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Design, synthesis and evaluation of novel inhibitors of class II PI4Ks and RIPK2/3 kinases
Misehe, Mbilo ; Nencka, Radim (advisor) ; Soural, Miroslav (referee) ; Baszczyňski, Ondřej (referee)
Synthetic kinase inhibitors are chemical tools to investigate cellular roles of kinase enzymes and, potentially, find new treatments for various diseases that are connected with their dysregulated expressions and activities. This thesis focuses on two projects that were devoted to design, synthesize and evaluate novel compounds as kinase inhibitors. In a first project, employing structure-based docking methods, novel 7-aryl- or 7-heteroaryl-substituted 4-aminoquinazoline-6-carboxamide compounds were developed as inhibitors of class II phosphatidylinositol 4-kinases (PI4K2A/2B). A simple synthetic approach enabled the preparation and the functionalization of the 4-aminoquinazoline scaffold in six steps. Enzymatic evaluation for activity and selectivity against PI4Ks (i.e., PI4K2A and class III PI4Ks) highlighted several compounds with low micromolar potency and good selectivity against PI4K2A. Moreover, the binding mode of the new compounds in the conserved ATP-binding sites of class II PI4Ks was corroborated by X-ray crystallography. This suggests the applied rationale of the design can be a strategical option to obtain more potent and selective PI4K class II inhibitors, to conduct additional investigations on these kinases. In a second project, novel 4,6- and 4,6,7-substituted quinazoline...
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Design and evaluation of potential viral methyltransferase inhibitors
Kocek, Hugo ; Nencka, Radim (advisor) ; Grantz Šašková, Klára (referee)
A global pandemic of SARS-CoV-2 confirmed the pandemic potential of the Coronaviridae family and pointed out the need for novel antiviral drugs. The SARS-CoV-2 pandemic has been tamed thanks to mRNA vaccines; however, monoclonal antibodies and small molecules such as nirmatrelvir (protease inhibitor), remdesivir (polymerase inhibitor), or molnupiravir (mutagen) are currently also available. It is worth noting that remdesivir and molnupiravir were previously investigated as antivirals against different pathogens. SARS-CoV-2 encodes 16 non-structural proteins, and two of them - methyltransferases (MTases) nsp14 and nsp16 - participate in RNA capping as the virus must mimic the host's mRNA to evade the cellular antiviral sensors (e.g., IFIT1) and replicate. These MTases are structurally very similar to those of SARS-Co-V; therefore, we might expect that inhibitors of SARS-CoV-2 MTases could be used in the future against different coronaviruses. For the reasons mentioned above, this thesis focuses on developing novel MTase inhibitors targeting SARS-CoV-2 nsp14 and nsp16. The design was based on S-adenosyl-L-homocysteine (SAH; endogenous inhibitor of MTases) and an in silico compound library was constructed with various replacements for SAH's amino acid moiety. The potential inhibitory activity was...
