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

• Online Access: http://hdl.handle.net/2047/d20002770

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).