Medicinal Chemistry Research

, Volume 26, Issue 7, pp 1535–1549 | Cite as

Design and microwave facilitated green synthesis of 2-[4-(3-carboxymethyl, methoxy carbonylmethyl-2,4-dioxo and 4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-2 and 3-methyl propionic acid ethyl ester derivatives: a novel structural class of antidyslipidemic agents

  • Ashok Kumar Singh
  • Avinash C. Tripathi
  • Aseem Tewari
  • Viney Chawla
  • Shailendra K. Saraf
Original Research
  • 127 Downloads

Abstract

An interesting hybrid molecular framework comprising of benzylidenethiazolidin-4-one, chalcone and fibrate was designed and synthesized (BRF112) in order to develop safe and efficacious compounds for the treatment of dyslipidemia, and related complications such as atherosclerosis. The synthesized derivatives were characterized by Fourier transform infrared spectroscopy, mass, and nuclear magnetic resonance spectral studies and evaluated for their antihyperlipidemic potential, using in vivo and in silico methods. All the synthesized compounds exhibited promising antidyslipidemic activity comparable to, and sometimes better than that of, the standard drug-fenofibrate at the tested dose of 30 mg/kg body weight. The most active compounds of the series, BRF4 and BRF6, demonstrated significant antidyslipidemic profile by lowering low density lipoprotein cholesterol, very low density lipoprotein cholesterol, and triglyceride and increasing the level of high density lipoprotein cholesterol, thereby decreasing the atherogenic index. Overall, these effects of BRF4 and BRF6 were found to be more potent than fenofibrate, in lipid lowering activity and reducing atherogenic index. Structure–activity relationship studies conclusively established that the presence of N-acetic acid methyl ester at 3rd position of the thiazolidin-4-one nucleus, and a C-3 fibric acid moiety at benzene nucleus were instrumental for enhanced biological activity. The binding mode of benzylidenethiazolidin-4-one fibrate class of compounds, showing crucial hydrogen bonds and pi–pi stacking interactions with the key amino acid residues Phe118, His440, and Tyr464 at the active site of PPARα receptor, was assessed by molecular docking studies.

Keywords

Anti-hyperlipidemic Rhodanine Microwave assisted synthesis Molecular docking Benzylidenethiazolidin-4-one Fibrates 

Notes

Acknowledgements

We express our sincere gratitude to Central Drugs Research Institute (CDRI), Lucknow, India for providing the library and sophisticated analytical instrument facilities. Authors are thankful to the All India Council for Technical Education (AICTE), New Delhi, India, for providing grant under the Research Promotion Scheme (RPS), through which the computational software facility has been made available at the host institute. We also acknowledge the technical support team/application scientists of Schrodinger Inc. for their help during computational studies.

Conflict of interest

The authors declare that they have no competing interests.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Pharmaceutical Chemistry, Faculty of PharmacyBabu Banarasi Das Northern India Institute of TechnologyLucknowIndia

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