DERIVATIVES OF 5-ALKYLPYRAZINE-2-CARBOXYLIC ACID AS POTENTIAL ANTI-INFECTIVES HALÍŘOVÁ MARTINA Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic In our previous study, we have demonstrated that 5-alkylamino-N- phenylpyrazine-2-carboxamides with longer alkyl chain (C5-C8) exerted micromolar growth inhibition activity against M. tuberculosis H37Rv. We speculated that the long alkylamino chain could facilitate the penetration of lipophilic mycobacterial cell envelope. To test this hypothesis, we performed the amino to methylene isosteric exchange and designed a series of 5-alkyl-N-phenylpyrazine-2-carboxamides. 5- Alkylpyrazine-2-carboxylic acids (5-Ak-POA) were prepared by homolytic alkylation of commercially available pyrazine-2-carbonitrile by respective alkanoic acid, followed by hydrolysis of the carbonitrile group. Final derivatives were prepared by CDI mediated coupling of 5-Ak-POA with corresponding aniline at RT. Final compounds were described by melting point, elementary analysis, IR spectroscopy and 1 H, 13 C NMR. Then they were tested in vitro for antimycobacterial activity against M. tuberculosis H37Rv and several non-tuberculous mycobacterial strains. Several compounds exerted MIC of 3.13-6.25 µg mL-1 ....

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Cristina Paredes de la Red Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Title of diploma thesis: Synthesis and antiinfective evaluation of substituted N-(pyrazine-2- yl)benzenesulfonamide Tuberculosis (TB) is among the ten leading causes of death, especially in developing countries. Even though it is an old disease with established treatment regimen, there has been an increased resistance to anti-TB drugs 1 . The anti-tubercular pyrazinamide has caught the attention of researchers as the different theories for its mechanism of action have made it an interesting entity for further investigation. Here we will discuss N-(pyrazine-2-yl)benzenesulfonamides (General structure is presented in the Figure below) as a new derivatization approach based on synergism methodology between pyrazinamide and sulfonamides. Sulfonamides exert their antimicrobial effect by competitive inhibition of folic acid synthesis and subsequent inhibition of bacterial growth and reproduction 18 . I have contributed to the synthesis and purification of 8 compounds in a series of total 22 N- pyrazinylsulfonamides. Two of the prepared compounds showed activity against Mycobacterium kansasii [2a (MIC...

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This thesis has been divided into five sections. The first chapter introduces the main themes of this thesis, including the description of the concepts of supramolecular chemistry, crystal engineering, hydrogen bonding and graph set analysis. The final section of chapter one describes a typical X-ray experiment used to determine the structures of the compounds presented in this thesis. Chapter two describes the synthesis and single crystal structures of copper(I) complexes with pyridine- and pyrazine-carboxylic acids. A series of novel solvent inclusion compounds of copper(I) complexes with pyridine- and pyrazine-carboxylic acids and the hydrogen bonding patterns adopted are also discussed. Chapter three reports the potential uses of boronic acids as building blocks for the design of novel solid-state architectures utilising hydrogen bonds. Novel copper(I) pyridine-/pyrazine-carboxylate complexes with boronic acid co-crystals are presented in which the heterodimeric boronic carboxylate R22(8) ring motif is present in all cases. Chapter four discusses the synthesis of novel ditertiary phosphines bearing functional groups with hydrogen bonding potential either via a three-step or single step synthetic route which involves a well known method of reductive amination followed by an efficient Mannich-based condensation. Complexation studies of these P,P-bidentate ligands with various transition metal centres such as Pt(II), Mo(0), Ru(II) and Au(I) are also presented. The effect on the structural motifs observed in these series of compounds by the regioselective incorporation of functional groups with potential hydrogen bonding capability such as hydroxyl and amide is also given. Finally, chapter five contains the synthesis and coordination studies of new phosphorus donor ligands leading to ideas for further work.

