Type
Text
Type
Thesis
Advisor
Van Nostrand, William | Frank F. Fowler | Peter J. Tonge.
Date
2010-12-01
Keywords
Chemistry
Department
Department of Chemistry
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/72584
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Tuberculosis affects one-third of the world's population and is caused by the bacteria Mycobacterium tuberculosis (Mtb). Due to the rise of multi-drug resistant strains of the bacteria, a new antibiotic needs to be developed. FtsZ, a tubulin homologue, plays an essential role in bacterial cell division therefore making it a novel anti-microbial target in drug resistant strains of Mtb. Previous works from our laboratory have shown that a number of 2,5,6- and 2,5,7-trisubstituted benzimidazoles possess significant activity against Mtb by interfering with filamental temperature sensitive protein Z (FtsZ) polymerization. Libraries of novel trisubstituted benzimidazoles were created through rational design. Based upon previous work, it was noted that two 2,5,6-trisubstituted benzimidazoles containing a pyrrolidine moiety at the 5 position exhibited excellent activity against both drug sensitive and drug resistant strains of Mtb. Therefore, a library of 240 2,5,6-trisubstituted benzimidazoles retaining the pyrrolidine moiety was synthesized, with functionalization of the 2 position with a furoyl, thiophene, tetrahydropyran, or benzyl moiety.In addition, several 2,5,7-trisubstituted benzimidazoles from a previously synthesized library containing a ethyl carbamate moiety at the 5 position also exhibited good activity against Mtb. In order to obtain more accurate MIC99 values, intermediates of these compounds were also synthesized in preparation for the resynthesis of the hit compounds.Synthesis of the trisubstituted benzimidazoles starts with nucleophilic aromatic substitution of different dinitroaromatic starting materials in the presence of an amine. Subsequent introduction of the desired moieties at the 2 or 5 position via acylation or Curtius rearrangement followed by reduction and cyclocondensation affords the desired final intermediates.
Recommended Citation
Li, Lucy, "I. Discovery and Optimization of 2,5,6- Trisubstituted Benzimidazole Leads for Tuberculosis Chemotherapy II. Resynthesis of Hit 2,5,7- Trisubstituted Benzimidazole Final Compounds" (2010). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 1788.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/1788