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Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity I
Brányik, Michal ; Zitko, Jan (advisor) ; Demuth, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Title of the thesis: Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity I Author: Michal Brányik Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: PharmDr. Martin Juhás, Ph.D. Antimicrobial resistance is an ever-growing problem that occurs worldwide. Many bacterial strains develop the ability to resist the otherwise efficient substances, thus posing a serious threat for the future. Mycobacterium tuberculosis (Mtb), the source of tuberculosis, is no exception. Given that it is the leading cause of death due to a single pathogen, many efforts have been put into finding new active compounds. The substances synthesized as a part of this thesis are based on previously prepared substances with potential antimicrobial activity. The basic structure consists of 2-aminooxazole or 2-aminothiazole and substituted pyridine or pyrazine carboxamides. The structures were confirmed by the 1 H and 13 C NMR spectra, IR spectra and mass spectrometry. All the substances were tested for in vitro activity against eight bacterial strains (four gram-positive and four gram-negative) as well as eight fungal strains (four yeast and four fungi). We also...
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Xanthone-boronic acids: An insight into the synthesis of borylated xanthone derivates
Houngbedji, Priam-Amedeo ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
CHARLES UNIVERSITY FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND PHARMACEUTICAL ANALYSIS DIPLOMA THESIS XANTHONE-BORONIC ACIDS: AN INSIGHT INTO THE SYNTHESIS OF BORYLATED XANTHONE DERIVATIVES Supervisor: prof. PharmDr. Martin Doležal, Ph.D. HRADEC KRÁLOVÉ 2021 PRIAM-AMEDEO HOUNGBEDJI Abstract - English The development of Bortezomib 5 and discovery of its potential in the treatment of multiple myeloma has sparked hope, and a close attention is paid in medicinal chemistry to the synthesis of boronic acid derivatives as well as the evaluation of their anticancer, antimicrobial, and other activities. Parallelly, xanthones and xanthone derivatives are compounds thoroughly studied for their potential in the treatment of cancer, and their good antimicrobial, anti-inflammatory, antiviral and anticonvulsant activity. It is only natural that efforts are oriented towards the synthesis of xanthone boronic derivatives. 3,6-Dihydroxyxanthone 10 was chosen as a precursor for the development of a procedure to borylate xanthones, mainly due to its easy synthesis and availability. From 10, 3,6-ditrifylxanthone 11 was easily prepared. The synthesis of 3,6- bis(pinacolatoboron)xanthone 8 from 11 was achieved using bis(pinacolatodiboron) B2pin2 as a borylation agent under Pd(dppf)Cl2 catalysis...
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Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity VI
Abdalrahman, Nechirwan Taimur ; Zitko, Jan (advisor) ; Nováková, Veronika (referee)
(In English) Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Nechirwan Abdalrahman Supervisor: Assoc. Prof. PharmDr. Jan Zitko, Ph.D. Title: Design, synthesis, and evaluation of heterocyclic compounds with potential antimicrobial activity VI Despite the existence of a well-established treatment regimens, tuberculosis (TB) continues to be the most leading cause of death by a single microorganism, as reported by WHO. One of the reasons behind treatment failure in completely eradicating this infection is drug resistance. Novel 3-(phenylureido)pyrazine-2-carboxamide derivatives, refer to figure below, were synthesized by reacting 3-chloropyrazine-2-carboxamide with ammonia to produce 3- aminopyrazine-2-carboxamide as an intermediate building block, followed by reacting with various substituted phenyl isocyanates using a microwave reactor. The synthesized compounds were evaluated for in vitro activity against various mycobacterial strains, where most active ones among them showed moderate to low activities; 4-tertiary butyl (MIC 62.5 µg/mL), 4-NO2 (MIC 62.5 µg/mL), 4-Bromo (MIC 250 µg/mL), 4-Cl (MIC 250 µg/mL), 2-F (MIC 250 µg/mL), and non-substituted (MIC 500 µg/mL). As a complementary study in silico, the synthesized...
