Design and synthesis of novel Y-shaped barbituric acid derivatives as PPAR gamma activators

作者：Dixit Vaibhav A; Rathi Prakash Chandra; Bhagat Shweta; Gohlke Holger; Petersen Rasmus K; Kristiansen Karsten; Chakraborti Asit K; Bharatam Prasad V^*

来源：European Journal of Medicinal Chemistry, 2016, 108: 423-435.

DOI：10.1016/j.ejmech.2015.11.030

• Y-shaped ligands
• PPAR gamma activation
• Anti-diabetic agents
• Barbituric acid derivatives
• Competitive binding

Novel Y-shaped barbituric acid (BA) derivatives have been designed using rational methods including molecular docking. Fourteen novel compounds were synthesized using hydroxyl group protection-deprotection strategies for PPAR gamma activation. Competitive binding analysis of the synthesized molecules using time -resolved fluorescence resonance energy transfer (FRET) method was carried out, and the IC50 values were determined. The symmetrically substituted derivatives have shown greater binding affinity than unsymmetrically substituted derivatives. Nitrobenzyl and cyanophenyl substituted derivatives have shown reasonable binding affinities (10.1 and 6.5 mu M, respectively), while mono and diacetate derivatives were found inactive. Molecular dynamics simulations show that the designed compounds have interaction profiles similar to partial agonists. The most significant finding of our study is that BA derivatives with symmetrically substituted weakly polar side chains result in the desired moderate level of PPAR gamma binding affinities.

• 出版日期2016-1-27