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Antimycobacterial isosters of salicylanilides
Matyk, Josef ; Waisser, Karel (advisor) ; Čižmárik, Jozef (referee) ; Lešetický, Ladislav (referee)
V PhD disertaci byla popsána skupina 79 látek (4-alkylfenyl)salicylamidů, N-heteroarylsalicylamidů, 3-(4-alkylfenyl)-2H-1,3-benzoxazin-2,4(3H)-dionů, 3- (4-alkylfenyl)-2H-1,3-bemzoxazin-4(3H)thioxo-2-onů, 3-(4-alkylfenyl)-2H-1,3- benzoxazin-2,4(3H)-dithionů a 3-heteroaryl-2H-1,3-benzoxazin-2,4(3H)-dionů. Látky byly hodnoceny na antimykobakteriální, antifungální a antibakteriální aktivitu. Vybrané látky byly hodnoceny na cytotoxicitu. Deriváty (4-alkylfenyl)salicylamidů byly analyzovány přístupem QSAR (Kvantitativní vztahy mezi strukturou a aktivitou) a to metodou podle Freeho a Wilsona. Struktura připravených látek byla ověřena 1 H-NMR a IČ-spektroskopií a jejich čistota elementární analýzou. Deriváty (4-alkylfenyl)salicylamidů, N-heteroarylsalicylamidů, 3-(4- alkylfenyl)-2H-1,3-benzoxazin-2,4(3H)-dionů, 3-(4-alkylfenyl)-2H-1,3- bemzoxazin-4(3H)thioxo-2-onů, 3-(4-alkylfenyl)-2H-1,3-benzoxazin-2,4(3H)- dithionů a 3-heteroaryl-2H-1,3-benzoxazin-2,4(3H)-dionů vykazovaly vysokou aktivitu vůči Mycobacsterium tuberculosis a atypickým kmenům mykobaktérií (M. avium a M. kansdasii).
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Synthesis of antimicrobial active anilides and their sulphur analogues
Oktábec, Zbyněk ; Vinšová, Jarmila (advisor) ; Macháček, Miloš (referee)
CHARLES UNIVERSITY IN PRAGUE PHARMACEUTICAL FACULTY IN HRADEC KRÁLOVÉ DEPARTMENT OF ANORGANIC AND ORGANIC CHEMISTRY Diploma Thesis Synthesis Of Antimicrobial Active Anilides and Their Sulphur Analogues Zbyněk Oktábec Implementation of tert-butyl group into the molecule of benzoxazoles leads to enhancement of lipophility and therefore better penetration through lipoid mycobacterial cell-wall. Several derivates had shown 100-90 % activity in concentration 6,25 μg/ml against Mycobacterium tuberculosis H37Rv in our series of 5,7-di-tert-butyl-benzoxazoles substituted in position No. 2 with aromatic substituent. Metabolism of benzoxazoles probably includes the opening of their structure. The goal of this thesis is to synthesize substituted N-(3,5-di-tert-butyl-2-hydroxyphenyl)benzamides and pyridinecarboxamides, their so-called "open forms". These structures could be also considered as "reversed salicylanilides" which have also a significant antitubercular activity. The first step of the synthesis of these analogues is preparation of 2-amino-3,5-di-tert- butylphenol. It was prepared by reaction of 3,5-di-tert-butylbenzo-1,2-quinone with ammonia and following reduction by NaBH4. Resulting DTB-aminophenol has been condensed with appropriate aromatic or heteroaromatic acids, while PCl3 in chlorobenzene was...
