Centro de Graduados e Investigación en Química, Tecnológico Nacional de México/IT de Tijuana, Tijuana, B.C., Mexico.
Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California Campus Tijuana, Tijuana, B.C., Mexico.
Bioorg Chem. 2020 Dec;105:104359. doi: 10.1016/j.bioorg.2020.104359. Epub 2020 Oct 7.
The stereoselective synthesis and anti- Hymenolepis nana activity of six Linezolid-type compounds, obtained by chemical modification of l-Alanine, are reported in this work. The synthetic strategy was to prepare diasteromeric N,N-dibenzylamino oxazolidinones 1 and 2, and coupling with 4-(4-bromophenyl)morpholine (3) to obtain N,N-dibenzylamino Linezolid analogues 4 and 5. A hydrogenolysis reaction over 4 and 5 resulted in amino-free Linezolid analogues 6 and 7, which were acetylated to reach diasteromeric Linezolid analogues 8 and 9. The six Linezolid analogues 4-9 show in vitro antiparasitic activity against Hymenolepis nana cestode, but not against several bacterial strains. Interestingly, compounds 6, 7 and 9 exhibit high potency, having shorter paralysis and death times after exposure (6-10 and 18-21 min, respectively), shorter than those found with antihelmintic compound Praziquantel (20 and 30 min) at 20 mg/mL. In addition, a cytocompatibility assay of 6-9 with human cells (ARPE-19 cells) demonstrate a non-cytotoxic effect at 0.4 mM. These results show the pharmacological potential of the newly reported Linezolid-type analogues as antiparasitic agents against Hymenolepis nana.
本文报道了通过 l-丙氨酸化学修饰得到的 6 种利奈唑烷类化合物的立体选择性合成及抗曼氏迭宫绦虫活性。该合成策略是制备非对映异构体 N,N-二苄基氨基恶唑烷酮 1 和 2，并与 4-(4-溴苯基)吗啉（3）偶联，得到 N,N-二苄基氨基利奈唑烷类似物 4 和 5。通过氢化反应得到氨基游离的利奈唑烷类似物 6 和 7，然后将其乙酰化得到非对映异构体利奈唑烷类似物 8 和 9。这 6 种利奈唑烷类似物 4-9 对曼氏迭宫绦虫表现出体外抗寄生虫活性，但对几种细菌菌株没有活性。有趣的是，化合物 6、7 和 9 表现出高活性，暴露后（分别为 6-10 和 18-21 分钟）的麻痹和死亡时间更短，比驱虫药吡喹酮（20 和 30 分钟）在 20 mg/mL 时的作用更快。此外，6-9 对人细胞（ARPE-19 细胞）的细胞相容性试验表明，在 0.4 mM 时没有细胞毒性。这些结果表明，新报道的利奈唑烷类类似物具有作为抗曼氏迭宫绦虫寄生虫药物的药理潜力。
