Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa 450054, Russian Federation.
Republican Research and Practical Center for Epidemiology and Microbiology, Minsk 220114, Belarus.
Steroids. 2021 Nov;175:108912. doi: 10.1016/j.steroids.2021.108912. Epub 2021 Sep 1.
To develop new potential agents against Chlamydia trachomatis among oleanane type triterpenoids the synthesis, spectral and X-ray analysis as well as antimicrobial screening of C-12 oxygen and nitrogen derivatives of erythrodiol is presented. The reduction of methyl 3β-acetoxy-12-oxo-oleanoate with LiAlH led to isomeric erythrodiol 12β- and 12α-hydroxy-derivatives, their stereochemistry with respect to the position of hydroxyl-group at C-12 was determined based on the multiplets splitting patterns, the magnitude of the spin-spin interaction, and NOESY interactions. Methyl 3β-acetoxy-12-oxo-oleanoate was transformed to 12E-hydroxyimino- and 12E-methoxyimino-derivatives by the interaction with NHOH∙HCl or CHONH∙HCl, respectively. By Beckmann rearrangement with SOCl in dioxane 12E-oxime was converted to C-lactame and its following reduction with LiAlH in THF or dioxane led to erythrodiol C-azepanone or C-azepane derivatives. The structure 3-O,12-N-bis-acetyl-derivative of C-azepane-erythrodiol was confirmed by the single crystal X-ray analysis. Erythrodiol 12β-hydroxy- and C-azepane derivatives were found to be lead compounds with significant activity against C. trachomatis with MIC 1.56 and 3.125 μg/mL. Molecular docking was employed to suggest potential binding interaction, the tested compounds are likely to act as Cdu1 protein inhibitors while 12β-hydroxy-erythrodiol exhibited the highest affinity towards this respective target protein. These results indicated that C-ring oxygen and nitrogen erythrodiol derivatives might be considered for further research in the design of antibacterial agents against Chlamydia trachomatis.
为了在齐墩果烷型三萜烯中开发针对沙眼衣原体的新型潜在药物，本文介绍了赤式-12-羟基-3β-乙酰氧基-12-氧代-齐墩果烷酸甲酯及其 C-12 位氧、氮衍生物的合成、光谱和 X 射线分析以及抗菌筛选。用 LiAlH 还原 3β-乙酰氧基-12-氧代-齐墩果酸甲酯得到赤式-12β-和 12α-羟基衍生物，根据偶合常数、自旋-自旋相互作用的大小和 NOESY 相互作用，确定了 C-12 位羟基的立体化学。用 NHOH·HCl 或 CHONH·HCl 分别将 3β-乙酰氧基-12-氧代-齐墩果酸甲酯转化为 12E-羟亚氨基和 12E-甲氧基亚氨基衍生物。用 SOCl 在二恶烷中进行 Beckmann 重排，得到 12E-肟，然后用 LiAlH 在 THF 或二恶烷中还原，得到赤式-12-氮杂环庚烷-3β-醇或 12-氮杂环庚烷衍生物。通过单晶 X 射线分析证实了 C-氮杂环庚烷-赤式-12-醇 3-O，12-N-双乙酰衍生物的结构。赤式-12-羟基和 C-氮杂环庚烷衍生物被发现是针对沙眼衣原体具有显著活性的先导化合物，MIC 为 1.56 和 3.125μg/mL。采用分子对接方法研究潜在的结合作用，结果表明，这些化合物可能作为 Cdu1 蛋白抑制剂，而 12β-羟基赤式-12-醇对相应的靶蛋白具有最高的亲和力。这些结果表明，C-环氧和氮赤式-12-醇衍生物可能被认为是进一步研究针对沙眼衣原体的抗菌药物的候选物。