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Synthesis of novel viral methyltransferase inhibitors
Kocek, Hugo ; Nencka, Radim (advisor) ; Česnek, Michal (referee)
Methyltransferases (MTases) are a class of enzymes that catalyze methylation of their substrates. These enzymes are found in all living organisms (including some viruses) as methylations are involved in numerous biological processes. Therefore, MTases are attractive targets for medicinal chemistry. Currently, only inhibitors of human MTases are used in medicine, for example, 5-azacytidine targeting DNA-MTase. However, viral MTases are potential drug targets as well. They enable viruses to escape the immune system and to use the host's translation machinery. As a consequence of the SARS-CoV-2 pandemic, coronaviral MTases became the center of attention, followed by the Mpox virus, which spread in the population in 2022. This thesis is focused on the synthesis of potential MTase inhibitors derived from adenosine-5'-carboxylic acid. The primary target is SARS-CoV-2 nsp14, however, the compound library will be used for screening against other MTases as well. Key words: methyltransferase; inhibitor; SARS-CoV-2; medicinal chemistry
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New kinase inhibitors
Hakrová, Kateřina ; Nencka, Radim (advisor) ; Tichý, Michal (referee)
Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by the occurrence of common myeloid progenitors, which then accumulate in the bone marrow and peripheral blood. This subsequently leads to a failure of hematopoiesis. Approximately one third of patients have a mutation in FMS-like tyrosine kinase (FLT3), which is associated with a higher risk of relapse and an overall worse prognosis. In recent years, several FLT3 inhibitors have been developed to facilitate the treatment of AML but patients develop resistance to most of them over time, leading to subsequent relapse of the disease. This bachelor's thesis discusses the synthesis of new potential inhibitors and the effect of imidazo[1,2-b]pyridazine core substitution on the inhibitory activity of these substances against the internal tandem duplication (ITD) type mutation in FLT3 kinase. Key words: AML, FLT3, imidazo[1,2-b]pyridazine, kinase inhibitors
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Synthesis, Biological Profiling and Photophysical Properties of Polycyclic Hetero-Fused 7-Deazapurine Nucleosides
Yang, Chao ; Hocek, Michal (advisor) ; Soural, Miroslav (referee) ; Nencka, Radim (referee)
This thesis describes the synthesis, photophysical properties and biological profiling of several series of polycyclic hetero-fused 7-deazapurine nucleosides. Modified 7-deazapurine ribonucleosides display a variety of biological effects. Previously, small (hetero)aromatic rings-fused 7-deazapurine nucleosides show submicromolar cytostatic effects or antiviral activities. Thus, the two isomeric series of new benzothieno-fused deazapurine nucleosides were designed as the extended analogues to the cytotoxic thieno-fused nucleosides and hetero-analogues of antiviral naphtho-fused nucleosides. The goal of the first part of my work was to synthesize these target compounds. Key steps include Negishi coupling of zincated pyrimidine with iodobenzothiophene, thermal or photochemical cyclization, glycosylation and final diversification. The furyl and benzofuryl derivatives exerted moderate anticancer and anti-HCV activities. Most of the free nucleosides showed moderate to strong fluorescence, and the corresponding 2′-deoxyribonucleoside triphosphate was incorporated into modified DNA and their fluorescence properties were studied The tri- and tetracyclic fused nucleobases can be synthesized either by multistep heterocyclization approach or through cross-coupling of zincated pyrimidine with hetaryl halides,...
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Synthesis of new nucleosides as potential inhibitors of flaviviral replication
Horkelová, Simona ; Nencka, Radim (advisor) ; Janeba, Zlatko (referee)
Viruses of the Flaviviridae family are the causative agents of many dangerous diseases for which we currently have no known cure, and research into new drugs against them therefore represents one of the major challenges for modern medicinal chemistry. Targeting the proteins encoded by viruses is the most common approach to combat them. For flaviviruses, the non- structural protein NS5 exhibiting methyltransferase (MTase) and RNA-dependent-RNA polymerase (RdRp) enzyme activity appears to be one of the most suitable molecular targets. This bachelor thesis deals with the synthesis of new potential drugs capable of inhibition skill of flaviviral RdRp. C-nucleoside analogues were prepared, containing 2 types of heterocyclical base: 3-fluoropicolamide modified in positions 5 or 6 and pyrido[3,2-d]pyrimidine-4-amine modified in positions 6 or 7 using aryl or heteroaromatic substituent Key words: C-nucleosides, polymerase, flaviviruses, Tick-borne encephalitis virus, Suzuki reaction, Grignard reaction
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Preparation of Pyrazinamide Derivatives as Potential Antituberculotics (Study of Structure Activity Relationships)
Semelková, Lucia ; Doležal, Martin (advisor) ; Malík, Ivan (referee) ; Nencka, Radim (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Mgr. Lucia Semelková Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Consultant: PharmDr. Jan Zitko, Ph.D. Title of Doctoral Thesis: Preparation of Pyrazinamide Derivatives as Potential Antituberculotics (Study of Structure Activity Relationships) This doctoral thesis is focused on search for novel pyrazinamide derivatives with potential antitubercular activity. The theoretical part summarizes issues connected with tuberculosis and its epidemiological situation along with factors (resistance and HIV co- infection) that complicate treatment of tuberculosis. A brief overview of antitubercular drugs used in current therapeutic regimens of tuberculosis is outlined. A single chapter is dedicated to pyrazinamide, which belongs to the first-line antitubercular drugs, and its possible mechanisms of action. The last part is focused on potential enzymatic targets of pyrazinamide derivatives. The practical part describes synthesis and biological evaluation of 112 pyrazinamide derivatives with modifications in amide moiety and position 3 on the pyrazine ring. First two series were derived from N-substituted 3-chloropyrazine-2-carboxamides, the third series...
