Dokument: Development of reverse N-substituted fosmidomycin analogs as P. falciparum 1-deoxy-D-xylulose 5-phosphate reductoisomerase inhibitors

Titel:	Development of reverse N-substituted fosmidomycin analogs as P. falciparum 1-deoxy-D-xylulose 5-phosphate reductoisomerase inhibitors
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65818
URN (NBN):	urn:nbn:de:hbz:061-20240516-165341-3
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Mahmoud, Mona [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 20,14 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 14.05.2024 / geändert 14.05.2024
Beitragende:	Prof. Dr. Kurz, Thomas [Gutachter] Prof. Dr. rer. nat. Gohlke, Holger [Gutachter]
Stichwörter:	Fosmidomycin, N-substituted hydroxamic acids, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR, IspC), non-mevalonate biosynthesis pathway, antiplasmodial activity, co-crystal structures.
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 540 Chemie
Beschreibung:	With the spread of multidrug-resistant Plasmodium species, the need for new, improved therapeutics to reduce malaria deaths and the discovery of new drug targets remains an urgent research goal. The enzyme 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is considered a clinically validated drug target in anti-infective drug discovery. DXR catalyzes the second rate-limiting step in the non-mevalonate pathway (MEP), a pathway used for isoprenoid biosynthesis. several human pathogens like Plasmodium falciparum (P. falciparum), Mycobacterium tuberculosis (M. tuberculosis ) and Escherichia choli (E. choli), where they are synthesized through the non-mevalonate pathway (MEP). Humans use the alternate mevalonate pathway to synthesize the same isoprenoid precursors. The absence of the MEP in humans makes it an attractive pathway for discovering novel anti-infective drug candidates. The natural antibiotic Fosmidomycin is a potent inhibitor of the DXR enzyme. Fosmidomycin also shows potent in vitro and in vivo antiplasmodial activity. Unfortunately, fosmidomycin suffers from low bioavailability, short plasma half-life, and malaria recrudescence. Therefore, there is a need for novel analogs with enhanced activity to overcome the shortcomings of this inhibitor. This thesis focuses on the development of new reverse fosmidomycin analogs that can serve as DXR inhibitors with potent antiplasmodial activity and new binding modes. The project was dedicated to developing novel reverse fosmidomycin analogs with large phenylalkyl substituents at the nitrogen atom of the hydroxamic acid metal binding group. However, the feasibility of synthesizing non-hydroxamic acid DXR inhibitors like amide and arylalkoxyamide analogs was also tested. The synthetic routes to these analogs were elaborated, and the compounds were evaluated for their ability to inhibit Plasmodium falciparum DXR (PfDXR), Escherichia coli DXR (EcDXR), and Mycobacterium tuberculosis DRX (MtbDXR). In addition, the compounds were then screened against two P. falciparum strains, PfDd2 and Pf3D7, to evaluate their antiproliferative potential. Finally, the compounds were tested for their cytotoxicity against human HepG-2 cells to ensure parasite selectivity. Furthermore, we provided crystallographic evidence for the binding mode of one of the most active analogs in PfDXR and demonstrated that N-linked phenylpropyl moiety showed a new inhibitor binding mode in previously overlooked hydrophobic sup-pocket in PfDXR. The novel co-crystal structures will serve as starting points for developing improved DXR inhibitors.
Lizenz:	Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:	16.05.2024
Dateien geändert am:	16.05.2024
Promotionsantrag am:	02.11.2023
Datum der Promotion:	12.04.2024