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Synthesis of xanthone derivates for in vitro and in vivo biological activity studies
Široká, Jitka ; Zimčík, Petr (advisor) ; Opletalová, Veronika (referee)
Synthesis of xanthone derivatives for in vitro and in vivo biological activity studies J. Siroka Xanthone derivatives are heterocyclic compounds with the dibenzo-γ-pyrone as the main molecular moiety. They contain different types of substituents in different positions, leading to a large variety of pharmacological activities. 3,4-Dihydroxyxanthone was revealed as a hit compound in a study involving the investigation of the inhibitory effect of oxygenated xanthones on several human tumor cell lines. In order to obtain enough quantity for in vivo assays and for further molecular modifications, the synthesis of 3,4-dihydroxyxanthone was accomplished: the condensation of 1,2,3-trimethoxyphenol with the appropriate substituted benzoyl chloride (2-methoxybenzoyl chloride) afforded benzophenone (2-hydroxy-2',3,4- trimethoxy benzophenone) which was further cyclized to give 3,4-dimethoxyxanthone. The 3,4-dimethoxyxanthone was demethylated to furnish 3,4- dihydroxyxanthone. Additionally, the synthesis of reactive formylated derivatives of xanthones, 1- formyl-3,4-dihydroxyxanthone and 1-formyl- 3,4-dimethoxyxanthone, was attempted by Duff formylation. Only 1-formyl-3,4- dihydroxyxanthone was obtained. Due to a small amount of 3,4-dihydroxyxanthone obtained from the first synthesis, the synthesis was repeated...
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Derivatives of Rhodanine as Potential Antifungal Drugs
El Zein, Mariana ; Opletalová, Veronika (advisor) ; Kopecký, Kamil (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Mariana El-Zein Consultant: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Derivatives of Rhodanine as Potential Antifungal Drugs Rhodanine (2-thioxo-1,3-thiazolidin-4-one) forms the basic skeleton of many biologically active substances and potential drugs. Antifungal properties of rhodanine derivatives have been studied since the early 1950s. Theoretical part of the thesis deals with mycoses and drugs that are currently used to treat them. The aim of the experimental work was to find suitable reaction conditions for Mannich reaction of (5Z)-5-(subst.)benzylidenes-2-thioxo-1,3-thiazolidin-4-ones with various amines. The attempts to prepare Mannich bases using diethylamine as the basic component were unsuccessful. (5Z)-5-benzylidene-3-(morpholin-4-yl-methyl)-2-thioxo-1,3-thiazolidin- 4-one was successfully obtained by treating (5Z)-5-benzylidene-2-thioxo-1,3-thiazolidin- 4-one with formaldehyde and morpholine in dimethylformamide. This compound was reported previously and exhibited antibacterial activity and acceptable toxicity. Hence, Mannich bases derived from (5Z)-5-arylalkylidene-2-thioxo-1,3-thiazolidin-4-ones deserve further attention as potential...
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Synthetic routes to 2-phenylbenzothiazoles with potential application in cancer therapy and PET imaging
Frydrych, Jan ; Opletalová, Veronika (advisor) ; Zimčík, Petr (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate: Jan Frydrych Supervisors: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Dr. Andrew Westwell Ph.D. Title of diploma thesis: Synthetic routes to 2-phenylbenzothiazoles with potential application in cancer therapy and PET imaging There are three main tasks reported in this thesis. The first is the report of an improved procedure for synthesis of biologically relevant 2-phenylbenzothiazoles with various substituents on phenyl ring. Reported 2-phenylbenzothiazoles were synthesised by heating equimolar amounts of 2-aminothiophenol disulfides with appropriate benzaldehydes with p-toluenesulfonic acid in the presence of polymer-bound triphenylphosphine using mixture of toluene and DMF as a solvent. Main features of reported method include simple product isolation (removal polymer-bound by-product by filtration through Celite® layer), avoidance of column chromatography, rapid synthesis and good yields of correspondent benzothiazole. The second goal of this thesis is the solution phase synthesis of 2-phenylbenzothiazoles bearing different substituents on both the benzothiazole and phenyl ring. Attempts were made to synthesise different 2-phenylbenzothiazoles by heating...
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Pyrazine derivatives as potential drugs IV
Lešňanská, Katarína ; Doležal, Martin (advisor) ; Opletalová, Veronika (referee)
Title of diploma thesis: Pyrazine derivates as potential drugs IV. Recherché about occurence of tuberculosis in the world, characteristics of this disease, treatment and drugs used was conducted first in this diploma thesis. Methods of preparing substituted pyrazinecarboxylic acid amids were found in chemical literature. Six new compounds, in chemical literature undocumented amides, were synthetized. Prepared products were described using melting temperature, elementary analysis, IR, 1 H and 13 C NMR spectroscopy. Group of compounds was tested in vitro for biological activity. Information about antimycobacterial, antifungal and herbicide activity was gained. Substances lipophilicity was evaluated. Values of log P were counted. At the end, relationship between biological activity, chemical structure and lipophilicity of prepared substances was evaluated.
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Current Trends in the Development of Anviral Drugs
Ioannidou, Olga ; Opletalová, Veronika (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Olga Ioannidou Consultant: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of Thesis: Current trends in the development of antiviral drugs Since the introduction of the first antiviral drug, a great progress has been made. Every year, many substances are tested for their activity against a wide range of viruses. Especially for serious diseases, like AIDS and hepatitis C, the need for safer and more effective drugs is increased. In the first part of the thesis older, but still important drugs are described and also their structures are given. Some of them have a wide spectrum of activity, such as ribavirin, which is used for the treatment of both hepatitis C and viral hemorrhagic fever. In the second part, newly developed drugs and drugs that are under clinical trials are discussed. New drugs have greater efficacy and fewer side effects. Nevertheless, there are some viral diseases that could not be managed with drugs and must be prevented by vaccines. To overcome all difficulties and develop both new drugs and vaccines remains a great challenge for the scientists
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Derivatives of thiazole as potential drugs II.
