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Synthesis of substituted oxadiazoles with potential antimycobacterial activity
Mészárosová, Daniela ; Karabanovich, Galina (advisor) ; Krátký, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Daniela Mészárosová Supervisor: Ing. Galina Karabanovich, Ph.D. Title of Diploma Thesis: Synthesis of substituted oxadiazoles with potential antimycobacterial activity Tuberculosis is an infectious disease caused by mycobacteria Mycobacterium tuberculosis, which is one of the top ten causes of death worldwide. According to the World Health Organization, 10.4 million new cases were reported in 2016 and 1.7 million people died of this disease (including 0.4 million people with HIV). Treatment of tuberculosis caused by drug-susceptible strains of M. tuberculosis is very successful, with up to 82% of patients cured. However, a major problem is the therapy of patients with drug resistant strains of M. tuberculosis. Multidrug-resistant tuberculosis (MDR-TB) is a TB that cannot be cured by isoniazid (INH) or rifampicin (RIF), the two most effective first-line antituberculotics. In this case, TB is treated with second-line antituberculotics, which should be administered for up to two years. However, according to statistics, only 32.2% of patients with MDR-TB are successfully cured in the European Union. Therefore, it is important to look for and develop new drugs that act on MDR-TB and can help...
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Investigation of the compounds influencing the melting temperature of oligonucleotide probes
Kostelanský, Filip ; Zimčík, Petr (advisor) ; Hocek, Michal (referee) ; Krátký, Martin (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Filip Kostelanský Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Doctoral Thesis: Investigation of the compounds influencing the melting temperature of oligonucleotide probes Real-time PCR is widely used method in various research fields like biomedicine, microbiology, veterinary medicine, etc. Quantification of gene expression, allelic discrimination and alteration detection are new and interesting application possibilities. Mismatch discrimination is not optimal when longer probes are used. Melting temperature difference between fully complementary duplex and mismatched duplex is negligible in the case of longer probes. The short oligodeoxynucleotide (ODN) probes, on the other hand, are suitable for good discrimination of single nucleotide variants. However, these probes suffer from low melting temperatures. Adding minor groove binders (MGB), or other substances, which can strongly interact with DNA such as intercalating dyes or polyamines, can increase the melting temperature of short probes duplexes. In this work, several series of acridine-4-carboxamide intercalators were synthesized. MGB (Hoechst 33258) and polyamine (spermine) were modified and...
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Synthesis and evaluation of potential biologically active rhodanine derivatives and analogues
Šimková, Adéla ; Krátký, Martin (advisor) ; Matouš, Petr (referee)
The topic of this thesis is the synthesis of rhodanine derivatives and evaluation of their biological activity, particularly as potential cholinesterases inhibitors. This group of compounds is important for treatment of many diseases, e.g., Alzheimer's disease or myasthenia gravis. All synthetized compounds are based on structure of rhodanine (2-thioxothiazolidine- 4-one), which is an important heterocyclic compound with a wide spectrum of biological properties. Its structure can be modified in many ways, which can be used in the development of new drugs. Its derivatives have been shown to have, for example, anti-inflammatory, anticancer, antibacterial and antifungal activities, as well as inhibitory activity against several enzymes, e.g., cholinesterases. Seventeen compounds were synthesized in sufficient amount for characterisation and assessment of biological activity (7-93 %). Most of them are amides based on the structure of 2-thioxothiazolidine-4-one and thiazolidine-2,4-dione, that were prepared by carbodiimide- mediated coupling, other derivatives are based on the structure of 2-thioxothiazolidine-4-one and from 2,4-dioxothiazolidine-3-acetic acid. These compounds were prepared by Knoevenagel condensation in glacial acetic acid. All compounds were tested for their inhibitory activity...
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Synthesis of Chromenopyridines with the New All-Carbon Quaternary Centre
Sedláček, Patrik ; Matouš, Petr (advisor) ; Krátký, Martin (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Candidate: Patrik Sedláček Supervisor: PharmDr. Petr Matouš, Ph.D. Title of thesis: Synthesis of Chromeno[3,4-c]pyridines with New All-Carbon Quaternary Centre This diploma thesis focuses on the synthesis of 3,4-disubstituted pyridine derivatives and their subsequent cyclization to form chromeno[3,4-c]pyridine derivatives with a new all-carbon quaternary center. Phenyl-propiolate reacts with an aryl-substituted propargyl amine protected with 4- methoxybenzenesulfonyl group to form a 1,5-enyne. Substituted 1,5-enyne undergoes intramolecular cyclization catalyzed by tri(2-furyl)phosphinogold(I)chloride [AuCl(TFP)] to form the corresponding dihydropyridine. In the presenece of concentrated H2SO4, dihydropyridine undergoes carbocyclization forming the corresponding chromenopyridine with a new all-carbon quaternary center. The compounds prepared and their derivatives could find application as potentially biologically active substances and intermediates in organic synthesis.
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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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Investigation of the compounds influencing the melting temperature of oligonucleotide probes
Kostelanský, Filip ; Zimčík, Petr (advisor) ; Hocek, Michal (referee) ; Krátký, Martin (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Filip Kostelanský Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Doctoral Thesis: Investigation of the compounds influencing the melting temperature of oligonucleotide probes Real-time PCR is widely used method in various research fields like biomedicine, microbiology, veterinary medicine, etc. Quantification of gene expression, allelic discrimination and alteration detection are new and interesting application possibilities. Mismatch discrimination is not optimal when longer probes are used. Melting temperature difference between fully complementary duplex and mismatched duplex is negligible in the case of longer probes. The short oligodeoxynucleotide (ODN) probes, on the other hand, are suitable for good discrimination of single nucleotide variants. However, these probes suffer from low melting temperatures. Adding minor groove binders (MGB), or other substances, which can strongly interact with DNA such as intercalating dyes or polyamines, can increase the melting temperature of short probes duplexes. In this work, several series of acridine-4-carboxamide intercalators were synthesized. MGB (Hoechst 33258) and polyamine (spermine) were modified and...
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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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