The discovery of small bioactive molecules is a central challenge in chemical biology and medicinal chemistry, and typically involves iterative cycles of design, synthesis and biological evaluation. A narrow toolkit of reliable synthetic methods drives such workflows, and focuses on heteroatom / sp2 carbon functionalization and protecting group manipulation. The dominance of the toolkit has tended to exacerbate the historically uneven exploration of chemical space, and to focus attention on flatter and more lipophilic compounds. Within fragment-based drug discovery, direct fragment growth is rare, essentially being limited to heteroatom functionalization. In practice, more elaborated fragments tend to be synthesised de novo when direct fragment elaboration would actually be desirable.
Direct fragment growth will not only contribute to improve productivity of early stages drug development by reducing the synthetic burden, but also will allow to navigate through unexplored chemical space. In particular, the exploitation of molecules with increased tridimensionality has been linked to the discovery of drug candidates with higher probabilities of reaching the market. Hence, the research proposed for the current action will contribute with know-how to the global efforts of targeting new diseases by providing new better drugs while increasing pipeline productivity.
The overall objective of the action is the development of a synthetic toolbox that facilitates the introduction of a range of medicinally-relevant functionalities into fragment molecules through their direct activation. The toolbox usefulness will be demonstrated by the discovery of new bioactive molecules able to interact with protein function.
