Azolopyrimidine‐Based Thioethers: Synthesis via Cross‐Dehydrogenative C–S Coupling and In Silico Evaluation of Anti‐SARS‐CoV‐2 Activity

Azoloazine derivatives are known as promising small molecules that are potentially able to counteract a broad spectrum of RNA viruses including SARS‐CoV‐2. However, a pool of synthetic pathways to provide convenient structural modification of such compounds without de novo construction of the heterocyclic scaffold is rather limited so far. This work proposes an approach to the direct C(sp2)–H functionalization of azolopyrimidine substrates with aromatic thiol residues, mediated by the iodine/persulfate reagent system. The reported herein sulfenylation protocol has afforded a series of previously undescribed azolopyrimidine‐based thioethers obtained in yields of up to 87%. Applicability of the approach to the selenium‐centered synthons has been demonstrated as well. Besides, the in silico study with regard to the achieved cross‐coupling products has suggested the possible affinity to the SARS‐CoV‐2 main protease (Mpro), as follows from the conducted pharmacophore search and the molecular docking experiments. As a result, the developed synthetic transformation is expected to be of utility in the design of novel antiviral agents based on small azaheterocyclic molecules.