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Synthesis of hydroxy derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione
Musilová, Jitka ; Macháček, Miloš (advisor) ; Kuneš, Jiří (referee)
Synthesis of hydroxy derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)- dione Jitka Musilová The thesis is concerned with the preparation of 16 cyclic analogues of hydroxy-salicylanilides, i.e. 3- phenyl-2H-1,3-benzoxazine-2,4(3H)-diones monosubstituted with a hydroxyl group on the heterocyclic ring. The starting hydroxysalicylanilides belonging to four series were synthesized by the microwave- assisted reaction of the respective hydroxysalicylic acid with aniline (unsubstituted or para- substituted by chlorine, methyl or methoxy groups) in the presence of phosphorus trichloride. Their treatment with ethyl-chloroformate afforded the expected 1,3-benzoxazine derivatives in 77 - 94 % yields. All compounds prepared were characterized by infrared and NMR spectroscopy and by elemental analysis. All the compounds were examined for antifungal activity in vitro against Candida albicans, C. tropicalis, C. krusei, C. glabrata, Trichosporon asahii, Trichophyton mentagrophytes, Aspergillus fumigates, and Absidia corymbifera, but none of these compounds was more active than ketoconazole. In general, parent hydroxysalicylanilides were more active than their cyclic counterparts.
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Synthesis of substituted arylguanidines as potential drugs VI.
Korábečný, Jan ; Palát, Karel (advisor) ; Macháček, Miloš (referee)
S Y N T H E S I S O F S U B S T I T U E D A R Y L G U A N I D I N E S A S P O T E N T I A L D R U G S V I . Author: Korábečný J. Tutor: Palát K. Dept. of Inorganic and Organic Chemistry Faculty of Pharmacy in Hradec Kralové Charles University in Prague, Czech Republic Background: High number of life imperilling mycotic infection carries with itself increased need of antifungal drugs and need of new substances. In usage of antimycobacterial drugs it is also the same. Increasing resistance of pathogenic organisms urges human population to search for new, effective drugs. Aim of study: The aim of my diploma work was to prepare series of substitued arylguanidines, mainly 1-[3-chlor-4- (alkylsulfanyl)phenyl]guanidines, which are tested on antifungal and antimycobacterial activity. Methods: 2-Chloro-1-(alkylsulfanyl)-4-nitrobenzenes were synthesized from 3,4-dichloronitrobenzene by custom methods; either by using of active copper or by using Pd2(dba)3 and Xantphos as catalyzers. The following reduction of nitrogroup to aminogroup was made by stannous chloride under nitrogen atmosphere. Rise of appropriate amonnium salts proceeded in reaction with gaseous dry hydrogen chloride, almost quantitatively. Reaction leading to rise of guanidines proceeded with cyanamide in the melt or ethanolic solution in autoclave at...
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Evaluation of a novel series of [1,2,4] triazolo [4,3-a] quinoxalines and related compounds: highly potent adenosine receptor antagonists
Krpelíková, Irena ; Vopršalová, Marie (advisor) ; Macháček, Miloš (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology, Czech Republic Performed at: University of Bonn, Pharmaceutical Institute, Department of Pharmaceutical Chemistry, Germany Candidate: Irena Krpelíková Supervisors: Prof. Dr. Christa Elisabeth Müller PharmDr. Marie Vopršalová, CSc. Title of diploma thesis: Evaluation of a novel series of [1,2,4]triazolo[4,3- ɑ]quinoxalines and related compounds: highly potent adenosine receptor antagonists Adenosine, a local modulator, acts in many diverse biological processes. Its effects are mediated through adenosine receptors (ARs). Four types of ARs have been described, A1, A2A, A2B and A3, which belong to the superfamily of G protein-coupled receptors. AR ligands are being developed as new drugs. This thesis deals with the study of a novel series of [1,2,4]triazolo[4,3- a]quinoxalines and related compounds as potential adenosine receptor antagonists. The presented results were obtained using radioligand binding assays. Series of quinoxalinones and tetrazoloquinoxalines exhibit significant selectivity for human (h) A3 ARs but their affinity is relatively low for tetrazoloquinoxalines and moderate for quinoxalinones. Triazoloquinoxalines comprise the largest group of this series. Generally, the R1...
