Synthesis, hypnotic properties and molecular modeling studies of 1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones

1,3-Dipolar cycloaddition reaction of nitrilimines with 5-arylidene-1,3-dimethyl-2,4,6-pyrimidinetriones 1a–i afforded 7,9-dimethyl-1,3,4-triaryl-1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones 3a–k in a high regioselective manner. Single crystal X-ray study of 3d added a conclusive support for the assigned structure. Potentiating effects of the synthesized compounds 3a–k (at a dose of 25 mg/kg body weight) on hypnotic action of sodium thiopental (at a dose of 75 mg/kg body weight i.p.) were investigated in vivo using Albino mice according to the standard method. Most of the tested compounds revealed promising hypnotic potentiating effects especially compounds 3k and 3e that could be nominated as short-acting hypnotics. A hypothesis of molecular modeling study, including fitting of the synthesized compounds into 3D-pharmacophore using Discovery Studio 2.5 software and their docking into optimized homology model of GABAA-α1 showed good results consistent with the observed pharmacological properties.

1,2,7,9-Tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones were regioselectively synthesized via 1,3-dipolar cycloaddition reaction of nitrilimines with 5-arylidene-1,3-dimethyl-2,4,6-pyrimidinetriones. Most of the synthesized compounds revealed promising hypnotic properties.Figure optionsDownload as PowerPoint slideHighlights
► A variety of 1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones were synthesized.
► The tested compounds revealed promising hypnotic potentiating effects.
► The hypnotic properties were consistent with a hypothesis of molecular modeling.