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Five enantiopure poly\u2010substituted pyrrolidine\u2010based scaffolds bearing the C1\u2010aminomethyl moiety were designed and synthesized from five\u2010membered cyclic nitrones. Each structurally diversified amide library of these scaffolds was rapidly generated via combinatorial parallel synthesis and applied for <jats:italic>in\u2010situ<\/jats:italic> inhibition study against \u03b1\u2010<jats:sc>l<\/jats:sc>\u2010Rha\u2010ase, allowing us to efficiently identify new inhibition hits. Surprisingly, all promising inhibitors are derived from the same scaffold <jats:bold>3<\/jats:bold>. Among them, the most potent and selective inhibitor is pyrrolidine <jats:bold>19<\/jats:bold> with <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=0.24\u2005\u03bcM, approximately 24\u2010fold more potent than the reference compound DAA (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>=5.7\u2005\u03bcM). It is the first study to comprehensively prepare pyrrolidine\u2010based scaffolds and libraries for inhibition study against \u03b1\u2010<jats:sc>l<\/jats:sc>\u2010Rha\u2010ase.<\/jats:p>","DOI":"10.1002\/asia.202200172","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T05:04:07Z","timestamp":1652159047000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Synthesis of Nitrone\u2010derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective \u03b1\u2010<scp>l<\/scp>\u2010Rhamnosidase Inhibitors"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9087-5414","authenticated-orcid":false,"given":"Wei\u2010An","family":"Chen","sequence":"first","affiliation":[{"name":"Genomics Research Centre Academia Sinica  128, Section\u20052, Academia Road 11529 Taipei 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