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Development of new group of potential antituberculotics
Divišová, Hana ; Waisser, Karel (advisor) ; Kolář, Karel (referee)
In this rigorous paper three problems were solved: a) synthesis and antimycobacterial activity of new halogenated salicylanilides substituted in position 4' with branch chain. b) synthesis and antimycobacterial activity of new halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones. c) influence of replacement of oxo group by thioxo group in the previously group of compounds. a) It was synthesized 8 halogenated derivatives of 4'-alkylsalicylanilides with branched alkyl chain. These compounds were evaluated in vitro on antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. b) It was synthesized 7 halogenated derivatives of benzoxazinediones with branch chain by reaction of salicylanilides with methylchloroformiate. Antimycobacterial activity of synthesized compounds was evaluated against three different mycobacterial strains. The most active compound was 7- chloro-3-(4-sec-butylphenyl)-1,3-benzoxazine-2,4-(3H)-dione. c) There were synthesized the following compounds: 7-chloro-3-(4-isopropylphenyl)-4-thioxo-2H-1,3- benzoxazine-2(3H)-one, 6-bromo-3-(4-isopropylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-one, 6- bromo-3-(4-sec-butylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-one, 6-chloro-3-(4-sec-...
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4'-alkylsalicylanilides with branched aliphatic chain and the corresponding derivatives of benzoxazinedions
Divišová, Hana ; Waisser, Karel (advisor) ; Kuneš, Jiří (referee)
Three problems of antimycobacterial compounds were solved in the work. a) It was synthesis of eight new halogenated 4' -alkylsalicylanilides with branched alkyl in position 4'. b) Synthesis of new halogenated 3-(4-alkylphenyl)-1,3-benzoxazin-2,4-(3H)-diones. ) with the branched alkyl on the phenyl. Seven new halogenated 3-(4-alkylphenyl)-1,3-benzoxazin-2,4-(3H)- diones were synthesized by reaction of salicylanilides and methyl choroformiate. All the compounds were screened in vitro against three different strains of mycobacterium. The results were not finished at the time of diploma work. We assume according hypothesis of professor Waisser that the activity of the new compounds will be very perspective. .
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Analysis of farnesylated peptides and proteins using LC-MS
Hessler, Filip ; Waisser, Karel (advisor) ; Kovaříková, Petra (referee)
Farnesylated proteins are important in transduction of signals in cell and therefore can figure in development of many diseases, mainly cancer. Electrospray mass spectrometry is a widely used method in analysis of peptides and proteins, thus it was chosen as a method to develop a simple way to detect farnesylated proteins in cell. A cleavage pattern of these proteins, when subjected to MS/MS, was found on examples of synthetically farnesylated simple peptides and bovine albumin. Distinctive features of MS/MS spectra of these peptides are two peaks, which both represent the virgin peptide fragment after the farnesyl moiety was cleaved off. These fragments have a different charge, because they originate from different type of cleavage. Homological cleavage of the bond between the farnesyl and sulfur leads to formation of a new charge on the peptide fragment, while the leaving farnesyl is also charged and has amu of 205. Second type of fragment rises from neutral loss of farnesyl moiety, there is no new charge generated on the peptide fragment and the amu of the leaving farnesyl moiety is 204, because it looses one of its hydrogen in favor of the peptide. This knowledge can be applied also to more complicated protein samples prepared from cells. When searching for farnesylated proteins in such a...
