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- Title
Synthesis of Nitrone‐derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective α‐l‐Rhamnosidase Inhibitors.
- Authors
Chen, Wei‐An; Li, Huang‐Yi; Sayyad, Ashik; Huang, Chun‐Yen; Cheng, Wei‐Chieh
- Abstract
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.
- Subjects
PYRROLIDINE synthesis; ISOXAZOLIDINES; COMBINATORIAL chemistry; NITRONES; PYRROLIDINE
- Publication
Chemistry - An Asian Journal, 2022, Vol 17, Issue 14, p1
- ISSN
1861-4728
- Publication type
Article
- DOI
10.1002/asia.202200172