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

• Novel Y-shaped barbituric acid based PPARγ activators are designed and synthesized.
• Docking analysis highlights the role of ARG288 in binding affinity.
• MD simulations show that BA derivatives have H-bonding patterns similar to partial agonists.
• Symmetrically substituted derivatives (15 and 26) showed highest binding affinities amongst all synthesized compounds.
• Y-shaped barbituric acid analogues may show desired balance in PPAR activation.

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 PPARγ 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 μM, 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 PPARγ binding affinities.

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