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Quinazoline derivatives as compounds with potential bronchodilatory effect III
Abo El Dahabová, Mona ; Špulák, Marcel (advisor) ; Vinšová, Jarmila (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Mona Abo El Dahabová Supervisor: PharmDr. Marcel Špulák, Ph.D. Title of diploma thesis: Quinazoline derivatives as compounds with potential bronchodilatory effect III Asthma and COPD are serious diseases worldwide, that are mostly medicated with agents possessing bronchodilatory activity. Based on our previous research, I did prepare quinazoline derivatives via changing the structure of (-)vasicinone, which showed promising bronchodilatory activity. The reactions took place mainly by the mechanism of nucleophilic substitution, which is characterized with binding of the nucleophile to the appropriate molecular target. During my diploma thesis, I have isolated the quinazoline derivatives in the form of a tertiary amine and a quaternary ammonium salts. For most of the prepared substances, I determined their bronchodilatory activity at ex vivo rat trachea, which indicated possible direction of the structure modifications of the original compounds. Keywords: Asthma, COPD, muscarine receptors, (-)vasicinon, quinazolines, bronchodilatory activity.
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Synthesis and evaluation of dual acting potential drugs for neurodegenerative diseases
Miffek, Dominik ; Krátký, Martin (advisor) ; Vinšová, Jarmila (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Dominik Miffek Supervisor: doc. PharmDr. Mgr. Martin Krátký, Ph.D. Title of diploma thesis: Synthesis and evaluation of dual acting potential drugs for neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative diseases that mainly affect the elderly population. The incidence of these diseases is still increasing worldwide, and currently, there is no cure that can permanently treat patients. Current medications mainly aim to slow the progression of these diseases. The goal is to improve the accessibility of treatment, prevent progression, or completely cure patients suffering from AD and PD. New potential drugs are also developing in this direction, which could exhibit a satisfactory effect in inhibiting cholinesterases. Acetylcholinesterase (ACh) and butyrylcholinesterase (BuChE) play a significant role in the pathogenesis of these diseases. Particularly in Alzheimer's disease (AD), there is a decrease in acetylcholine as a neurotransmitter that ensures the homeostasis and proper functioning of the central nervous system (CNS). In AD treatment, acetylcholinesterase inhibitors (AChEIs) such as rivastigmine, galantamine, and donepezil are used...
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Natural compounds active against mycobacteria (review)
Kunáková, Martina ; Krátký, Martin (advisor) ; Vinšová, Jarmila (referee)
The main topic of the bachelor thesis is compounds isolated from natural sources, which contribute significantly to the discovery of new therapeutic methods in many medical problems. The aim of the work, was to focus specifically on those compounds that showed significant antimycobacterial activity against pathogens of the genus Mycobacterium, especially against M. tuberculosis. The theoretical part focuses on the genus Mycobacterium itself and its basic characteristics. In addition, the work also focused on the specific species causing the non-tuberculous forms of the disease and those behind the outbreak of tuberculosis in the human body. The last chapter of the theoretical part deals with tuberculosis and its brief description, together with the treatment and the issues related to development of drug resistance during treatment. In the following section, specific compounds that exhibit antimycobacterial activity and have the potential to be developed as new drugs are described. Keywords: aldehydes, alkaloids, antituberculotics, compounds of natural origin, cyanobacteria, essential oils, Mycobacterium tuberculosis, mycobacteria, naphthoquinones, resistance, steroid hormones, terpenes, triterpenes, tuberculosis
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Synthesis and evaluation of potential antimycobacterial agents based on hydrazine derivatives
Koklarová, Apolena ; Krátký, Martin (advisor) ; Vinšová, Jarmila (referee)
Based on research in past years, we have synthetized two similar series of compounds with potential antimycobacterial activity. First series based on isoniazid are (E)-4-[(2- isonicotinoylhydrazineylidene)methyl]-N-phenylbenzamides with great activity (MIC for Mtb. of 0.03-0.125 μM) with few derivatives with moderate activity on nontuberculous mycobacterium M. kansasii (MIC of 2-4 μM). In second series pyridin-4-yl moiety has been exchanged for 3,5-dinitrophenyl, which has shown to be highly effective antimycobacterial scaffold in recent years, therefore derivatives of (E)-4-{[2-(3,5- dinitrobenzoyl)hydrazineylidene]methyl}-N-phenylbenzamide have been prepared. These molecules have shown moderate activity against drug-susceptible Mtb. (MIC of 2-32 μM), and only 4-chloro derivative has surprisingly high activity against non-tuberculous M. avium (MIC of 16-32 μM). Four molecules from the second series even exhibit some activity against MDR- TB and XDR-TB strains.
