Abstract

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH₂O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC₅₀ value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

摘要

采用合理的方法重新利用基于吡咯烷的 3-脱氧鞘氨醇磷酰胆碱类似物，其具有可变的酰基链、不同的立体化学构型和/或位置关系。结构特征对活性有很大影响。其中，对映异构体1e具有 -CH ₂ O- 和N-酰基部分的1,2-邻位关系、饱和的棕榈酰链和与天然鞘脂相反的立体化学构型，是对抗前鞭毛体的最有效的命中化合物，其 IC ₅₀值为28.32 微米。相应的对映异构体1a 的效力低 2 倍，在前鞭毛体中显示出 0.54 的 eudismic 比率。化合物1a和1e相对于前鞭毛体更有效地抑制无鞭毛体的生长。其中，对映异构体1a的选择性更高，更安全。使用杜氏利什曼原虫肌醇磷酸神经酰胺合酶 (IPCS)同源模型进行的计算机对接研究为所发现活性的分子因素提供了合理的推理。总的来说，这项研究表明化合物1a和1e作为潜在的命中化合物，可用于进一步开发新的抗利什曼病药物。