From Chemical Discovery to Biological Evaluation of Novel Heterobicyclic Scaffolds as Potential GLP-1 Secretagogues

This PhD project integrates synthetic organic chemistry and biological investigation to explore a novel class of heterobicyclic small molecules with potential in treating metabolic and neurodegenerative diseases. These compounds, featuring 1,3-diaza-4-oxa-[3.3.1]-bicyclic scaffolds, were identified in Prof. Pineschi’s group as GLP-1 secretagogues, a target of growing interest for type 2 diabetes and obesity. The research focused on the design and synthesis of new heterobicyclic scaffolds, including optimized gram-scale preparation of the lead compound. A key goal was the stereoselective construction of hit and lead compounds to identify eutomers and study structure–activity relationships. Parallel work involved developing and optimizing transformations such as nitroso Diels–Alder reactions via electrochemical and photochemical methods, with attention to scope, mechanism, and structural diversity. Unexpected reactivities were also investigated, providing mechanistic insights and expanding accessible chemical space. Biological evaluation included in vitro metabolic and neuroprotective assays, along with chronic treatments in diabetic mice to assess therapeutic potential. Overall, the project bridges molecular design and biological function, advancing understanding of GLP-1 secretagogues and their therapeutic potential.