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Synthesis and evaluation of potential antitubercular drugs based on isoniazid
Kučerová, Kateřina ; Krátký, Martin (advisor) ; Vinšová, Jarmila (referee)
Isoniazid is a first-line drug used against tuberculosis. It is a bactericidal drug with a selectivity for Mycobacterium tuberculosis (Mtb.). The mechanism of action is primarily based on the blockade of mycolic acid synthesis and thus cell wall synthesis. The development of resistance is limiting the therapeutic potential of isoniazid and that is the reason for the development of its new structural modifications. This diploma thesis is focused on synthesis and evaluation of novel isoniazid analogues based on a hydrazone obtained from isoniazid and glyoxalic acid. The free carboxyl group was further modified by various amines to form amides. A total of sixteen substituted 2-(2- isonicotinoylhydrazono)-N-phenylacetamides were prepared and tested for their in vitro antimycobacterial activity on selected strains of mycobacteria - Mtb., M. avium and M. kansasii. The best activity against Mtb. was shown by (E)-2-(2- isonicotinoylhydrazineylidene)-N-(4-propylphenyl)acetamide and (E)-N-(4-butylphenyl)-2-(2- isonicotinoylhydrazineylidene)acetamide, their minimal inhibitory concentration (MIC) is 0.125 µM compared to isoniazid's MIC of 0.5 µM. They were also active against nontuberculous mycobacterium M. kansasii (MIC from 2 µM). Their activity against multidrug- resistant strains was lower due to...
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Synthesis and evaluation of antimycobacterial 1,3,4-oxadiazole derivatives
Šikorová, Enikő ; Krátký, Martin (advisor) ; Vinšová, Jarmila (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Enikő Šikorová Supervisor: doc. PharmDr. Mgr. Martin Krátký, Ph.D. Consultant: Mgr. Václav Pflégr Title of diploma thesis: Synthesis and evaluation of antimycobacterial 1,3,4-oxadiazole derivatives Tuberculosis (TB) is a serious infectious disease caused by obligately pathogenic rods of Mycobacterium tuberculosis complex (Mtb.), and it is still among the ten most common causes of death worldwide. One of the main complications of TB therapy is the ever-increasing resistance of mycobacterial strains to conventional drugs. Therefore, the development of new antimycobacterial compounds is crucial to overcome this issue. Research and development of new potential antimycobacterial agents often involve structure modifications of clinically used drugs - frequently the first-line drug, isoniazid (INH). The starting point of this work is also the structure of the already mentioned INH. First, a series of 2-alkyl-5-(pyridine-4-yl)-1,3,4-oxadiazoles and N'-acylisonicotinohydrazides as their synthetic precursors were prepared and evaluated with very promising activity (expressed as minimal inhibitory concentration - MIC) against several mycobacterial strains (MIC Mtb. H37Rv of 1-8 µM). Furthermore,...
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Synthesis and evaluation of potential antimycobacterial agents based on hydrazine derivatives
Koklarová, Apolena ; Krátký, Martin (advisor) ; Vinšová, Jarmila (referee)
Based on research in past years, we have synthetized two similar series of compounds with potential antimycobacterial activity. First series based on isoniazid are (E)-4-[(2- isonicotinoylhydrazineylidene)methyl]-N-phenylbenzamides with great activity (MIC for Mtb. of 0.03-0.125 μM) with few derivatives with moderate activity on nontuberculous mycobacterium M. kansasii (MIC of 2-4 μM). In second series pyridin-4-yl moiety has been exchanged for 3,5-dinitrophenyl, which has shown to be highly effective antimycobacterial scaffold in recent years, therefore derivatives of (E)-4-{[2-(3,5- dinitrobenzoyl)hydrazineylidene]methyl}-N-phenylbenzamide have been prepared. These molecules have shown moderate activity against drug-susceptible Mtb. (MIC of 2-32 μM), and only 4-chloro derivative has surprisingly high activity against non-tuberculous M. avium (MIC of 16-32 μM). Four molecules from the second series even exhibit some activity against MDR- TB and XDR-TB strains.
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Modification of antimycobacterial active sulphonamides
Kufa, Martin ; Krátký, Martin (advisor) ; Vinšová, Jarmila (referee)
The importance of the searching for novel antimycobacterial active agents is continually increasing with growing mycobacterial resistance to currently used drugs. However, the resistance-related problems are also associated with other bacteria and fungi. The systematic modification of compounds with a known antimicrobial activity represents one of the possible approaches to overcome this problem. Sulphonamide derivatives may be considered to be such a kind of compounds. That is why we synthesized various sulphathiazole derivatives. Amides were obtained by the reaction of sulphathiazole with appropriate acyl chlorides, substituted ureas from corresponding isocyanates. These ureas were cyclized via oxalyl chloride to form substituted 2,4,5-trioxoimidazolidines. Among derivatives evaluated for their antimycobacterial action, 4-(3- phenethylureido)-N-(thiazol-2-yl)benzenesulphonamide showed the highest activity. Its minimum inhibitory concentrations (MIC) against Mycobacterium tuberculosis My 331/88 (4 µmol/l) were superior to those obtained for sulphathiazole. In the case of nontuberculous mycobacteria (M. avium My 330/88, M. kansasii My 235/88 and M. kansasii My 6509/96), their activities were comparable (≥ 2 µmol/l). Amides showed also a significant antimycobacterial activity, especially against M....
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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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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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