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Development of New Potential Antimycobacterial Active Agent Based on the Group of Salicylanilides
Monreal Férriz, Juana ; Vinšová, Jarmila (advisor) ; Opletalová, Veronika (referee) ; Polanc, Slovenko (referee)
Salicylanilides are an important class of aromatic compounds with a wide range of pharmacological activities, such as antibacterial, antifungal and anti-inflammatory, among others. Furthermore; several studies reported their potent antimycobacterial effect. Their activity results from multiple mechanisms. They are therefore interesting compounds for medicinal chemists. As phenolic- containing drugs, we hypothesised that a prodrug approach will make possible the improvement of the pharmaceutical, pharmacokinetic and/or pharmacodynamic properties of salicylanilides. This thesis describes the development of new potential antimycobacterial active agents based on this group that have shown interesting antimycobacterial activity against Mycobacterium tuberculosis, and some atypical strains. As the starting point for our research, the different strategies used in order to overcome the limited bioavailability of phenolic drugs were reviewed. Then new potentially antibacterial active prodrugs of salicylanilides, particularly N-benzyloxycarbonyl-ester and alkyl-carbamate derivatives of salicylanilide, active against M. tbc., MDR-TB strains or non-TB strains such as M. avium and M. kansasii, were prepared. Finally the physicochemical and pharmacokinetic properties of the most active synthesised compounds were...
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Usage of the annelid Tubifex tubifex Müll. as a model organism for biological activity assessment
Vytlačilová, Jitka ; Jahodář, Luděk (advisor) ; Kočí, Vladimír (referee) ; Fiala, Zdeněk (referee)
The aim of the presented doctoral thesis was to use the sludge worm Tubifex tubifex as a model for biological activity testing. In the presented study, the Tubifex worm was used to evaluate photosensibilisation, i.e. sensibilisation of an organism towards UVA radiation (365 nm; radiant flux density of 350 μW/cm2) after contact with certain substances. The tested substances included proven photosensibilizing agents - rose bengal, khellin and xanthotoxin; isolated natural substances - thiophene polyacetylene umbelliferon, scopoline, and scopoletine; synthetic compounds - salicylanilides and thiosalicylanilides; and penicillin drugs Augmentin and Ospamox and their active substance standard amoxicillin. The final evaluation of photosensibilizing properties of the substances was carried out according to the Commission Directive 2000/33/EC PHOTOTOXICITY - IN VITRO 3T3 NRU PHOTOTOXICITY TEST. The test was performed in 24-well plates where one set of plates with the photosensibilizing agent was irradiated and the second set was placed in an incubator (20±2řC) as a dark control without any light presence for the whole period of the experiment. The plates were evaluated immediately after the given period of irradiation (15, 30, 45, 60, 120, and 240 minutes). Mortality and percentual number of damaged individuals were...
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Usage of the annelid Tubifex tubifex Müll. as a model organism for biological activity assessment
Vytlačilová, Jitka
The aim of the presented doctoral thesis was to use the sludge worm Tubifex tubifex as a model for biological activity testing. In the presented study, the Tubifex worm was used to evaluate photosensibilisation, i.e. sensibilisation of an organism towards UVA radiation (365 nm; radiant flux density of 350 μW/cm2) after contact with certain substances. The tested substances included proven photosensibilizing agents - rose bengal, khellin and xanthotoxin; isolated natural substances - thiophene polyacetylene umbelliferon, scopoline, and scopoletine; synthetic compounds - salicylanilides and thiosalicylanilides; and penicillin drugs Augmentin and Ospamox and their active substance standard amoxicillin. The final evaluation of photosensibilizing properties of the substances was carried out according to the Commission Directive 2000/33/EC PHOTOTOXICITY - IN VITRO 3T3 NRU PHOTOTOXICITY TEST. The test was performed in 24-well plates where one set of plates with the photosensibilizing agent was irradiated and the second set was placed in an incubator (20±2řC) as a dark control without any light presence for the whole period of the experiment. The plates were evaluated immediately after the given period of irradiation (15, 30, 45, 60, 120, and 240 minutes). Mortality and percentual number of damaged...
