Details
| Originalsprache | Englisch |
|---|---|
| Qualifikation | Doctor rerum naturalium |
| Gradverleihende Hochschule | |
| Betreut von |
|
| Datum der Verleihung des Grades | 15 Apr. 2024 |
| Erscheinungsort | Hannover |
| Publikationsstatus | Veröffentlicht - 26 Apr. 2024 |
Abstract
antibakteriellen Eigenschaften aus der Natur bekannt ist.[7] Mit den Cystobactamiden wurde eine vielversprechende Verbindungsklasse von Antibiotika gefunden und intensiv in Richtung eines anwendbaren Medikaments weiterentwickelt.[8-11] In dieser Arbeit wurde die derzeit bekannte Cystobactamid-Bibliothek synthetisch erweitert und die in-vitro-Wirksamkeit der neuen Analoga gegen diverse Bakterien, einschließlich der hochrelevanten ESKAPE-Erreger, bestimmt. Ausgehend von dem aktuellen Cystobactamid CN-CC 861 als Leitstruktur[11] wurden mehrere neue CDE-Fragmente synthetisiert. Verschiedene hochsubstituierte Aromaten wurden synthetisch
zugänglich gemacht und als Ring-D-Derivate eingesetzt. Diese Methoden umfassen unter anderem die metallvermittelte aromatische Funktionalisierung und Heterocyclisierungen. Die Cystobactamid-Synthesevorschriften hin zur Zielverbindung wurden verbessert und auf mehrere Derivate angewendet. Eine neue allgemeine SAR von Ring D wurde abgeleitet, indem die Ergebnisse der Aktivitätstests aller neuen Verbindungen ausgewertet wurden. Dabei erwies sich sowohl die Substitution der Hydroxygruppe als auch eine Versteifung zwischen Ring D und E als schwierig. Die Analyse der Aktivität gegen ESKAPE-Erreger führte zu neuen Erkenntnissen über die Auswirkungen dieser Modifikationen, auf deren Grundlage künftige Cystobactamid-Analoga angestrebt wurden. Eine invertierte Amidbindung zwischen Ring C und D erwies sich hier als äußerst vorteilhaft im Hinblick auf die Breitspektrum-Aktivität. Die neuen
CDE-Fragmente wurden mit den Western-Fragmenten von sowohl der Leitverbindung, als auch von aktuellen Cystobactamid-Favoritstrukturen kombiniert. Letztere enthielten Benzimidazole, Bicyclo[1.1.1]pentan und Pyridin als Strukturelemente, bzw. Isostere für Benzol. Die beiden aktivsten Verbindungen dieser Arbeit waren Teil einer präklinischen in vivo ADME-Studie und werden in weiterführende Studien einbezogen. Außerdem wurde Serin als zentrale Aminosäure gut toleriert und stellt eine höher polare Alternative
für die zentrale Aminosäure dar, was sich möglicherweise positiv auf die Löslichkeit auswirkt.
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Hannover, 2024. 277 S.
Publikation: Qualifikations-/Studienabschlussarbeit › Dissertation
}
TY - BOOK
T1 - Synthetic optimization of cystobactamids as broad-spectrum antibiotics
AU - Stappert, Moritz Dominik
PY - 2024/4/26
Y1 - 2024/4/26
N2 - Bacterial resistance is omnipresent and expected to be a future problem as warned by the World Health Organization (WHO) reports and guidelines since 2014,[1-3] Centers for Disease Control and Prevention (CDC)[4] and European Centre of Disease Prevention and Control (ECDC)[5]. Novel scaffolds for broad-spectrum antibiotics that can displace β-lactams and quinolones are rare and their development is slow,[6] although a variety of compounds with antibacterial properties is known from nature.[7] With the cystobactamids, a highly promising antibiotic compound class was found and comprehensively expanded towards an applicable medication.[8-11] In this Thesis, the currently known library of cystobactamids was synthetically extended and the in vitro efficacy of the novel analogues was determined against various bacteria, including the highly relevant ESKAPE pathogens. Based on the current cystobactamid CN-CC 861 as lead-scaffold,[11] several new CDE-fragments were synthesized. Various highly substituted aromatic systems were synthetically accessed and implemented as ring Derivatives. These methods embrace metal-mediated aromatic functionalization, and heterocyclization among others. The cystobactamid assembly protocols were improved and simplified and applied to several new derivatives. An updated general SAR of ring Dwas derived by evaluating the activity test results of all new compounds. Thereby, both replacement of the hydroxy group and a rigidification between ring D and E proved difficult. Analysis of the activity against ESKAPE pathogens led to new insights into the effects of these modifications, based on which future cystobactamid analogues were targeted. A reversed amide bond between ring C and D proved to be highly advantageous here in terms of broad-spectrum activity. Novel CDE-fragments were combined with Western-fragments of the lead compound, as well as of current front-running cystobactamids. The latter included benzimidazoles, bicyclo[1.1.1]pentane and pyridin as substructures, resp. isosteres for benzene. The two most active compounds in this Thesis were part of a preclinical in vivo ADME study and will be included in follow-up trials. Besides, serine as central amino acid was found to be well tolerated and represents a more polar alternative for the central alkylamino acid which probably has a positive effect on solubility.
AB - Bacterial resistance is omnipresent and expected to be a future problem as warned by the World Health Organization (WHO) reports and guidelines since 2014,[1-3] Centers for Disease Control and Prevention (CDC)[4] and European Centre of Disease Prevention and Control (ECDC)[5]. Novel scaffolds for broad-spectrum antibiotics that can displace β-lactams and quinolones are rare and their development is slow,[6] although a variety of compounds with antibacterial properties is known from nature.[7] With the cystobactamids, a highly promising antibiotic compound class was found and comprehensively expanded towards an applicable medication.[8-11] In this Thesis, the currently known library of cystobactamids was synthetically extended and the in vitro efficacy of the novel analogues was determined against various bacteria, including the highly relevant ESKAPE pathogens. Based on the current cystobactamid CN-CC 861 as lead-scaffold,[11] several new CDE-fragments were synthesized. Various highly substituted aromatic systems were synthetically accessed and implemented as ring Derivatives. These methods embrace metal-mediated aromatic functionalization, and heterocyclization among others. The cystobactamid assembly protocols were improved and simplified and applied to several new derivatives. An updated general SAR of ring Dwas derived by evaluating the activity test results of all new compounds. Thereby, both replacement of the hydroxy group and a rigidification between ring D and E proved difficult. Analysis of the activity against ESKAPE pathogens led to new insights into the effects of these modifications, based on which future cystobactamid analogues were targeted. A reversed amide bond between ring C and D proved to be highly advantageous here in terms of broad-spectrum activity. Novel CDE-fragments were combined with Western-fragments of the lead compound, as well as of current front-running cystobactamids. The latter included benzimidazoles, bicyclo[1.1.1]pentane and pyridin as substructures, resp. isosteres for benzene. The two most active compounds in this Thesis were part of a preclinical in vivo ADME study and will be included in follow-up trials. Besides, serine as central amino acid was found to be well tolerated and represents a more polar alternative for the central alkylamino acid which probably has a positive effect on solubility.
U2 - 10.15488/17239
DO - 10.15488/17239
M3 - Doctoral thesis
CY - Hannover
ER -