Ziel dieser Arbeit war die Entwicklung einer allgemein anwendbaren Methode für die Simulation von ultraschnellen Prozessen und experimentellen Observablen. Hierfür wurden die Berechnung der elektronischen Struktur mit der zeitabhängigen Dichtefunktionaltheorie (TDDFT) und das Tully-Surface-Hopping-Verfahren für die nichtadiabatische Kerndynamik auf der Basis klassischer Trajektorien miteinander kombiniert. Insbesondere wurde eine Beschreibung der nichtadiabatischen Kopplungen für TDDFT entwickelt. Diese Methode wurde für die Simulation noch komplexerer Systeme durch die Tight-Binding-Näherung für TDDFT erweitert. Da die zeitaufgelöste Photoelektronenspektroskopie (TRPES) ein exzellentes experimentelles Verfahren für die Echtzeitbeobachtung von ultraschnellen Prozessen darstellt, wurde eine TDDFT-basierte Methode für die Simulation von TRPES entwickelt. Der Methode liegt die Idee zu Grunde, das System aus Kation und Photoelektron näherungsweise durch angeregte Zustände des neutralen Moleküls oberhalb der Ionisierungsgrenze zu beschreiben. Um diese Zustände mit TDDFT berechnen zu können wurde eine Beschreibung der Übergangsdipolmomente zwischen angeregten TDDFT-Zuständen entwickelt. Des Weiteren wurden Simulationen im Rahmen des Stieltjes-Imaging-Verfahrens, das eine Möglichkeit der Rekonstruktion des Photoelektronenspektrums aus den spektralen Momenten bietet, durchgeführt. Diese spektralen Momente wurden aus den diskreten TDDFT-Zuständen berechnet. Die breite Anwendbarkeit der entwickelten theoretischen Methoden für die Simulation von komplexen Systemen wurde an der Photoisomerisierung in Benzylidenanilin sowie der ultraschnellen Photodynamik in Furan, Pyrazin und mikrosolvatisiertem Adenin illustriert. Die dargestellten Beispiele demonstrieren, dass die nichtadiabatische Dynamik im Rahmen von TDDFT bzw. TDDFTB sehr gut für die Untersuchung und Interpretation der ultraschnellen photoinduzierten Prozesse in komplexen Molekülen geeignet ist. / The goal of this thesis was the development of a generally applicable theoretical framework for the simulation of ultrafast processes and experimental observables in complex molecular systems. For this purpose, a combination of the time-dependent density functional theory (TDDFT) for the description of the electronic structure with the Tully''s surface hopping procedure for the treatment of nonadiabatic nuclear dynamics based on classical trajectories was employed. In particular, a new approach for the calculation of nonadiabatic couplings within TDDFT was devised. The method was advanced for the description of more complex systems such as chromophores in a solvation shell by employing the tight binding approximation to TDDFT. Since the time-resolved photoelectron spectroscopy (TRPES) represents a powerful experimental technique for real-time observation of ultrafast processes, a TDDFT based approach for the simulation of TRPES was developed. The basic idea is the approximate representation of the combined system of cation and photoelectron by excited states of the neutral species above the ionization threshold. In order to calculate these states with TDDFT, a formulation of the transition dipole moments between excited states within TDDFT was devised. Moreover, simulations employing the Stieltjes imaging (SI) procedure were carried out providing the possibility to reconstruct photoelectron spectra from spectral moments. In this work, the spectral moments were calculated from discrete TDDFT states. The scope of the developed theoretical methods was illustrated on the photoisomerization in benzylideneaniline as well as on the ultrafast photodynamics in furan, pyrazine, and microsolvated adenine. The examples demonstrate that the nonadiabatic dynamics simulations based on TDDFT and TDDFTB are particularly suitable for the investigation and interpretation of ultrafast photoinduced processes in complex molecules.

This research is focused on single-collision energy transfer events between highly vibrationally excited benzene-like donor molecules and small bath molecules, CO2 and N2O in the vibrational ground level. Measuring how much energy is transferred from donors to bath molecules was accomplished by probing bath molecules scattered into specific-rotational states using a tunable Δv=0.0003 cm-1 solid state diode laser. The normalized energy transfer probability distribution function, P(E,E'), determined from energy gain information, is very useful in comparing collisional energy transfer efficiency between various collision systems. P(E,E') is also used to investigate the effects of donor and bath physical properties on collisional energy transfer. The first chapter details the C6H5F–CO2 system, which is the basis of a study on the effect of donor fluorination on strong collision energy transfer. The second chapter is about all fluorobenzene–CO2 systems, which investigates the effect of excess vibrational excitation energy of donors on supercollision energy transfer efficiency as well as donor fluorination effect. The third chapter focuses on how the physical properties of bath molecules affect supercollision energy transfer by measuring state-specific energy gain of N2O scattered into 0000, J=59−75. Instead of CO2, N2O was used as a bath molecule with a pyrazine donor to compare energy gain results of bath molecules with somewhat different physical properties. N2O and CO2 are isoelectronic and have similar mass, but N2O has a small dipole moment. Comparison of P(E,E') obtained from pyrazine–CO2, –N2O, –DCl, and –H2O systems helps to elucidate the effect of the bath physical properties on supercollision energy transfer efficiency. The last chapter is dedicated to the extension of the measurement range of N2O energy gain to the mid J states (J=37–75). In this chapter I discuss reliability of P(E,E') obtained from only high J tail as well as the correction of overall energy transfer rate constant.

