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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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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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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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Design and synthesis of tacrine-quinone hybrids as multitarget ligands against Alzheimer's disease
Nepovimová, Eugenie ; Opletalová, Veronika (advisor) ; Musílek, Kamil (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Eugenie Nepovimová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Design and synthesis of tacrine-quinone hybrids as multi-target ligands against Alzheimer's disease Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder that manifests as memory loss, personality changes, global cognitive dysfunction, and functional impairment. It is the leading cause of dementia in aged humans. Nowadays, there are no effective preventative measures, definitive diagnostic guidlines, or curative therapy for AD, its precise ethiology, too, remains unknown. To date, the pharmacotherapy of AD has relied on acetylcholinesterase (AChE) inhibitors - donepezil, rivastigmine and galantamine - and, more recently, on an N-methyl-D- aspartate (NMDA) receptor antagonist - memantine. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting AChE which hydrolyses acetylcholine. Furthermore, it has been demonstrated that AChE plays an important role in Aβ-aggregation during the early stages of senile plaque formation, one of the hallmarks of AD. Therefore, AChE inhibition represents a critical target for the effective...
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Derivatives of thiazole as potential drugs.
Doležel, Jan ; Opletalová, Veronika (advisor) ; Doležal, Martin (referee) ; Musílek, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Jan Doležel Supervisor Doc. RNDr. Veronika Opletalová, Ph.D. Title of Doctoral Thesis Derivatives of thiazole as potential drugs The doctoral thesis is focused on preparation of thiazole derivatives. Sixty seven compounds were prepared, thirty one of them are original. Structure-activity relationships between the chemical structure, physical properties and biological activities of the evaluated compounds are discussed. First from five series were 5-benzylidenerhodanine derivatives and 5-hetarylmethylidenerhodanine derivative. Compounds were gained by Knovenagel condensation of rhodanine with aromatic or heterocyclic aldehydes. At the same time the earlier prepared condensation product of rhodanine and ketones derived mainly from substituted acetylpyrazines were further tested for biological properties. The next part was given to the preparation of condensation products of N-substituted rhodanine with aromatic and heterocyclic aldehydes or ketones. Last series of compounds are of 5-(1-hetarylalkylidene)hydrazonothiazolidine-4-one derivatives prepared by cyclization of analogous thiosemicarbazones. The prepared compounds were evaluated for their antifungal 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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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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Design and synthesis of BCA2 inhibitors.
Soukupová, Jitka ; Doležal, Martin (advisor) ; Musílek, Kamil (referee) ; Westwell, Andrew D. (referee)
BCA 2 (Breast Cancer Associated Protein2) is a novel monomeric RING (Really Interesting New Gene 2) - type ubiquitin E3 ligase. It was found to be overexpressed in 56 % of invasive breast cancers and its expression is correlated with a positive estrogen receptor status. The RING-type family of proteins possesses ubiquitin ligase activity and involves in protein degradation. Ubiquitylation is used to target proteins of different biological processes including proteosomal degradation or endocytosis. Polyubiquitination of target protein substrates is carried out by three classes of ubiquitin ligase enzymes, of which the diverse E3 ligase family catalyse the final step of ubiquitin transfer to specific lysyl residues of target proteins prior to proteosomal destruction. The RING-type proteins can be defined as unique linear series of conserved cysteine and histidin residues and binds two zinc atoms in a cross-brace arrangement. Studies of zinc-ejecting compounds have led to the identification of disulfiram, which has been used for alcohol aversion therapy for alcohol aversion therapy as an alcohol dehydrogenase inhibitor. In this thesis I describe the synthesis of three series of novel zinc-affinic compounds, in order to optimise selectivity of BCA2 inhibitors which could lead to the identification of...
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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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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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