Design, synthesis & evaluation of human Aurora kinase and phosphodiesterase inhibitors for anti-trypanosomal drug discovery via target repurposing

Permanent URL: http://hdl.handle.net/2047/d20002770
Title:
Design, synthesis & evaluation of human Aurora kinase and phosphodiesterase inhibitors for anti-trypanosomal drug discovery via target repurposing
Creator:
Ochiana, Stefan O. (Author)
Contributor:
Pollastri, Michael P. (Advisor)
Jones, Graham B. (Committee member)
Hanson, Robert N. (Committee member)
Ondrechen, Mary Jo (Committee member)
Publisher:
Boston, Massachusetts : Northeastern University, 2012
Date Accepted:
December 2012
Date Awarded:
May 2013
Type of resource:
Text
Genre:
Dissertations
Format:
electronic
Digital origin:
born digital
Abstract/Description:
Neglected tropical diseases (NTDs) represent a group of infectious diseases that blight the lives of approximately one billion people, and collectively cause around 550,000 deaths each year. These diseases are generally concentrated in low-income countries from Africa and Latin America, but are also known to take a heavy toll in parts of South Asia. The current therapies have many limitations such as cost, route of administration, toxicity and the emergence of resistance. The current work is focused on targeting the pathogenic parasite that causes African sleeping sickness, Trypanosoma brucei (T.b.), by designing new inhibitors by a "target repurposing approach." The strategy implemented in the development of the projects described herein relies on the identification of biological targets in the pathogenic parasite that show homology to biological targets in humans that have already been pursued for drug discovery efforts. This knowledge from these efforts (compounds, structural information) is repurposed in the design, synthesis, and optimization of new agents that inhibit the parasite targets. The current research consists of two distinct projects, focused on the optimization of compounds for two potential drug targets from T. brucei: Aurora Kinase 1 (TbAUK1) and phosphodiesterases B1 and B2 (TbrPDEB1 and B2).

Chapter 1 introduces in detail NTDs and target repurposing as a viable strategy for drug discovery. A comparison of target based screens and phenotype driven screens is also provided. New drug targets such as TbAUK1 and TbrPDEB1/B2 for Human African trypanosomiasis (HAT) are discussed, and their homologous human enzymes are further reviewed.

Chapter 2 describes our first efforts to improve human Aurora (h-Aur) kinase inhibitors for potency against trypanosomes which have led to a preliminary focus on the chemical series related to the Phase II clinical candidate danusertib. This chapter details our results in repurposing the human Aurora kinase inhibitor danusertib, an investigational cancer therapeutic, for treating HAT. New TbAUK1 inhibitors have been designed based on the danusertib chemotype with the guidance of homology modeling of the parasitic enzyme. Some danusertib analogs are effective in parasite killing in vitro and display good selectivity over host cells. The concept of ligand efficiency is introduced together with analogs designed to improve it. Synthesis of clickable danusertib analogs to elucidate other off-targets is also reported. AT-9283 is another repurposed human Auk inhibitor that is synthesized and studied as a potential anti-trypanosomal drug. Finally, a possible structure activity relationship cross-over between human Aurora kinase inhibitors is proposed.

Chapter 3 is focused on the synthesis and evaluation of human PDE4 and PDE5 as starting points to develop new anti-trypanosomal drugs. The first part of the chapter studies the tadalafil chemotype, and explains why this scaffold was not pursued further for the design of TbrPDEB1/B2 inhibitors. Then, the next synthetic efforts are revealed with a primary focus on more promising hPDE4 inhibitor chemotypes. The SAR developed on a "Parasite" specific pocket using the human PDE4 inhibitor piclamilast as a starting point is described. Finally, the SAR of another human PDE4 inhibitor GSK256066 is explored in detail and the findings for each explored region are disclosed.

Chapter 4 summarizes the importance of this thesis and provides future directions for the advancement of both projects.
Subjects and keywords:
HAT
NTDs
TbAUK1
TbrPDEB1
Chemistry
Medicinal-Pharmaceutical Chemistry
DOI:
https://doi.org/10.17760/d20002770
Permanent Link:
http://hdl.handle.net/2047/d20002770
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