Les récepteurs Toll-like 7 et 8 jouent un rôle important dans l’activation de la réponse immunitaire innée et adaptative. Leur stimulation conduit à la production des cytokines pro-inflammatoires et d’interférons de type I. L’imiquimod et son dérivé le résiquimod sont les premières molécules de faible poids moléculaire décrites comme agonistes du TLR7 et TLR8. Ces deux molécules ont montré des activités anticancéreuses et adjuvantes très importantes. Récemment, les TLR 7 et 8 ont fait l’objet de plusieurs publications visant à développer de nouveaux agonistes TLR7 et/ou TLR8 dans la perspective d’être utilisés comme adjuvants vaccinaux. Malgré les rôles essentiels de TLR7 et TLR8 dans la stimulation du système immunitaire, une activation immunitaire chronique peut être responsable de plusieurs maladies infectieuses et auto-immunes. D’où l’importance de développer également des antagonistes TLR7 et/ou TLR8.Ce travail de thèse est consacré à la synthèse et le développement de nouvelles molécules hétérocycliques, analogues de l’imiquimod et de résiquimod, dans le but d’identifier de nouveaux ligands TLR7 et/ou TLR8. Des voies de synthèse innovantes, permettant une modulation chimique importante grâce à des couplages croisés pallado-catalysés, ont été mises au point et ont permis d’obtenir une cinquantaine de molécules appartenant à trois séries chimiques différentes de type imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline et pyrazolo[1,5-a]quinoxaline. De nombreux essais d’alkylation ont été tentés sur ces trois séries chimiques afin d’introduire une large variété de substituants sur le cycle à cinq sommets. L’application du couplage croisé de Sonogashira nous a permis d’établir une liaison C-C et introduire diverses chaines alkyles. Ces composés ont été testés pour leur activité agoniste et antagoniste TLR7 et 8. Aucun des composés cibles n'a présenté d’activité agoniste TLR7 et TLR8, dans l'intervalle des concentrations testées. Par contre, tous les composés ont montré une activité antagoniste sélective du TLR7. Les composés les plus actifs, 5.35a et 5.35b, membres de la série pyrazolo[1,5-a]quinoxaline ont montré des IC50 de l’ordre de 10 μM. Ces résultats prometteurs nous ont permis la découverte d’une activité antagoniste TLR7 importante pour la série pyrazolo[1,5-a]quinoxaline, une série très peu développée dans la littérature. La modulation chimique des molécules actives nous permet de donner naissance à de nouveaux leaders, qui peuvent jouer un rôle important dans la thérapie de plusieurs maladies infectieuses et auto-immunes. / Toll-like receptors 7 and 8 play an important role in immune system activation. Their stimulation leads to the production of pro-inflammatory cytokines and type I interferons. Both receptors recognize viral ssRNA, as well as synthetic tricyclic imidazoquinoline derivatives such as imiquimod (TLR7 agonist) and resiquimod (TLR7/8 agonist). These two molecules showed significative anti-cancer and adjuvant activities. Many reports in the literature have been focused on the development of new TLR7/8 agonists belonging to different chemical series. These agonists strongly induce the production of T helper 1-polarizing cytokines and may therefore serve as promising candidate vaccine adjuvants. Despite the essential roles of TLR7 and TLR8 in the immune system stimulation, chronic immune activation may be responsible for several infectious and autoimmune diseases. Consequently, the development of TLR7 inhibitors may play an important role in the therapy of these diseases.In this study, we are interested in the synthesis and development of new heterocyclic molecules, analogs of imiquimod and resiquimod, in order to identify new TLR7 and/or TLR8 ligands. Different synthetic pathways have been developed, using cross coupling reactions, in order to obtain a wide variety of molecules belonging to three chemical series: imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline et pyrazolo[1,5-a]quinoxaline. Various alkylation reactions were attempted on these three chemical series in order to introduce a wide variety of substituents on the five-membered ring. The application of Sonogashira's cross-coupling allowed us to establish a C-C bond and introduce various alkyl chains. All compounds have been tested for their TLR7/8 agonistic and antagonistic activity using HEK-Blue™-hTLR7/8 cells. The synthesized compounds are completely inactive as TLR7/8 agonists and are selective TLR7 antagonists. Two compounds of the pyrazolo[1,5-a]quinoxaline series, compound 5.35a and 5.35b, bearing butyl and isobutyl chain respectively, are potent and selective TLR7 antagonists with low micromolar IC50. Results allowed us to discover significative activity for the pyrazolo[1,5-a]quinoxaline series as selective TLR7 antagonists, which may therefore play an important role in the therapy of several infectious or autoimmune diseases.

Thesis presents synthesis and study of thiophene monomers, oligomers and polymers. The new series of thieno[3,4-b]pyrazine copolymers based on 3-dodecylthiophene and pyrazine monomers were prepared by oxidative polymerization with FeCl3. The effective synthetic method for preparation of 3-alkylthiophenes and thiophene oligomers was developed by optimizing of Kumada cross-couplig. The mentioned method could be realized for multikilos scale with possibility of transfer to pilot plant production. The second part of thesis focuses on synthesis and study of new thiophene compounds, which consist of both 2,3-diazo-1,3-butadiene bridge with two terminal chromophores and two thiophene units linked together via -position by pyrazine or hydrazine bridge. Finally, the new type of regular alternating copolymer consists of 2,2´:5´,2´´-terthiophene-5,5´-dicarboxylic acid (TEDA) and polyethyleneoxide (PEO) was prepared. Formation of polymer nano-subunits as separated phases in solid state was confirmed by TEM.