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Molecular Diversity

, Volume 21, Issue 3, pp 533–546 | Cite as

Synthesis, pharmacological evaluation and molecular docking of pyranopyrazole-linked 1,4-dihydropyridines as potent positive inotropes

  • Rakesh KumarEmail author
  • Neha Yadav
  • Rodolfo Lavilla
  • Daniel Blasi
  • Jordi Quintana
  • José Manuel Brea
  • María Isabel Loza
  • Jordi Mestres
  • Mamta Bhandari
  • Ritu Arora
  • Rita Kakkar
  • Ashok K. Prasad
Original Article

Abstract

1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification.

Graphical Abstract

Keywords

Pyranopyrazole-1 4-Dihydropyridines Inotropic effect Molecular docking Structure–activity analysis CYP450 inhibition Microwave synthesis \(\hbox {SeO}_{2}\) 

Notes

Acknowledgements

This work was partially supported by ChemBiobank, the Chemical Biology infrastructure initiative in Spain, carrying out the predictive and the biological activity of the synthesized compounds. The authors would like to thank CDRI, Lucknow, for carrying out the in vivo studies, Defence Research and Development Organization (DRDO) for financial support and University of Delhi, Delhi, for providing the laboratory and instrumentation facility.

Supplementary material

11030_2017_9738_MOESM1_ESM.docx (6 mb)
Supplementary Data Supplementary data (1H NMR, 13C NMR spectra and UPLC-MS results) associated with this article can be found. (doc 5.98MB)

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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Rakesh Kumar
    • 1
    Email author
  • Neha Yadav
    • 1
  • Rodolfo Lavilla
    • 2
  • Daniel Blasi
    • 3
  • Jordi Quintana
    • 3
  • José Manuel Brea
    • 4
  • María Isabel Loza
    • 4
  • Jordi Mestres
    • 5
  • Mamta Bhandari
    • 1
  • Ritu Arora
    • 1
  • Rita Kakkar
    • 1
  • Ashok K. Prasad
    • 1
  1. 1.Bio-organic Laboratory, Department of ChemistryUniversity of DelhiDelhiIndia
  2. 2.Laboratory of Organic Chemistry, Department of Pharmacology and Therapeutical Chemistry, Faculty of PharmacyUniversity of BarcelonaBarcelonaSpain
  3. 3.Drug Discovery PlatformParc Científic de BarcelonaBarcelonaSpain
  4. 4.USEF Screening Platform, Centre of Research on Molecular Medicine and Chronic Diseases (CIMUS)Universidad de Santiago de Compostela (USC)Santiago de CompostelaSpain
  5. 5.Systems Pharmacology, Research Program on Biomedical Informatics (GRIB)IMIM Hospital del Mar Medical Research Institute and University Pompeu FabraBarcelonaSpain

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