Parallel synthesis of 5′-amino-5′-deoxy-adenosine derivatives for focused chemical space exploration and their application as methyltransferase inhibitors

Parallel syntheses and their throughput capabilities are powerful tools for the rapid generation of molecule libraries, making them highly beneficial for accelerating hit identification in early-stage drug discovery. Utilizing chemical spaces and virtual libraries enhances time and cost efficiency, enabling the faster exploitation of chemically diverse compounds. In this study, a parallel synthesis method for rapidly generating a 5'-amino-5'-deoxy adenosine-based amide and sulfonamide library of 42 compounds is described with high yields and purity, which is economical and ecological due to the reduced requirements for extensive purification. Methyltransferases recently emerged as promising drug targets. The adenosine-derived library was screened using a fluorescence polarization (FP) assay against model enzymes human DNMT2 and METTL3/14, and SARS-CoV-2 nsp14/10, resulting in the identification of three compounds binding with nanomolar affinity to nsp14/10 and three compounds binding METTL3/14 with low micromolar affinity. To demonstrate the accessibility of a broad variety of adenosine derivatives, a focused virtual chemical space of 25 241 5'-amino-5'-deoxy adenosine amides and sulfonamides, which are accessible <i>via</i> the described synthetic procedure, was generated. This chemical space was further investigated for potential biological applications through virtual screening against nsp14/10 which led to the identification of four additional ligands with low micromolar affinities.