Synthesis and Biological Evaluation of FR900098 Inhibitor Analogs as Antimicrobials

The methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis in pathogens such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), Acinetobacter baumanii (Ab), and Klebsiella pneumoniae (Kp). The process and its products are vital to microbial metabolism and survival. This pathway represents an attractive set of drug targets due to its essentiality in these pathogens but absence in humans. The second step in the MEP pathway is the conversion of 1-deoxy-D-xylulose-5-phosphate (DXP) to MEP and is catalyzed by 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR). Natural products fosmidomycin and FR900098 inhibit DXR, however they lack the required lipophilicity to reach the desired target inside the cell. To further increase lipophilicity, a prodrug strategy, using acyloxy- and aryloxy-prodrug esters, were synthesized, and added to this novel series of FR900098 analogs. In addition to prodrug implementation, lipophilic modifications at various sites showed promise, resulting in increased activity against our pathogens of interest. Data from these compounds suggest that this combination of substituents is advantageous in designing a new generation of antimicrobials.

Author

• Bague, Darean

Language

• English

Keyword

• medicinal chemistry
• eskape pathogens
• antimicrobials
• fosmidomycin
• malaria
• tuberculosis

Date created

• 2024

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Chemistry

Degree

• Ph.D.

Advisor

• Dowd, Cynthia S

Committee Member(s)

• Boyes, Stephen
• Hao, Ling

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/1g05fc49n