Hovorková, Jana ; Opletalová, Veronika (advisor) ; Zimčík, Petr (referee)
Jana Hovorková Derivatives of Thiazole as Potential Drugs II. Diploma Thesis, Department of Pharmaceutical Chemistry and Drug Control, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, 2010 Abstract Within this diploma thesis, preexisting (E)-2-(1-pyrazin-2-yl- ethylidene)hydrazonocarbothioamides and new (E)-2-[1-(5-benzylpyrazin-2-yl)- ethylidene]hydrazonocarbothioamide were prepared. Reaction of substituted acetylpyrazines with thiosemicarbazide proceeded according the procedure reported previously. Antimicrobial activity of prepared substances was tested against eight bacteria by the microdilution broth method with utilization bacitracin and neomycin as positive controls. Promising inhibition effect against Staphylococcus epidermidis was found with (E)-2-[1-(5-terc-butylpyrazin-2-yl)ethylidene]- hydrazonocarbothioamide. Next, reaction of the prepared thiosemicarbazones with maleinanhydrid was studied. In this reaction no identifiable compounds were prepared. The final experiments were aimed at preparing derivatives of 4-phenyl-2-[2- (1-pyrazin-2-yl)ethylidene]hydrazinylthiazole by the reaction of thiosemicarbazones with phenacylbromide. It was found that the cyclization wasn't completed, only addition of phenacylbromide on sulfur of thiosemicarbazone proceeded. Through this reaction...
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Synthesis of compounds influencing the nucleic acids chains interactions.
Ondrej, Martin ; Miletín, Miroslav (advisor) ; Opletalová, Veronika (referee)
Substances which can bind selectively to the DNA structures and modify its' functions are in the center of study of many researchers for several decades. A place of their action is the minor groove of DNA. Distamycin A, netropsin, Hoechst 33258 and many other compounds are substances with a potential to interact with DNA sequences, especially with A T base pairs rich ones. My thesis is focused on searching and synthesizing of molecules structurally and functionally similar to compounds mentioned above. In order to find the structure with required properties as well as the method for the synthesis, screening by preparation of various compounds has been made. Each synthesis was performed using various methods confirming that the methodology is not entirely uniform. Common required result of each synthesis was preparation of final compound in a water soluble salt. Many partial reactions were not always successful, but necessary for terminal synthesis of required compounds. Syntheses of four compounds were successful, which were tested by molecular biology methods for increasing the melting temperature. The performed tests have shown low activity of the prepared compounds. N,N'-(1,3-phenylenebis(methylene))bis(4- ((diaminomethylene)amino)-1-methyl-1H-pyrrole-2-carboxamide) seems to be the most...
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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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Preparation of New Acetylcholinesterase Reactivators with an Amidoxime Functional Group and Their In Vitro Testing
Zemek, Filip ; Opletalová, Veronika (advisor) ; Jun, Daniel (referee)
1. SUMMARY Originally organophosphorus compounds were used as pesticides. Unfortunately, their irreversible inhibition of AChE was discovered, and they were widely misused as warfare agents. Presently, there is not a reactivator good enough to reverse completely irreversible inhibition of AChE. Thus, especially for military purposes, it is very important to look for better reactivators. As the reactivators can both reactivate inhibited AChE and inhibit the intact AChE, they have also been tested as potential therapeutics for Alzheimer's disease. New modification of oxime group with -NH2 was tried for better reactivation or inhibition results compared to widely used conventional drugs. Also monoquartenary and bisquartenary modifications were tested for possible improvement in activity. Wide range of substances was synthesized, which differed in homologous unit -CH2-. Thus substances with short aliphatic side chains, with partly hydrophilic properties, and those with long chains with mainly liphophilic properties as well as bisquarternary derivatives with various linking chains between two pyridininum centers were prepared and tested. Unfortunately these modifications did not prove to have any positive effect on activity or on inhibition. Some substances have shown mild reactivation possibility or inhibited...
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Amidoximes as synthetic intermediates and potential drugs I.
Horká, Michaela ; Opletalová, Veronika (advisor) ; Kopecký, Kamil (referee)
AMIDOXIMES AS SYNTHETIC INTERMEDIATES AND POTENTIAL DRUGS I. Michaela Horká Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control In the theoretical part of this diploma thesis, biological activities of amidoximes are resumed. They have been studied mainly as prodrugs that are reduced to active compounds - amidines. Some amidoximes reached clinical trials but due to their significant undesirable effects have not been developed further. Methodical part deals with various synthetic procedures for the preparation of amidoximes. In the frame of the experimental part, four 5-alkylpyrazine-2-carbonitriles were synthesized at first. Using hydroxylamine hydrochloride, the nitriles were converted to corresponding amidoximes: N'-hydroxy-5-propylpyrazine-2-carboximidamide N'-hydroxy-5-isopropylpyrazine-2-carboximidamide N'-hydroxy-5-pentylpyrazine-2-carboximidamide N'-hydroxy-5-hexylpyrazine-2-carboximidamide None of the obtained products have been reported yet. They were characterized by melting points, IR, NMR spectra. Their purity was checked by elemental analysis. The compounds were tested for antifungal and antibacterial activity but were found non-effective. This is probably due to the fact that in vitro their bioactivation...
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