Synthesis of erythrodiol C-ring derivatives and their activity against Chlamydia trachomatis

Abstract

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 LiAlH₄ 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 NH₂OH∙HCl or CH₃ONH₂∙HCl, respectively. By Beckmann rearrangement with SOCl₂ in dioxane 12E-oxime was converted to C-lactame and its following reduction with LiAlH₄ 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.

Keywords: Azepane; Chlamydia trachomatis; Erythrodiol; Lactam; Oleanolic acid; Oxime; Triterpenoids.