title: Design and synthesis of novel Y-shaped barbituric acid derivatives as PPARγ activators.
abstract: 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.
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, 160062, Punjab, India.
authors.forename: Vaibhav A
authors.initials: VA
authors.lastname: Dixit
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225, Germany.
authors.forename: Prakash Chandra
authors.initials: PC
authors.lastname: Rathi
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, 160062, Punjab, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Bhagat
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, 40225, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke
authors.affiliation: Department of Biology, University of Copenhagen, Ole MaaløesVej 5, DK-2200, Copenhagen N, Denmark.
authors.forename: Rasmus K
authors.initials: RK
authors.lastname: Petersen
authors.affiliation: Department of Biology, University of Copenhagen, Ole MaaløesVej 5, DK-2200, Copenhagen N, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, 160062, Punjab, India.
authors.forename: Asit K
authors.initials: AK
authors.lastname: Chakraborti
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, 160062, Punjab, India. Electronic address: pvbharatam@niper.ac.in.
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Bharatam
mesh_terms: D001463:Barbiturates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001463:Barbiturates; D047495:PPAR gamma; C032232:barbituric acid
keywords: Anti-diabetic agents; Barbituric acid derivatives; Competitive binding; PPARγ activation; Y-shaped ligands