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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 salicylanilide prodrugs
Krátký, Martin ; Vinšová, Jarmila (advisor) ; Imramovský, Aleš (referee)
KRÁTKÝ, Martin. Synthesis of Salicylanilide Prodrugs. Hradec Králové: Faculty of Pharmacy of Charles University, 2008. 75 pp. Diploma Thesis. This diploma thesis is concerned with synthesis of antibacterial prodrugs based on esters of salicylanilides with amino acids. First there are characterized prodrugs and their importance and then biological activities and application of salicylanilides. The main goal of this work was the synthesis of prodrugs of salicylanilides amino acids esters. Some synthesized compounds were evaluated especially for their activity against atypical Mycobacteria strains. These compounds possess antimycobacterial activity, but it is lower than initial salicylanilide 5-chloro- N-(3-chlorophenyl)-2-hydroxybenzamide. This diploma thesis acknowledges rearrangement after N-deprotection and α-amino group liberation of N-protected amino acids esters with salicylanilides to furnish diamides. The diamide was esterified by Z-amino acids (L-phenylalanine and glycine). These obtained esters were N- deprotected and the amino group was liberated. After this liberation there was described rearrangement to furnish probably triamides, analogously to furnishing of diamides. There are discussed two possible mechanisms of rearrangement - with forming of seven-membered benzoxazepinedione rings...
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Evaluation of activity of potentional antifungal substances through the use of microdilution broth method II
Poučová, Michaela ; Křivčíková, Lucie (advisor) ; Vacková, Jana (referee)
Poučová Michaela Evaluation of activity of potentional antifungal substances through the use of microdilution broth method II Diploma thesis Charles University in Prague, Faculty of Pharmacy in Hradec Kralove Specialist in laboratory methods The main concern of this study was to test potential antifungal agents and evaluate their activities. During the experiment were tested two groups of compounds, derivatives pyrazin-2-carboxamide and salicylanilide. Using microdilution broth method were measured the activities of these substances against eight strains of filamentous fungi and yeasts, which included C. albicans, C. tropicalis, C. krusei, C. glabrata, T. beigelii, A. fumigatus, A. corymbifera and T. mentagrophytes. For determining the sensitivity of these strains of fungi against tested substances was prepared eleven different concentrations (500 mol∙l-1 , 250 mol∙l-1 , 125 mol∙l-1 , 62,5 mol∙l-1 , 31, 25 mol∙l-1 , 15,625 mol∙l-1 , 7,813 mol∙l-1 , 3,906 mol∙l-1 , 1,953 mol∙l-1 , 0,977 mol∙l-1 and 0,488 mol∙l-1 ), which let incubate with the fungi. Performing microdilution broth method was determined the minimum inhibitory concentration (MIC), whose value indicates the lowest concentration of test substance that causes visible suppression of growth of yeasts or filamentous fungi. Based on the...
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Design and Synthesis of New Compounds Active Especially Against Multidrug-Resistant Mycobacterial Strains
Krátký, Martin ; Vinšová, Jarmila (advisor) ; Doležal, Martin (referee) ; Rádl, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate Martin Krátký Supervisor Prof. Dr. Jarmila Vinšová, Ph.D. Title of Doctoral Thesis Design and Synthesis of New Compounds Active Especially against Multidrug-Resistant Mycobacterial Strains This work is focused mainly on the field of searching of new potential antimicrobial agents, particularly against multidrug-resistant Mycobacterium tuberculosis strains, based on the modification of the salicylanilide (2-hydroxy-(N-phenyl)benzamide) group. The second research topic is a study of the rearrangement in the series of salicylanilide amino acids esters to form 2-hydroxy-N-[2-oxo-2-(phenylamino)-alkan-2-yl]benzamides called "diamides". At the beginning, the thesis summarizes some basic facts about tuberculosis, a very important and serious bacterial infectious disease caused by Mycobacterium tuberculosis complex, about its treatment and related troubles and limitations. Proper attention is given for the problematic of drug-resistant tuberculosis, especially multidrug-resistant and extensively drug-resistant forms, their epidemiology and therapy. The development of new drugs against multidrug-resistant tuberculosis is largely discussed, including requirements for them, recent...
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