Synthesis of Nitrone‐derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective α‐l‐Rhamnosidase Inhibitors

A general and flexible approach toward the development of α‐l‐rhamnosidase (α‐l‐Rha‐ase) inhibitors is described. Five enantiopure poly‐substituted pyrrolidine‐based scaffolds bearing the C1‐aminomethyl moiety were designed and synthesized from five‐membered cyclic nitrones. Each structurally diversified amide library of these scaffolds was rapidly generated via combinatorial parallel synthesis and applied for in‐situ inhibition study against α‐l‐Rha‐ase, allowing us to efficiently identify new inhibition hits. Surprisingly, all promising inhibitors are derived from the same scaffold 3. Among them, the most potent and selective inhibitor is pyrrolidine 19 with Ki=0.24 μM, approximately 24‐fold more potent than the reference compound DAA (Ki=5.7 μM). It is the first study to comprehensively prepare pyrrolidine‐based scaffolds and libraries for inhibition study against α‐l‐Rha‐ase. An efficient strategy to develop selective α‐l‐rhamnosidase inhibitors is described. Five functionalized pyrrolidine scaffolds were rationally designed and synthesized from cyclic nitrones. Their corresponding diverse libraries prepared by combinatorial chemistry enable us to increase the chemical space of pyrrolidine‐based iminosugars and allow us to identify selective and potent α‐l‐rhamnosidase inhibitors.