compared to the commercial available compounds. The structure activity relationship (SAR) studies of the novel acetylcholinesterase reactivators were prepared according to the in vitro results. Moreover, other novel acetylcholinesterase reactivators were synthesised based on the previous SAR data. Recently, some of the novel compounds are tested in vivo. In conclusion, it was prepared, determined and evaluated over than 70 novel acetylcholinesterase reactivators. The review and experimental papers (25 papers) were published in the scientific journals and presented as the short communications or posters at the scientific meetings in the Czech Republic or abroad.
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