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Synthesis of xanthone derivatives by microwave-assisted methods
Vrbata, Petr ; Macháček, Miloš (advisor) ; Vinšová, Jarmila (referee)
Synthesis of Xanthone Derivatives by Microwave-assisted Methods Petr Vrbata This diploma thesis deals with preparation of xanthone derivatives as inhibitors of growth of human cancer cell lines. A new methodology for synthesis of dihydropyranoxanthones 1 and 2, based on the usage of heterogeneous catalysis combined with microwave irradiation, was optimized. This allowed decreasing significantly the reaction time and improving yields. Along with this the Grover, Shah and Shah method (J. Chem. Soc. 1955, 3982) for synthesis of xanthone derivatives was improved due to usage of microwave heating. Using this method a new xanthone derivate 5,8,10-trihydroxy-7H-benzo[c]xanthen-7-on (3) was prepared. Its structure was verified by IR, 1 H NMR and 13 C NMR spectra. O O O OH O O O OH O OH OHO OH 1 2 3
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Synthesis of substituted arylguanidines as potential drugs VII.
Bromand, Nasir ; Palát, Karel (advisor) ; Macháček, Miloš (referee)
Pathological fungi carry the ability to cause serious medical problems and moreover cause various diseases. Drug therapy and new active compounds against these medical problems are still being researched. The long-term objective is to uncover the active compounds at the Faculty of Pharmacy, Charles University. In our study, we synthesized 3-(4-bromophenyl)-1,1-diethylguanidine, and 2 novel compounds: 3-(4- dodecylsulfanylphenyl)-1,1-diethylguanidine and 3-(3-bromophenyl)-1,1- diethylguanidine. We also studied the oxidation of 1-(4- tetradecylsulfanylphenyl)guanidinium nitrate, thus, making it the third novel compound 1-(4-tetradecylsulfonylphenyl)guanidinium nitrate we synthesized.
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Synthesis and Biological Activity of Dihydroxybenzoic Acids Derivates
Skála, Pavel ; Macháček, Miloš (advisor) ; Pytela, Oldřich (referee) ; Doležal, Martin (referee)
The dissertation focuses on such derivatives of dihydroxybenzoic acids which can be considered to be derived from salicylic acid. The prepared substances were evaluated for their antimycobacterial and antifungal activity in vitro. The work on the dissertation produced 102 compounds, including 72 original ones. The prepared initial compounds included four series of dihydroxy-N- phenylbenzamides, in which one hydroxy group is in position 2 and the position of the second one is successively changed. Their thionation using the patented method developed by our laboratory produced the corresponding dihydroxy-N-phenylthiobenzamides. The cyclization reaction of the initial dihydroxy-N-phenylbenzamides with methyl-chloroformate yielded four series of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones with hydroxy groups in positions 8, 7, 6, and 5. Direct melting of prepared 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones with Lawesson's reagent provided the expected products, 3-phenyl-4-thioxo-3,4-dihydro-2H- 1,3-benzoxazin-2-ones and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones, but only in the series of 5-hydroxy derivatives. It was the reason for a search for other methods for the preparation of thionated derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione. The highest antifungal activities were exerted by...
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Synthesis of new derivatives of combretastatine
Brůža, Zbyněk ; Pour, Milan (advisor) ; Macháček, Miloš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate: Zbyněk Brůža Consultant: Prof.RNDr. Milan Pour, Ph.D. Title of Thesis: Synthesis of new derivatives of combretastatin The aim of this work was the synthesis of novel structural analogues of combretastatin, including further structural modifications. Synthetic modifications might improve biological activity as well as pharmacokinetics of the compounds. Two 3,4-diaryl-2,5-dihydrofuran-2- ones were synthesized. The sequence comprises well-known reactions starting from α-halogenated acetophenones, which are converted to esters of phenylacetic acids. The esters are then cyclized to the final 2,5-dihydrofuran-2-ones analogues under basic conditions. The title compounds were screened for their antibacterial, antifungal and cytotoxic activity. Because of the difficulties especially in the cyclization step, we have tried to develop an alternative synthetic procedure based on Pd-catalysed cross-coupling reactions of different aryl halides with heterocycles as bridging structural fragments.
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