Ce manuscrit de thèse concerne le développement d'une stratégie de synthèse multi-étapes de nouveaux composés comportant plusieurs plateformes hétérocycliques (rhodanine, benzimidazole, pyrazole et imidazole) à visée thérapeutique multiple contre la malaria, la leishmaniose, le cancer et les maladies neurodégénératives. Les pharmacomodulations de ces composés ont été élaborées sur la base du modèle de la pentamidine 35 comportant 2 motifs benzamidines (parties « Ouest » et « Est »). En effet, la substitution de sa partie « Ouest » par une plateforme rhodanine ou benzimidazole et de sa partie « Est » par un système aromatique plan ou système azole (pyrazole, imidazole) a permis d’accéder respectivement aux 5-arylidènes rhodanines (50, 58), aux dérivés ''aza'' (99,100) et aux dérivés ''aza azoles'' 174 qui sont des analogues de la pentamidine. Les rendements de ces composés sont respectivement compris entre 26 et 98%, 10 et 93% et 10 et 97%. L’ensemble des composés synthétisés dans les chapitres II, III et IV de ces travaux ont été l'objet d'évaluations pour leur activité antiproliférative sur les lignées cellulaires et pour leur activité inhibitrice sur les protéines kinases. / This thesis manuscript is focused on the development of multi-steps synthesis strategy of new compounds bearing several heterocyclic platforms (rhodanine, benzimidazole, pyrazole and imidazole) for multiple therapeutic use to fight malaria, leishmaniasis, cancer et neurodegenarative diseases. The pharmacomodulations of these compounds were developped from the design of pentamidine 35 which containins 2 fragments benzamidine (parts ''West'' and ''East''). Indeed, the substitution of its part ''West'' by a platform rhodanine or benzimidazole and its part ''East'' by an "azole" aromatic ring system (pyrazole, imidazole) lead respectively to 5-arylidene rhodanines (50, 58), to derivatives ''aza'' (99,100) and to derivatives ''aza azoles'' 174 which are pentamidine analogs. The chemical yields of these compounds are ranging respectively from 26 to 98%, 10 to 93% and 10 to 97%. All the compounds synthesized in the chapters II, III and IV of this research work were evaluated for their antiproliferative activity on tumoral cell lines and for their inhibitory activity on protein kinases.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Study program: Pharmacy Author: Simona Novotná Supervisor: RNDr. Klára Konečná, Ph.D. Title of diploma thesis: Advanced antibacterial activity testing of candidate newly synthesized compounds Background: The aim of this thesis was to perform an extended study of the antibacterial activity of selected newly synthesized rhodanine derivatives. In this study, activity against clinical isolates of bacterial strains of the genus Staphylococcus and Enterococcus was evaluated. The main part of the work also includes the evaluation of the antibacterial activity of one selected substance in combination with commercially available antibiotics using the checkerboard method. Methods: Evaluation of the antibacterial activity of tested substances was performed using the broth microdilution method according to EUCAST guidelines (with minor modifications). The activity of these substances was evaluated against clinical isolates of bacteria of the genera Staphylococcus and Enterococcus and one Staphylococcus aureus MRSA reference strain (ATCC 43300, CCM 4750). For a selected compound with a demonstrably promising antistaphylococcal effect, the combined effect of this substance was tested with three...

In der Alzheimer-Forschung (engl.: Alzheimer Disease, AD) wird immenser Aufwand zur Entwicklung von den Krankheitsverlauf verändernden Medikamenten betrieben. Studien zeigten, dass die abnormale Aggregation des Tau-Proteins offenbar zum Zusammenbruch der Zellkommunikation führt. Niedermolekulare Substanzen, die die Tau-Protein-Aggregation inhibieren und sogar bereits gebildete Aggregate wieder auflösen können wurden entwickelt, sind jedoch oft aufgrund von schlechten Wasserlöslichkeiten nur unter Zusatz von Dimethylsulfoxid (DMSO) in Biotests einsetzbar. Durch das Design maßgeschneiderter Peptid-Polyethylenglykol (PEG)-Konjugate war die spezifische Bindung und anschließende Freisetzung ausgewählter potentieller anti-AD-Wirkstoffe in DMSO-freien Biotests möglich. Für den Entwurf der Wirkstoff-Transporter wurden Peptidbibliotheken mit Raman- und Fluoreszenz-Mikroskopie-basierten Methoden hinsichtlich der Anreicherung der Wirkstoffe an Peptiden mit hoher Wirkstoff-Bindekapazität getestet. Mithilfe von Matrix-unterstützter Laser-Desorption/Ionisation (MALDI)-Massenspektrometrie (MS/MS)-Fragmentierung konnten die Peptidsequenzen der positiven Treffer identifiziert werden. Die zugehörigen Konjugate wurden synthetisiert, mit den Wirkstoffen beladen und die entstehenden sehr gut wasserlöslichen Wirkstoff-Konjugat-Komplexe analysiert. Für biomedizinische Anwendungen sind kompakte und definierte Systeme von Vorteil. Zur Strukturaufklärung der Wirkstoff-Konjugat-Komplexe konnten zahlreiche Untersuchungen erfolgreich durchgeführt werden. Viele Komplexe wurden zudem in DMSO-freien Biotests der Tau-Protein-Aggregation eingesetzt. Die Bioverfügbarkeit der schwerlöslichen anti-AD-Wirkstoffe konnte durch die Solubilisierung mit maßgeschneiderten Peptid-PEG-Konjugaten enorm verbessert werden. Die auf Raman-aktive Substanzen erweiterte Screeningprozedur kann wahrscheinlich auf eine Großzahl von Wirkstoffen mit ungünstigen pharmakologischen Eigenschaften angewendet werden. / Considerable efforts are devoted in Alzheimer Disease (AD) research to develop disease modifying drugs. Various studies have demonstrated that abnormal aggregation of Tau protein probably interrupts communication between cells. Tau protein aggregation can be inhibited and even preformed aggregates can be redissolved by small-molecule compounds. Unfortunately, these molecules often can only be applied in limited biotests using dimethyl sulfoxide (DMSO) as co-solvent due to their poor water solubility and bioavailability. The solubilization of selected potential anti-AD drugs by tailored peptide-poly(ethylene glycol) (PEG) conjugates enabled the specific binding und subsequent release of these drugs in DMSO-free biotests. For the design of the drug conjugate carriers, large peptide libraries have been screened using Raman or fluorescence microscopy-based methods to follow drug enrichment on certain peptide library beads which exhibit high drug affinity. Identification of peptide sequences of positive hits was performed by Matrix-assisted Laser Desorption/Ionization (MALDI)-mass spectrometry (MS/MS) fragmentation. The corresponding conjugates were synthesized; loaded with the potential drugs and the resulting highly water-soluble drug transporter complexes were analyzed. Compact and defined complexes are desirable with regard to biomedical applications. Various studies on drug-peptide interactions, specifity of drug binding and influence of the different parts of the conjugates for drug capacities were performed successfully. Generated drug transporter complexes were finally tested in DMSO free bioassays. Depending on drug and peptide structures, the complexes could reach effects comparable to the drugs solubilized by DMSO. The bioavailability of poor water-soluble anti-AD compounds was largely improved. Presumably, the new developed Raman-screening procedure can be expanded to a great extent of compounds suffering from unfavorable pharmacological characteristics.