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Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity IV
Fekri, Amir Hossein ; Zitko, Jan (advisor) ; Miletín, Miroslav (referee)
(English) Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Thesis title: Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity IV Candidate: Amirhossein Fekri Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: Mgr. Vinod S. K. Pallabothula Tuberculosis has remained one of the deadliest infectious diseases worldwide caused by a single infectious agent, the rapid growth of resistance to anti-tubercular drugs hinders the successful control and treatment of TB worldwide, which challenges the scientific community to develop new drugs to improve currently available treatment. This diploma thesis represents the design, synthesis, and biological evaluation of two series of compounds including cyclized (pyrazine- oxazinone) and carboxamide derivatives as potentially active antimycobacterial agents sharing a pyrazine core as common structural features that could potentially target mycobacterial aspartate decarboxylase (PanD) and prolyl-tRNA synthetase (mtProRS), respectively. Synthesis of final compounds was achieved through individual reaction steps involving acylation of methyl 3-aminopyrazine-2-carboxylate for preparation of a common intermediate which in turn was used for the...
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Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity I
Brányik, Michal ; Zitko, Jan (advisor) ; Demuth, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Title of the thesis: Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity I Author: Michal Brányik Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: PharmDr. Martin Juhás, Ph.D. Antimicrobial resistance is an ever-growing problem that occurs worldwide. Many bacterial strains develop the ability to resist the otherwise efficient substances, thus posing a serious threat for the future. Mycobacterium tuberculosis (Mtb), the source of tuberculosis, is no exception. Given that it is the leading cause of death due to a single pathogen, many efforts have been put into finding new active compounds. The substances synthesized as a part of this thesis are based on previously prepared substances with potential antimicrobial activity. The basic structure consists of 2-aminooxazole or 2-aminothiazole and substituted pyridine or pyrazine carboxamides. The structures were confirmed by the 1 H and 13 C NMR spectra, IR spectra and mass spectrometry. All the substances were tested for in vitro activity against eight bacterial strains (four gram-positive and four gram-negative) as well as eight fungal strains (four yeast and four fungi). We also...
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Amaryllidaceae alkaloids of montanine type and their derivatives as potential drugs.
Maafi, Negar ; Cahlíková, Lucie (advisor) ; Šmejkal, Karel (referee) ; Havlík, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Negar Maafi Supervisor: Prof. Ing. Lucie Cahlíková, Ph.D. Title of Doctoral Thesis: Amaryllidaceae alkaloids of montanine type and their derivatives as potential drugs. Based on the knowledge of the biological activity of montanine-type alkaloids of Amaryllidaceae, these alkaloids were selected for the preparation of their semisynthetic derivatives to study the relationship between structure and the activity. Derivatives of montanine-type alkaloids were prepared using haemanthamine and montanine as starting substances. The montanine-type alkaloid 3-O- methylpancracine was prepared using intramolecular rearrangement of haemanthamine. Previously isolated montanine from bulbs of Hippeastrum x hybridum cv. Ferrari was used in synthesize of derivatives. In total, more than 80 aliphatic and aromatic derivatives of montanine and 3-O- methylpancracine have been prepared. All compounds were identified using 1D- and 2D-NMR, MS, HRMS, and so forth. The prepared derivatives were screened for a wide range of biological activities (inhibitory potential against hAChE/hBuChE, antimycobacterial, antibacterial and antifungal activity, cytotoxicity, and others). In the hAChE/hBuChE study, the...
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Xanthone-boronic acids: An insight into the synthesis of borylated xanthone derivates
Houngbedji, Priam-Amedeo ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
CHARLES UNIVERSITY FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND PHARMACEUTICAL ANALYSIS DIPLOMA THESIS XANTHONE-BORONIC ACIDS: AN INSIGHT INTO THE SYNTHESIS OF BORYLATED XANTHONE DERIVATIVES Supervisor: prof. PharmDr. Martin Doležal, Ph.D. HRADEC KRÁLOVÉ 2021 PRIAM-AMEDEO HOUNGBEDJI Abstract - English The development of Bortezomib 5 and discovery of its potential in the treatment of multiple myeloma has sparked hope, and a close attention is paid in medicinal chemistry to the synthesis of boronic acid derivatives as well as the evaluation of their anticancer, antimicrobial, and other activities. Parallelly, xanthones and xanthone derivatives are compounds thoroughly studied for their potential in the treatment of cancer, and their good antimicrobial, anti-inflammatory, antiviral and anticonvulsant activity. It is only natural that efforts are oriented towards the synthesis of xanthone boronic derivatives. 3,6-Dihydroxyxanthone 10 was chosen as a precursor for the development of a procedure to borylate xanthones, mainly due to its easy synthesis and availability. From 10, 3,6-ditrifylxanthone 11 was easily prepared. The synthesis of 3,6- bis(pinacolatoboron)xanthone 8 from 11 was achieved using bis(pinacolatodiboron) B2pin2 as a borylation agent under Pd(dppf)Cl2 catalysis...
