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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

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dc.contributor.advisor Van Nostrand, William en_US
dc.contributor.author Li, Lucy en_US
dc.contributor.other Department of Chemistry en_US
dc.date.accessioned 2012-05-15T18:04:55Z
dc.date.available 2012-05-15T18:04:55Z
dc.date.issued 1-Dec-10 en_US
dc.date.submitted Dec-10 en_US
dc.identifier Li_grad.sunysb_0771M_10386.pdf en_US
dc.identifier.uri http://hdl.handle.net/1951/55526
dc.description.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. en_US
dc.description.sponsorship Stony Brook University Libraries. SBU Graduate School in Department of Chemistry. Lawrence Martin (Dean of Graduate School). en_US
dc.format Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Chemistry en_US
dc.title 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 en_US
dc.type Thesis en_US
dc.description.advisor Advisor(s): Iwao Ojima. Committee Member(s): Frank F. Fowler; Peter J. Tonge. en_US
dc.mimetype Application/PDF en_US


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