Synthesis and anti‐coronavirus activity of a series of 1‐thia‐4‐azaspiro[4.5]decan‐3‐one derivatives

A series of 1‐thia‐4‐azaspiro4.5]decan‐3‐ones bearing an amide group at C‐4 and various substitutions at C‐2 and C‐8 were synthesized and evaluated against human coronavirus and influenza virus. Compounds 7m , 7n , 8k , 8l , 8m , 8n , and 8p were found to inhibit human coronavirus 229E replication. The most active compound was N‐(2‐methyl‐8‐tert‐butyl‐3‐oxo‐1‐thia‐4‐azaspiro4.5]decan‐4‐yl)‐3‐phenylpropanamide ( 8n ), with an EC₅₀ value of 5.5 µM, comparable to the known coronavirus inhibitor, (Z)‐N‐3‐4‐(4‐bromophenyl)‐4‐hydroxypiperidin‐1‐yl]‐3‐oxo‐1‐phenylprop‐1‐en‐2‐yl]benzamide ( K22 ). Compound 8n and structural analogs were devoid of anti‐influenza virus activity, although their scaffold is shared with a previously discovered class of H3 hemagglutinin‐specific influenza virus fusion inhibitors. These findings point to the 1‐thia‐4‐azaspiro4.5]decan‐3‐one scaffold as a versatile chemical structure with high relevance for antiviral drug development.