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New groups of potential antituberculotics with thioxo group
Husáková, Petra ; Waisser, Karel (advisor) ; Kolář, Karel (referee)
. ENGLISH ABSTRACT In the rigorous thesis are described the influence of replacement oxo group for thioxo group in the series of halogenated 3-(4-ethylphenyl)benzoxazine-2,4(3H)-diones and 6-chloro-3- (4-butylphenyl)benzoxazine-2,4(3H)-dione. The starting ethyl (or butyl) salicylanilides were synthesis from substituted salicylic acid and ethyl (or butyl) aniline in toluene by the presence of phosphorus trichloride. (The set of halogenated salicyl acids compounds: 4-chloro-, 5-chloro-, 5- bromo- and 3,5-dibromosalicylic acid). The halogenated 4'-ethylsalicylanilides were reacted in dry pyridine with methyl-chloroformiate to form 3-(4-ethylphenyl)benzoxazine-2,4(3H)-diones. Similar were prepared 6-chloro-3-(4-butylphenyl)benzoxazine-2,4(3H)-diones. The mixture of 3- (4-ethyphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-one and 3-(4-ethylphenyl)-2H-1,3- benzoxazine-2,4(3H)-dithione was prepared by the reaction of the halogenated 3-(4- ethylphenyl)- 2H-1,3-benzoxazine-2,4(3H)-diones with phosphorus pentasulfide. The products were separated by chromatography. The 3-(4-ethylphenyl)-6-chloro-4-thioxo-2H-1,3- benzoxazine-2(3H)-ones and 6-chloro-3-(4-ethylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones were prepared by similar way. The compounds were tested in vitro for antimycobacterial activity against Mycobacterium...
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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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Antituberculosis Agents and Their Antimicrobial Effects.
Novotná, Eva ; Waisser, Karel (advisor) ; Kvasničková, Eva (referee) ; Lešetický, Ladislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Organic and Inorganic Chemistry Candidate: Mgr. Eva Petrlíková Supervisor: Prof. RNDr. Karel Waisser, DrSc. Title of Doctoral Thesis: Antituberculosis Agents and Their Antimicrobial Effects. The dissertation focuses on the preparation of antimycobacterially active compounds. Some of the prepared compounds were also screened for the in vitro antibacterial and antifungal activity. The prepared compounds included sulfur derivatives of 3-benzyl-2H-1,3-benzoxazine- 2,4(3H)-diones, N-(pyridylmethyl)salicylamides, sulfur derivatives of 3-(4-alkylphenyl)- 2H-1,3-benzoxazine-2,4(3H)-diones, N-benzylthiosalicylamides, benzaldehyde- Sbenzylisothiosemicarbazones, salicylaldehyde-S-benzylisothiosemicarbazones, derivatives of 1,2-bis(9H-fluoren-9-ylidene)-N,N'-diarylethane-1,2-diamine, and hybrid molecules of cholesterol and terpenes. The highest antimycobacterial activity was exerted by 3-benzyl-2H-1,3-benzoxazine- 2,4(3H)-dithione and 3-(3,4-dichlorobenzyl)-2H-1,3-benzoxazine-2,4(3H)-dithione, 3-(4- secbutylphenyl)- 7-methyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-one, N-(4-methylbenzyl) thiosalicylamide and 4-methyl-N-(4-methylbenzyl)thiosalicylamide. Salicylaldehyde- S-(4-chlorobenzyl)isothiosemicarbazone was the most active...
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Quantitative structure-antimycobacterial acitivity relationships in the group of potential antituberculotics
Doležal, Rafael ; Waisser, Karel (advisor) ; Lehotay, Jozef (referee) ; Ponec, Robert (referee)
DOLEŽAL Rafael: Quantitative relationships between the structure and antimycobacterial activity of selected potential antituberculotics. Hradec Králové: Faculty of Pharmacy in Hradec Králové, Charles University in Prague, 2008, 274 pp. Ph.D. Thesis. The Ph.D. thesis deals with analysis of quantitative relationships between the structure and antimycobacterial activity (QSAR) of four structural classes of potential antituberculotics - derivatives of N-phenylcarbamic acid esters, derivatives of 1-phenyl-1H-tetrazole-5-thiol, derivatives of salicylamides and derivatives of salicylthioamides. In total, 600 computer models of different compounds were created. 204 of them, after conformational analysis in HyperChem 7.52 and geometric optimization with the B3LYP/6-31G* DFT method in Gaussian 03, provided data for calculation of several types of descriptors. Attention was turned especially to local, quantum-chemical descriptors of electronic properties, such as superdelocalizability, index of frontier electron density and Mulliken electric charge. The QSAR analyses are based on searching for statistically significant correlations between the antimycobacterial activities in vitro and a matrix of various descriptors by means of multiple linear regression (MLR) with the use of a selection algorithm, by the...
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