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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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Application of Pd-Catalyzed Reactions to the Synthesis of Lactones
Šnajdr, Ivan ; Pour, Milan (advisor) ; Kotora, Martin (referee) ; Opletalová, Veronika (referee)
Within the framework of this Thesis, a method fot the preparation of 3,6- disubstituted pyranones was developed and 15 final lactones were synthesized, and their cytostatic and antifungal activity was investigated. Principal steps in the preparation of the compounds were Yamaguchi-Hirao alkylation, hydroalumination followed by iodation and Pd- catalyzed carbonylative lactonization. None of the target compounds displayed interesting cytostatic or antifungal activity (IC50 < 10 μmol/L), which was suprising given the significant antifungal activity of analogous butenolides. The development of the synthesis of 3- monosubstituted pyranones is described next. Our strategy is based on the use of 5,6-dihydro-2H- pyran-2-one as the starting material, which was converted into the 3-iodo-5,6-dihydro-2H- pyran-2-one in one step. The key step of the synthesis was Pd-catalyzed Suzuki coupling. Finally, the preparation of α- and β-substituted-γ-alkylidenepentenolides is described. The target compounds exhibited significant cytostatic activity (IC50 < 5 μmol/L) against all tested tumor cells (CCRF-CEM, HeLa S3, HT 29, HL 60, L 1210).
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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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Biological activity of plant metabolites IV. Influence of alkaloids from Chelidonium majus L. on acetylcholinesterase
Nagyová, Jana ; Opletal, Lubomír (advisor) ; Opletalová, Veronika (referee)
SOUHRN K izolaci alkaloidů z Chelidonium majus bylo použito 41,8 kg celé sušené rostliny (nať a kořen). Na extrakci drogy jsem se podílela spolu s dalšími diplomantkami Šárkou Brožovou, Evou Vítkovou a Dagmar Kubincovou. Přípravou extraktu a jeho čištěním jsme získaly pseudokyanidy, kvarterní baze z pseudokyanidů, chloridy ve vodě rozpustné a chloridy ve vodě nerozpustné. Zabývala jsem se dělením alkaloidů jejichž chloridy byly ve vodě rozpustné a izolovala jsem látku CH-M/A- 2. Tenkovrstvá chromatografie ukázala, že alkaloid připravený naším postupem (sloupcová chromatografie na oxidu hlinitém z frakcí 13+14, 15-17, 18, 19-26) je čistý. Neznám ale jeho přesnou strukturu a musím počkat na výsledky spektrálních analýz. U této látky byla změřena její biologická aktivita (schopnost inhibovat acetylcholinesterázu). Naměřená hodnota, IC50 = 35 mg/l, ukazuje, že účinnost látky CH-M/A-2 je nízká. Jedná se však pouze o výsledek předběžný, protože hodnotu IC50 nebylo možné přesně stanovit vzhledem k tomu, že není známa přesná struktura látky.
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Acetylpyrazines as intermediates for the synthesis of biologically active derivative of pyrazine III.
Zobalová, Dana ; Opletalová, Veronika (advisor) ; Palát, Karel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Analysis Candidate Mgr. Dana Honcová-Zobalová Consultant RNDr. Veronika Opletalová, Ph.D. Title of Thesis Acetylpyrazines as intermediates for the synthesis of biologically active derivatives of pyrazine III. The rigorous thesis is aimed at the preparation of 5-alkylpyrazin-2-carbonitriles, 5-alkyl-2-acetylpyrazines and their thiosemicarbazones and N,N-dimethylthiosemicarbazones. N,N-dimethylthiosemicarbazone of acetophenone was prepared for comparison. Theoretical part deals with the structure and properties of thiosemicarbazones and their biological effects. The following compounds were prepared and characterized during experimental work: 5-isopropylpyrazin-2-carbonitrile 5-pentylpyrazin-2-carbonitrile 5-hexylpyrazin-2-carbonitrile 5-heptylpyrazin-2-carbonitrile 1-(5-isopropylpyrazin-2-yl)ethan-1-one 1-(5-pentylpyrazin-2-yl)ethan-1-one 1-(5-hexylpyrazin-2-yl)ethan-1-one 1-(5-heptylpyrazin-2-yl)ethan-1-one 1-(5-hexylpyrazin-2-yl)ethan-1-one thiosemicarbazone 1-pyrazin-2-ylethan-1-one N,N-dimethylthiosemicarbazone 1-(5-pentylpyrazin-2-yl)ethan-1-one N,N-dimethylthiosemicarbazone 1-(5-hexylpyrazin-2-yl)ethan-1-one N,N-dimethylthiosemicarbazone ...
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