The 3F Library: Fluorinated Fsp3 -Rich Fragments for Expeditious 19 F NMR Based Screening

Abstract

Fragment-based drug discovery (FBDD) is a popular method in academia and the pharmaceutical industry for the discovery of early lead candidates. Despite its wide-spread use, the approach still suffers from laborious screening workflows and a limited diversity in the fragments applied. Presented here is the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges. The 3F library of 115 fluorinated, Fsp³ -rich fragments is shape diverse and natural-product-like with desirable physicochemical properties. The library is perfectly suited for rapid and efficient screening by NMR spectroscopy in a two-stage workflow of ¹⁹ F NMR and subsequent ¹ H NMR methods. Hits against four diverse protein targets are widely distributed among the fragment scaffolds in the 3F library and a 67 % validation rate was achieved using secondary assays. This collection is the first synthetic fragment library tailor-made for ¹⁹ F NMR screening and the results demonstrate that the approach should find broad application in the FBDD community.

Keywords: NMR spectroscopy; drug discovery; fluorine; molecular diversity; synthesis design.