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Design, synthesis and evaluation of pyridine derivatives as potential antimicrobial compounds
Bachtíková, Andrea ; Zitko, Jan (advisor) ; Demuth, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Thesis title: Design, synthesis and evaluation of pyridine derivatives as potential antimicrobial compounds Author: Andrea Bachtíková Thesis supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: PharmDr. Martin Juhás Tuberculosis is a global problem even today. It is the second most common cause of death from infectious diseases according to the WHO and resistance to common antituberculosis drugs, which have been used in therapy for decades, increases. These facts are the main reasons why research into new potential drugs is needed. This thesis presents design, synthesis and evaluation of antimicrobial properties of a series of substituted N-oxazolyl and N-thiazolyl carboxamides of different pyridinecarboxylic acids. Final compounds were characterized by 1 H and 13 C-NMR spectroscopy, IR spectra, melting point and HRMS (High resolution mass spectrometry). Obtained compounds were tested for in vitro activity against M. tuberculosis H37Rv, M. tuberculosis H37Ra and four other clinically less important mycobacterial strains. In addition, compounds were tested for antibacterial activity against four G+ and four G- bacterial strains, antifungal activity against yeasts and fungi,...
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Synthesis of aerothionin analogs as potential antimycobacterial agents
Šimovičová, Martina ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Martina Šimovičová Supervisors: Assoc. Prof. PharmDr. Jan Zitko, Ph.D.; Adjunct Prof. Paula Kiuru, Ph.D. Title of diploma thesis: Synthesis of aerothionin analogs as potential antimycobacterial agents Key words: antimycobacterial; tuberculosis; synthesis; aerothionin; bromotyrosines Drugs currently used for the treatment of tuberculosis are the result of studies carried out 50 or 60 years ago. With the constantly growing bacterial resistance to these pharmaceuticals grows also the importance of research for new antimycobacterially active compounds. The marine environment undoubtedly holds an enormous potential for discovering new leads for the development of antitubercular agents. One of these leads is a spirocyclic compound called aerothionin (1), which was found to be active against multidrug-resistant strains of Mycobacterium tuberculosis, as well as three non-tuberculosis mycobacteria (Figure 1). In addition, several spirocyclic structures (not only from marine origin) were discovered to affect on the M. tuberculosis in recent years, making this structure segment attractive for antitubercular research. Figure 1: Aerothionin (1) and general structure of the...
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Synthesis and evaluation of N-pyridylbenzamides as potential antimicrobial compounds
Suchánková, Eliška ; Zitko, Jan (advisor) ; Nováková, Veronika (referee)
SYNTHESIS AND EVALUATION OF N-PYRIDYLBENZAMIDES AS POTENTIAL ANTIMICROBIAL COMPOUNDS Eliška Suchánková Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic The derivatives of N-pyridylbenzamide were designed and synthesized to be in vitro tested for antimycobacterial activity against Mycobacterium tuberculosis H37Ra, M. smegmatis, M. aurum and in vitro cytotoxicity in HepG2 cells. These compounds are pyridinyl analogues of previously prepared N-pyrazinylbenzamides that have shown a significant in vitro antimycobacterial activity. The title compounds were synthesized by acylation of aminopyridine or chloropyridine-2-amine by selected benzoyl chlorides. Final compounds were described by elementary analysis, melting point, 1 H and 13 C spectra and IR spectroscopy. Generally, prepared compounds possess lower antimycobacterial activity than previously tested N-pyrazinylbenzamides. However, there are some cases, in which the derivatives of pyridine were more effective compared to the derivatives of pyrazine; mainly against M. smegmatis. The best antimycobacterial activity was proved for derivatives of 2-amino-6-chloropyridine and substituted benzoyl chloride, corresponding with higher lipophilicity of these compounds;...
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