Enantiomeric series of C-4 hydroxymethyl depleted DAB and LAB derivatives (trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines), designed as β-glucosidase inhibitors by molecular docking calculations, have been synthesized in 2 steps from l- and d-tartaric acid derived enantiomeric cyclic nitrones 29L and 29D, respectively. Both series of C-4 hydroxymethyl depleted DAB and LAB derivatives 28Da-e and 28La-e, which are structurally trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines, were potent and selective human lysosome acid β-glucosidase (GCase) inhibitors, of which 28Dd and 28Ld with C-4 biphenyls showed the highest potency relative to other compounds of the same series. The work provided a series of pyrrolidine-type potent and selective GCase inhibitors with minimal hydroxyl substitutions and synthetic procedures. Structure-activity relationship study revealed not only the rationality of hydrophobic and aromatic properties of the binding sites in GCase, but also the great potential of pyrrolidine family in development of new GCase inhibitors with minimized undesirable side effects. The results indicate a strategy for the development of drugs for the treatment of related diseases targeting acid β-glucosidase, such as Gaucher disease and Parkinson's disease.

通过分子对接计算设计为 β-葡萄糖苷酶抑制剂的 C-4 羟甲基耗尽的 DAB 和 LAB 衍生物（反式、反式-2 - C-芳基-3,4-二羟基吡咯烷）的对映体系列已从l - 2 步合成和d-酒石酸衍生的对映体环状硝酮分别为29L和29D。这两个系列的 C-4 羟甲基耗尽的 DAB 和 LAB 衍生物28Da-e和28La-e在结构上是反式、反式-2 - C -芳基-3,4-二羟基吡咯烷，是有效和选择性的人溶酶体酸 β-葡萄糖苷酶。 GCase) 抑制剂，其中28Dd与C-4 联苯的28Ld相对于同系列的其他化合物显示出最高的效力。这项工作提供了一系列吡咯烷型强效和选择性 GCase 抑制剂，具有最少的羟基取代和合成程序。构效关系研究不仅揭示了 GCase 结合位点疏水性和芳香性的合理性，而且揭示了吡咯烷家族在开发新的 GCase 抑制剂方面的巨大潜力，并将不良副作用降至最低。结果表明了一种开发用于治疗针对酸性β-葡萄糖苷酶的相关疾病的药物的策略，例如戈谢病和帕金森病。