Synthesis of a dysidiolide-inspired compound library and discovery of acetylcholinesterase inhibitors based on protein structure similarity clustering (PSSC)

Biologically relevant compound collections are a major prerequisite for efficient protein ligand development and ultimately for drug discovery. We herein describe the development of a compound collection inspired by the decalin core motif of two natural products, dysidiolide 1 and sulfiricin 2, both inhibitors of the Cdc25A phosphatase. Several keto-functionalized decalinols were synthesized in solution, immobilized on Merrifield resin equipped with a dihydropyranyl linker, and then subjected to aldol condensation reactions with different aldehydes leading to exocyclic E-configured olefins. Further diversity-increasing transformations on the solid support included Sonogashira, Suzuki, and Heck reactions, Cu-catalyzed conjugate addition and Grignard reactions, alkylation reactions in the α-position to a ketone, Wittig reactions, and reductive animations. In total, 483 compounds were synthesized. Cdc25A and AChE exhibit structural similarity in their ligand-sensing cores and were thus grouped into a protein structure similarity cluster (PSSC). A screen for AChE inhibition of a subset of 162 compounds yielded three micromolar inhibitors of AChE with IC50 values <20 μM.