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Carbocyclic analogues of nucleosides and nonnucleoside inhibitors of thymidine phosphorylase
Nencka, Radim ; Hřebabecký, Hubert (advisor) ; Černý, Miloslav (referee) ; Ledvina, Miroslav (referee) ; Kefurt, Karel (referee)
!ntroduction Analogues ofnucleic acid components belong to the most successful classes oftherapeutics. Extensive modifications ofnucreobases, nucreosides and nucleotides led to the discovery ofa huge group of compounds with remarkable biological activity. The most important are perhaps the effects on various severe diseases such as cancer, leukemia or viral infectrons. The essential aim ofthis Thesis was the preparation ofbiologically active compounds related to the nucleic acid components. Since the carbocyclic anďogues ofnucleosides have been a long-time interest of our group, the first part of this work was devoted to the development of practical synthetic routes towards their new derivatives and to the synthesis of the novel analogues for further biological activity screening. However, the preliminary biological tests of the prepared compounds uncovered very promising lead to the compretely different field than it was expected. During the primer studies, I synthesized several 5,6-disubstituted uracils, initially prepared just as moder compounds for development of nover synthetic approaches towards carbocyclic nucleosides, that showed to posses outstanding inhibitory activity against thymidine phosphorylase. Therefore, the development of novel derivatives based on these findings was estabrished as a new...
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SARS-CoV-2 methyltransferases as druggable targets
Kocek, Hugo ; Nencka, Radim (advisor) ; Bouřa, Evžen (referee)
Novel coronavirus (earlier referred to as "nCoV2019") became part of our lives in March 2020 and overnight turned everything upside-down. This virus is transmitted via respiratory droplets and causes respiratory diseases COVID-19 which can be severe and even fatal. So far, no effective treatment has been discovered and vaccination is our biggest hope thanks to its high efficacy. It is important to point out, that new mutations may possess problems and escape immunity induced by the vaccination. During the whole pandemic, many approved drugs were tested against SARS-CoV-2 (for example favipiravir, toremifene, and hydroxychloroquine) but none of those drugs showed to be effective against SARS-CoV-2 in clinical trials. The only approved antiviral drug is nucleotide analog remdesivir which showed significant efficacy against SARS-CoV-2 in clinical trials. However, timing and overall patient's health condition play a key role. Development of new antiviral drugs is necessary given the fact that this is the third time we face coronavirus with the potential to cause pandemic since the beginning of the 21st century. Therefore, it is likely that another new coronavirus will emerge. This thesis focuses on S-adenosylmethionine-dependent methyltransferases nsp14 and nsp16 from SARS-CoV-2 because they play a key...
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Preparation of fluorinated carbocyclic derivatives of nucleosides as potential viral replication inhibitors
Štefek, Milan ; Nencka, Radim (advisor) ; Šimák, Ondřej (referee)
This master thesis is dedicated to the preparation of fluorinated derivatives of carbocyclic nucleosides, that may serve as flaviviral replication inhibitors. Preparation of both monofluorinated as well as gem-difluorinated analogs of ribo and 2'-deoxyribonucleoside was attempted. While a suitable and reliable route for the preparation of monofluorinated compounds way found, synthesis of gem-difluorinated turned out to be rather challenging. Although most of the presented work dealt with compounds bearing adenine as a nucleobase, the universal applicability of the developed procedures, demonstrated on the preparation of a guanosine-type molecule, suggests that after slight optimization larger series of this type of compounds could be prepared.
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