Type
Text
Type
Dissertation
Advisor
Tonge, Peter J | Ojima, Iwao | Drueckhammer, Dale G | Del Poeta, Maurizio.
Date
2016-12-01
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/11401/77025
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
In 2014, an estimated 480,000 people developed MDR-TB and 190,000 people died as a result of it. Approximately 9.7 % of people with MDR-TB are estimated to have XDR-TB. With the increase in the number of MDR-TB and XDR-TB cases, there is a dire need for the development of new anti-TB agents with novel mechanism of action. FtsZ, a crucial bacterial cytokinesis protein is a potential target for the development of new anti-TB agents. Previously a library of 2,5,6- and 2,5,7-trisubstituted benzimidazoles were synthesized and tested for their anti-TB activity. The lead molecules inhibited the assembly of Mycobacterium tuberculosis FtsZ by enhancing the GTPase activity. Based on the SAR studies, a new series of 2,5,6-trisubstituted benzimidazole library containing a dimethylamino group at the 6-position and various modifications at the 2-position was designed and synthesized. Trisubstituted indole analogs of the lead benzimidazoles were also synthesized as a part of SAR studies. Fungal infections affect an estimated 300 million people globally. With existing drugs displaying drawbacks like drug-drug interactions, toxicity and narrow spectrum of activity and emergence of fungal infections resistant to current drugs, new antifungal agents with novel targets are crucial. In this context, fungal sphingolopids is a promising target as it is essential for their virulence in alkaline environment. Screening of a library of 49,120 compounds from ChemBridge against C. neoformans, led to the identification of two hits, BHBM and D0 with MFC of 4 μg/mL and 1.2 μg/mL respectively. Further screening found three more hit compounds, which exhibited potent antifungal activity (MIC80 0.03 μg/mL). Based on these results, a new library of aromatic acylhydrazides has been designed and synthesized for SAR studies. Synthesis, biological activity, and SAR study of the new library of anti-fungal acylhydrazones will be presented. | In 2014, an estimated 480,000 people developed MDR-TB and 190,000 people died as a result of it. Approximately 9.7 % of people with MDR-TB are estimated to have XDR-TB. With the increase in the number of MDR-TB and XDR-TB cases, there is a dire need for the development of new anti-TB agents with novel mechanism of action. FtsZ, a crucial bacterial cytokinesis protein is a potential target for the development of new anti-TB agents. Previously a library of 2,5,6- and 2,5,7-trisubstituted benzimidazoles were synthesized and tested for their anti-TB activity. The lead molecules inhibited the assembly of Mycobacterium tuberculosis FtsZ by enhancing the GTPase activity. Based on the SAR studies, a new series of 2,5,6-trisubstituted benzimidazole library containing a dimethylamino group at the 6-position and various modifications at the 2-position was designed and synthesized. Trisubstituted indole analogs of the lead benzimidazoles were also synthesized as a part of SAR studies. Fungal infections affect an estimated 300 million people globally. With existing drugs displaying drawbacks like drug-drug interactions, toxicity and narrow spectrum of activity and emergence of fungal infections resistant to current drugs, new antifungal agents with novel targets are crucial. In this context, fungal sphingolopids is a promising target as it is essential for their virulence in alkaline environment. Screening of a library of 49,120 compounds from ChemBridge against C. neoformans, led to the identification of two hits, BHBM and D0 with MFC of 4 μg/mL and 1.2 μg/mL respectively. Further screening found three more hit compounds, which exhibited potent antifungal activity (MIC80 0.03 μg/mL). Based on these results, a new library of aromatic acylhydrazides has been designed and synthesized for SAR studies. Synthesis, biological activity, and SAR study of the new library of anti-fungal acylhydrazones will be presented. | 261 pages
Recommended Citation
Haranahalli Raghunandan, Krupanandan, "Development of novel antimicrobial agents through inhibition of cytokinetic protein FtsZ in Mycobacterium tuberculosis and sphingolipid GlcCer in fungi" (2016). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2880.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2880